Next, a retrospective analysis compared adjuvant capecitabine or capecitabine + oxaliplatin (CapeOX) for resected stage II-III colorectal cancer in 606 patients. Fifty-four of these patients were taking a proton pump inhibitor (PPI) as well. The authors found that concomitant use of a PPI with capecitabine monotherapy led to shorter relapse-free survival (adjusted hazard ratio, 2.48; P = .013) compared with those not taking a PPI. Interestingly, the effect on RFS was not observed in patients receiving CapeOX. A proposed mechanism for this finding is that the increased pH in PPI-treated stomachs decreases dissolution of the capecitabine tablet. Certainly, direct observation would be required to prove this, but these data alone may be enough for oncologists to think twice before prescribing capecitabine to patients who must remain on a PPI.

Lastly, a well-done analysis from the Nurses' Health Study found that higher intake of sugar-sweetened beverages and total fructose was associated with increased incidence of and mortality from proximal colon cancer, but interestingly not distal colon or rectal cancers. The hazard ratios for both the incremental incidence of proximal colon cancer for intake of one serving of sugar-sweetened beverage per day and for 25 g/day of fructose were 1.18 (P_trend = .02), and the hazard ratios for mortality were 1.39 (P_trend = .002) and 1.42 (P_trend = .003), respectively. I am often asked by my patients what, if any, utility there might be in limiting sugar intake when undergoing cancer treatment. This study provides the basis for an answer that is more than just hand-waving.

Next, a retrospective analysis compared adjuvant capecitabine or capecitabine + oxaliplatin (CapeOX) for resected stage II-III colorectal cancer in 606 patients. Fifty-four of these patients were taking a proton pump inhibitor (PPI) as well. The authors found that concomitant use of a PPI with capecitabine monotherapy led to shorter relapse-free survival (adjusted hazard ratio, 2.48; P = .013) compared with those not taking a PPI. Interestingly, the effect on RFS was not observed in patients receiving CapeOX. A proposed mechanism for this finding is that the increased pH in PPI-treated stomachs decreases dissolution of the capecitabine tablet. Certainly, direct observation would be required to prove this, but these data alone may be enough for oncologists to think twice before prescribing capecitabine to patients who must remain on a PPI.

Lastly, a well-done analysis from the Nurses' Health Study found that higher intake of sugar-sweetened beverages and total fructose was associated with increased incidence of and mortality from proximal colon cancer, but interestingly not distal colon or rectal cancers. The hazard ratios for both the incremental incidence of proximal colon cancer for intake of one serving of sugar-sweetened beverage per day and for 25 g/day of fructose were 1.18 (P_trend = .02), and the hazard ratios for mortality were 1.39 (P_trend = .002) and 1.42 (P_trend = .003), respectively. I am often asked by my patients what, if any, utility there might be in limiting sugar intake when undergoing cancer treatment. This study provides the basis for an answer that is more than just hand-waving.

Next, a retrospective analysis compared adjuvant capecitabine or capecitabine + oxaliplatin (CapeOX) for resected stage II-III colorectal cancer in 606 patients. Fifty-four of these patients were taking a proton pump inhibitor (PPI) as well. The authors found that concomitant use of a PPI with capecitabine monotherapy led to shorter relapse-free survival (adjusted hazard ratio, 2.48; P = .013) compared with those not taking a PPI. Interestingly, the effect on RFS was not observed in patients receiving CapeOX. A proposed mechanism for this finding is that the increased pH in PPI-treated stomachs decreases dissolution of the capecitabine tablet. Certainly, direct observation would be required to prove this, but these data alone may be enough for oncologists to think twice before prescribing capecitabine to patients who must remain on a PPI.

Lastly, a well-done analysis from the Nurses' Health Study found that higher intake of sugar-sweetened beverages and total fructose was associated with increased incidence of and mortality from proximal colon cancer, but interestingly not distal colon or rectal cancers. The hazard ratios for both the incremental incidence of proximal colon cancer for intake of one serving of sugar-sweetened beverage per day and for 25 g/day of fructose were 1.18 (P_trend = .02), and the hazard ratios for mortality were 1.39 (P_trend = .002) and 1.42 (P_trend = .003), respectively. I am often asked by my patients what, if any, utility there might be in limiting sugar intake when undergoing cancer treatment. This study provides the basis for an answer that is more than just hand-waving.

The Food and Drug Administration announced on June 1 it has withdrawn approval of the lymphoma drug umbralisib (Ukoniq) following an investigation into a “possible increased risk of death.”

Umbralisib had received accelerated approval in February 2021 to treat adults with relapsed or refractory marginal zone lymphoma following at least one prior therapy and those with relapsed or refractory follicular lymphoma who had received at least three prior therapies.

But safety concerns began to emerge in the phase 3 UNITY-CLL trial, which evaluated the drug in a related cancer type: chronic lymphocytic leukemia.

Last February, the FDA said it was investigating a possible increased risk of death associated with umbralisib.

Five months later, the results are in.

“Updated findings from the UNITY-CLL clinical trial continued to show a possible increased risk of death in patients receiving Ukoniq. As a result, we determined the risks of treatment with Ukoniq outweigh its benefits,” the FDA wrote in a drug safety communication published June 1.

In April, the drug manufacturer, TG Therapeutics, announced it was voluntarily withdrawing umbralisib from the market for its approved uses in marginal zone lymphoma and follicular lymphoma.

The FDA’s safety notice includes instructions for physicians and patients. The FDA urges health care professionals to “stop prescribing Ukoniq and switch patients to alternative treatments” and to “inform patients currently taking Ukoniq of the increased risk of death seen in the clinical trial and advise them to stop taking the medicine.”

In special instances in which a patient may be benefiting from the drug, the company plans to make umbralisib available under expanded access.

The FDA also recommends that patients who discontinue taking the drug dispose of unused umbralisib using a drug take-back location, such as a pharmacy, or throwing it away in the household trash after placing it in a sealed bag mixed with dirt or cat litter and removing personal identification information.

A version of this article first appeared on Medscape.com.

The Food and Drug Administration announced on June 1 it has withdrawn approval of the lymphoma drug umbralisib (Ukoniq) following an investigation into a “possible increased risk of death.”

Umbralisib had received accelerated approval in February 2021 to treat adults with relapsed or refractory marginal zone lymphoma following at least one prior therapy and those with relapsed or refractory follicular lymphoma who had received at least three prior therapies.

But safety concerns began to emerge in the phase 3 UNITY-CLL trial, which evaluated the drug in a related cancer type: chronic lymphocytic leukemia.

Last February, the FDA said it was investigating a possible increased risk of death associated with umbralisib.

Five months later, the results are in.

“Updated findings from the UNITY-CLL clinical trial continued to show a possible increased risk of death in patients receiving Ukoniq. As a result, we determined the risks of treatment with Ukoniq outweigh its benefits,” the FDA wrote in a drug safety communication published June 1.

In April, the drug manufacturer, TG Therapeutics, announced it was voluntarily withdrawing umbralisib from the market for its approved uses in marginal zone lymphoma and follicular lymphoma.

The FDA’s safety notice includes instructions for physicians and patients. The FDA urges health care professionals to “stop prescribing Ukoniq and switch patients to alternative treatments” and to “inform patients currently taking Ukoniq of the increased risk of death seen in the clinical trial and advise them to stop taking the medicine.”

In special instances in which a patient may be benefiting from the drug, the company plans to make umbralisib available under expanded access.

The FDA also recommends that patients who discontinue taking the drug dispose of unused umbralisib using a drug take-back location, such as a pharmacy, or throwing it away in the household trash after placing it in a sealed bag mixed with dirt or cat litter and removing personal identification information.

A version of this article first appeared on Medscape.com.

The Food and Drug Administration announced on June 1 it has withdrawn approval of the lymphoma drug umbralisib (Ukoniq) following an investigation into a “possible increased risk of death.”

Umbralisib had received accelerated approval in February 2021 to treat adults with relapsed or refractory marginal zone lymphoma following at least one prior therapy and those with relapsed or refractory follicular lymphoma who had received at least three prior therapies.

But safety concerns began to emerge in the phase 3 UNITY-CLL trial, which evaluated the drug in a related cancer type: chronic lymphocytic leukemia.

Last February, the FDA said it was investigating a possible increased risk of death associated with umbralisib.

Five months later, the results are in.

“Updated findings from the UNITY-CLL clinical trial continued to show a possible increased risk of death in patients receiving Ukoniq. As a result, we determined the risks of treatment with Ukoniq outweigh its benefits,” the FDA wrote in a drug safety communication published June 1.

In April, the drug manufacturer, TG Therapeutics, announced it was voluntarily withdrawing umbralisib from the market for its approved uses in marginal zone lymphoma and follicular lymphoma.

The FDA’s safety notice includes instructions for physicians and patients. The FDA urges health care professionals to “stop prescribing Ukoniq and switch patients to alternative treatments” and to “inform patients currently taking Ukoniq of the increased risk of death seen in the clinical trial and advise them to stop taking the medicine.”

In special instances in which a patient may be benefiting from the drug, the company plans to make umbralisib available under expanded access.

The FDA also recommends that patients who discontinue taking the drug dispose of unused umbralisib using a drug take-back location, such as a pharmacy, or throwing it away in the household trash after placing it in a sealed bag mixed with dirt or cat litter and removing personal identification information.

A version of this article first appeared on Medscape.com.

Predicting severe disease is of great importance in rheumatoid arthritis (RA), ideally to establish which poor prognostic factors allow for early aggressive and targeted treatment for a subset of patients. In a post hoc analysis of the AGREE study by Durez and colleagues, 509 treatment-naive patients randomized to either methotrexate or methotrexate with abatacept were evaluated for predictors of joint damage and disease activity. Baseline swelling in the knee, temporomandibular joint (TMJ), elbow, and wrist was correlated with severe disease activity as well as tender and swollen joint counts, whereas baseline swelling at the second metacarpophalangeal joint was correlated with erosive disease. Overall, remission rates were better in patients with baseline wrist, TMJ, elbow, and knee swelling treated with combination therapy vs methotrexate alone, suggestive of a better response to more aggressive therapy. Further studies of patients with RA with poor prognostic factors would be helpful.

Laboratory biomarkers can also serve as prognostic indicators for patients with RA. Based in part on the association of obesity and lower rates of remission in people with RA, Baker and colleagues investigated the possible association of adipocytokines and disease activity in a cohort study of over 1200 patients with Disease Activity Score for Rheumatoid Arthritis (DAS28) > 3.2 enrolled in the Veterans Affairs RA registry. Of these, about 800 achieved low disease activity while the remainder did not. Interestingly, obesity was not a baseline characteristic associated with disease activity, though chronic obstructive pulmonary disease, heart failure, and mood disorders were. Baseline adipocytokine levels on average did not differ between the two groups, though higher baseline adiponectin and leptin levels (based on quartile) were associated with a lower likelihood of achieving low disease activity. Interestingly, this change did not increase progressively with higher quartile. Because these are baseline levels and were not tracked prospectively with medication use, it is difficult to assess the importance of this finding. The association may not reflect a causative relationship but may be affected by medications or disease duration. However, it appears worthwhile investigating in therapy-naive patients as well as those being observed with treatment.

Finally, with respect to novel therapeutic regimens, Fleischmann and colleagues report the results of a multicenter randomized clinical trial of a Bruton tyrosine kinase inhibitor, elsubrutinib, alone or in combination with the Janus kinase (JAK) inhibitor upadicitinib in the treatment of 242 patients with RA. At the end of 12 weeks, DAS28 with C-reactive protein scores were not measurably lower in patients treated with elsubrutinib at different doses. In addition, patients receiving the combination therapy of 15 mg upadicitinib with the highest dose of elsubrutinib (60 mg) did not have greater DAS28 improvement than patients treated with upadicitinib alone, suggesting a lack of synergistic effect. Short-term safety data does not suggest significant differences. Though this combination is also being investigated in systemic lupus erythematosus, it is not clear that the combination of two targeted synthetic disease-modifying antirheumatic drugs is feasible in RA, nor that long-term safety concerns would make it advisable.

Predicting severe disease is of great importance in rheumatoid arthritis (RA), ideally to establish which poor prognostic factors allow for early aggressive and targeted treatment for a subset of patients. In a post hoc analysis of the AGREE study by Durez and colleagues, 509 treatment-naive patients randomized to either methotrexate or methotrexate with abatacept were evaluated for predictors of joint damage and disease activity. Baseline swelling in the knee, temporomandibular joint (TMJ), elbow, and wrist was correlated with severe disease activity as well as tender and swollen joint counts, whereas baseline swelling at the second metacarpophalangeal joint was correlated with erosive disease. Overall, remission rates were better in patients with baseline wrist, TMJ, elbow, and knee swelling treated with combination therapy vs methotrexate alone, suggestive of a better response to more aggressive therapy. Further studies of patients with RA with poor prognostic factors would be helpful.

Laboratory biomarkers can also serve as prognostic indicators for patients with RA. Based in part on the association of obesity and lower rates of remission in people with RA, Baker and colleagues investigated the possible association of adipocytokines and disease activity in a cohort study of over 1200 patients with Disease Activity Score for Rheumatoid Arthritis (DAS28) > 3.2 enrolled in the Veterans Affairs RA registry. Of these, about 800 achieved low disease activity while the remainder did not. Interestingly, obesity was not a baseline characteristic associated with disease activity, though chronic obstructive pulmonary disease, heart failure, and mood disorders were. Baseline adipocytokine levels on average did not differ between the two groups, though higher baseline adiponectin and leptin levels (based on quartile) were associated with a lower likelihood of achieving low disease activity. Interestingly, this change did not increase progressively with higher quartile. Because these are baseline levels and were not tracked prospectively with medication use, it is difficult to assess the importance of this finding. The association may not reflect a causative relationship but may be affected by medications or disease duration. However, it appears worthwhile investigating in therapy-naive patients as well as those being observed with treatment.

Finally, with respect to novel therapeutic regimens, Fleischmann and colleagues report the results of a multicenter randomized clinical trial of a Bruton tyrosine kinase inhibitor, elsubrutinib, alone or in combination with the Janus kinase (JAK) inhibitor upadicitinib in the treatment of 242 patients with RA. At the end of 12 weeks, DAS28 with C-reactive protein scores were not measurably lower in patients treated with elsubrutinib at different doses. In addition, patients receiving the combination therapy of 15 mg upadicitinib with the highest dose of elsubrutinib (60 mg) did not have greater DAS28 improvement than patients treated with upadicitinib alone, suggesting a lack of synergistic effect. Short-term safety data does not suggest significant differences. Though this combination is also being investigated in systemic lupus erythematosus, it is not clear that the combination of two targeted synthetic disease-modifying antirheumatic drugs is feasible in RA, nor that long-term safety concerns would make it advisable.

Predicting severe disease is of great importance in rheumatoid arthritis (RA), ideally to establish which poor prognostic factors allow for early aggressive and targeted treatment for a subset of patients. In a post hoc analysis of the AGREE study by Durez and colleagues, 509 treatment-naive patients randomized to either methotrexate or methotrexate with abatacept were evaluated for predictors of joint damage and disease activity. Baseline swelling in the knee, temporomandibular joint (TMJ), elbow, and wrist was correlated with severe disease activity as well as tender and swollen joint counts, whereas baseline swelling at the second metacarpophalangeal joint was correlated with erosive disease. Overall, remission rates were better in patients with baseline wrist, TMJ, elbow, and knee swelling treated with combination therapy vs methotrexate alone, suggestive of a better response to more aggressive therapy. Further studies of patients with RA with poor prognostic factors would be helpful.

Laboratory biomarkers can also serve as prognostic indicators for patients with RA. Based in part on the association of obesity and lower rates of remission in people with RA, Baker and colleagues investigated the possible association of adipocytokines and disease activity in a cohort study of over 1200 patients with Disease Activity Score for Rheumatoid Arthritis (DAS28) > 3.2 enrolled in the Veterans Affairs RA registry. Of these, about 800 achieved low disease activity while the remainder did not. Interestingly, obesity was not a baseline characteristic associated with disease activity, though chronic obstructive pulmonary disease, heart failure, and mood disorders were. Baseline adipocytokine levels on average did not differ between the two groups, though higher baseline adiponectin and leptin levels (based on quartile) were associated with a lower likelihood of achieving low disease activity. Interestingly, this change did not increase progressively with higher quartile. Because these are baseline levels and were not tracked prospectively with medication use, it is difficult to assess the importance of this finding. The association may not reflect a causative relationship but may be affected by medications or disease duration. However, it appears worthwhile investigating in therapy-naive patients as well as those being observed with treatment.

Finally, with respect to novel therapeutic regimens, Fleischmann and colleagues report the results of a multicenter randomized clinical trial of a Bruton tyrosine kinase inhibitor, elsubrutinib, alone or in combination with the Janus kinase (JAK) inhibitor upadicitinib in the treatment of 242 patients with RA. At the end of 12 weeks, DAS28 with C-reactive protein scores were not measurably lower in patients treated with elsubrutinib at different doses. In addition, patients receiving the combination therapy of 15 mg upadicitinib with the highest dose of elsubrutinib (60 mg) did not have greater DAS28 improvement than patients treated with upadicitinib alone, suggesting a lack of synergistic effect. Short-term safety data does not suggest significant differences. Though this combination is also being investigated in systemic lupus erythematosus, it is not clear that the combination of two targeted synthetic disease-modifying antirheumatic drugs is feasible in RA, nor that long-term safety concerns would make it advisable.

Real-World Retrospective Study Suggests Inferior Outcomes to First-Line Systemic Treatment in Advanced NFE2L2 and KEAP1 Mutant Squamous NSCLC

Targeted therapies against oncogene-driven lung cancer, such as epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK), in lung adenocarcinoma have revolutionized lung cancer treatment. However, there are no US Food and Drug Administration–approved targeted therapies for commonly occurring mutations in advanced squamous non–small cell lung cancer (NSCLC).

NFE2L2 and KEAP1 mutations are molecular alterations that occur in about 25%-30% of squamous NSCLC. NFE2L2 encodes for the NRF2 transcription factor that is involved in the oxidative stress pathway and KEAP1 encodes for the KEAP1 protein, which is the negative regulator of NFE2L2.¹ When the NRF2-KEAP1 signaling pathway is disrupted, there is persistent activation of NRF2, which promotes cell proliferation and carcinogenesis and may contribute to resistance to cancer-directed treatments. Previous retrospective studies suggest that patients with lung cancers harboring NFE2L2 and KEAP1 mutations have a poorer prognosis and do worse with both systemic anticancer treatments and radiation.^2-5

Wu and colleagues, in a retrospective cohort study, identified 703 patients with squamous NSCLC from 2011 to 2018 who had NFE2L2 or KEAP1 mutations identified by comprehensive genomic profiling in the Flatiron Health-Foundation Medicine Clinico-Genomic Database. Real-world progression-free survival (PFS), defined as a distinct episode where the clinician concluded that there was growth or worsening of disease, was assessed by line and type of treatment, as was overall survival (OS). Patients with squamous NSCLC with NFE2L2/KEAP1 mutations had shorter real-world PFS to first-line treatment compared with patients whose tumors were wild-type for these mutations (4.54 months vs 6.25 months; P = .0027). Median OS was numerically shorter in patients with NFE2L2/KEAP1 mutations, but this was not statistically significant (13.59 vs 17.37 months; P = .41). This retrospective real-world analysis suggests that patients with squamous NSCLC and NFE2L2/KEAP1 mutations have inferior outcomes with systemic treatments and may have worsened OS; however, this was not statistically significant. Many of these patients were treated before the approval of the KEYNOTE-407 chemo-immunotherapy regimen in squamous NSCLC, so they did not have what we would consider contemporary standard treatment. Further studies are needed to evaluate the role of NRF2 activation in resistance to NSCLC treatments, and there is a need for therapeutics to target these common mutations in squamous NSCLC. Fortunately, there are current ongoing clinical trials.^[6]

Segmentectomy Is Noninferior to and Improves Overall Survival Compared With Lobectomy in Selected Cases of Small Peripheral Early-Stage NSCLC              

Lobectomy has been the standard of care for surgical treatment of early-stage NSCLC. Saji and colleagues investigated whether segmentectomy was noninferior to lobectomy in selected cases of small-sized peripheral NSCLC. This randomized, controlled, noninferiority trial was conducted at 70 institutions in Japan.

Patients with selected stage IA (American Joint Committee on Cancer [AJCC], seventh edition) NSCLC (peripheral tumors, £ 2 cm diameter, consolidation-to-tumor ratio > 0.5) were randomly assigned to undergo segmentectomy or lobectomy. The primary endpoint was OS. Pertinent secondary endpoints included postoperative respiratory function, relapse-free survival, and adverse events.

A total of 1106 patients were enrolled: 554 in the lobectomy group and 552 in the segmentectomy group. The 5-year OS was 94.3% for segmentectomy and 91.1% for lobectomy (hazard ratio 0.663; one-sided P < .001 for noninferiority; P = .0082 for superiority). In addition to the modestly improved OS observed, 5-year relapse-free survival was comparable between the groups (88% for segmentectomy and 87.9% for lobectomy). However, more local relapse was observed for segmentectomy (10.5%) than for lobectomy (5.4%) (P = .0018). Despite significantly more locoregional recurrences with segmentectomy compared with lobectomy, rates of combined distant and locoregional relapses were similar. Slightly more patients died in the lobectomy group than the segmentectomy group, and the rate of cancer-related deaths, including second primary lung cancers, was higher in the lobectomy group. Interestingly, although segmentectomy had better OS, the survival advantage was not cancer-specific.

The mechanism by which segmentectomy improved survival over lobectomy in these selected patients with small, peripheral stage IA NSCLC is still unclear. Limitations of the study included that all patients were from one geographic region (Japan) and that the study was unblinded, which can introduce bias. We await the results of CALGB 140503: A Randomized Phase III Trial of Lobectomy versus Sublobar Resection for Small (< 2cm) Peripheral Non-Small Cell Lung Cancer (NCT00499330). This study is being done in a US population and includes nonanatomic wedge in its sublobar resection cohort.

The study by Saji and colleagues suggests that surgeons should consider segmentectomy in appropriate patients (select small stage IA NSCLC [peripheral tumors, £ 2 cm diameter, consolidation-to-tumor ratio > 0.5]), based on the modest improvement in OS compared with lobectomy.

Immunotherapy Activity in Cachexic and Noncachexic Patients With Advanced NSCLC and Clinical Outcomes, by Adipose Tissue Loss on Treatment

There are emerging data that body mass index (BMI) and the presence or absence of cachexia in cancers, including NSCLC, may change the efficacy of programmed cell death-ligand 1 (PD-L1) immune checkpoint inhibitors. Nishioka and colleagues, in a single-center retrospective cohort, examined patients with advanced NSCLC (40 with cachexia and 34 without cachexia) who received PD-L1 inhibitors (pembrolizumab, nivolumab, or atezolizumab). Patients were excluded if they had poor performance status, EGFR/ALK/ROS1 oncogene drivers, unknown PD-L1 expression status, and unknown weight loss in the 6 months before immunotherapy administration. In addition to BMI, measurements of adipose tissue quantity and muscle mass were used.

The overall response rate was 28.4% in the 74 patients analyzed. Patients with cachexia had a lower overall response rate than those without cachexia (15.0% vs 44.1%; P < .05). Among the patients without cachexia, those with total adipose tissue loss had a significantly longer PFS than those with total adipose tissue maintenance (18.5 months vs 2.86 months; P = .037), including in a multivariate analyses (hazard ratio 0.34; P < .05), after adjustment for PD-L1 expression and performance status (Eastern Cooperative Oncology Group [ECOG] 0 vs. 1).

Mechanistically, a paradoxical effect of obesity on T-cell function that relates to leptin, which is secreted by adipose tissue, has been observed in preclinical studies.⁷ In a previously published study, obesity resulted in tumor progression and PD-1–mediated T-cell dysfunction, which can be overcome by PD-L1 blockade with improved clinical outcomes to these therapies in patients with obesity and cancer, including NSCLC.⁷ This "obesity paradox" may underlie some of the findings observed in Nishioka and colleagues' study. More research needs to be done regarding the activity of immune checkpoint inhibition in NSCLC as it relates to BMI, cachexia, and amount of adipose tissue.

Additional References

1.           Shibata T, Ohta T, Tong KI, et al. Cancer related mutations in NRF2 impair its recognition by Keap1-Cul3 E3 ligase and promote malignancy. Proc Natl Acad Sci U S A. 2008;105(36):13568-13573. doi: 10.1073/pnas.0806268105

2.           Frank R, Scheffler M, Merkelbach-Bruse S, et al. Clinical and pathological characteristics of KEAP1- and NFE2L2-mutated non-small cell lung carcinoma (NSCLC). Clin Cancer Res. 2018;24:3087-3096. doi: 10.1158/1078-0432.CCR-17-3416

3.           Binkley MS, Jeon YJ, Nesselbush M, et al. KEAP1/NFE2L2 mutations predict lung cancer radiation resistance that can be targeted by glutaminase inhibition. Cancer Discov. 2020;10(12):1826-1841. doi: 10.1158/2159-8290.CD-20-0282

4.           Hellyer JA, Padda SK, Diehn M, et al. Clinical implications of KEAP1-NFE2L2 mutations in NSCLC. J Thorac Oncol. 2021;16(3):395-403. doi: 10.1016/j.jtho.2020.11.015

5.           Jeong Y, Hellyer JA, Stehr H, et al. Role of KEAP1/NFE2L2 mutations in the chemotherapeutic response of patients with non-small cell lung cancer. Clin Cancer Res. 2020;26(1):274-281. doi: 10.1158/1078-0432.CCR-19-1237

6.           Riess JW, Frankel P, Shackelford D, et al. Phase 1 trial of MLN0128 (sapanisertib) and CB-839 HCl (telaglenastat) in patients with advanced NSCLC (NCI 10327): Rationale and study design. Clin Lung Cancer. 2021;22:67-70. doi: 10.1016/j.cllc.2020.10.006

Real-World Retrospective Study Suggests Inferior Outcomes to First-Line Systemic Treatment in Advanced NFE2L2 and KEAP1 Mutant Squamous NSCLC

Targeted therapies against oncogene-driven lung cancer, such as epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK), in lung adenocarcinoma have revolutionized lung cancer treatment. However, there are no US Food and Drug Administration–approved targeted therapies for commonly occurring mutations in advanced squamous non–small cell lung cancer (NSCLC).

NFE2L2 and KEAP1 mutations are molecular alterations that occur in about 25%-30% of squamous NSCLC. NFE2L2 encodes for the NRF2 transcription factor that is involved in the oxidative stress pathway and KEAP1 encodes for the KEAP1 protein, which is the negative regulator of NFE2L2.¹ When the NRF2-KEAP1 signaling pathway is disrupted, there is persistent activation of NRF2, which promotes cell proliferation and carcinogenesis and may contribute to resistance to cancer-directed treatments. Previous retrospective studies suggest that patients with lung cancers harboring NFE2L2 and KEAP1 mutations have a poorer prognosis and do worse with both systemic anticancer treatments and radiation.^2-5

Wu and colleagues, in a retrospective cohort study, identified 703 patients with squamous NSCLC from 2011 to 2018 who had NFE2L2 or KEAP1 mutations identified by comprehensive genomic profiling in the Flatiron Health-Foundation Medicine Clinico-Genomic Database. Real-world progression-free survival (PFS), defined as a distinct episode where the clinician concluded that there was growth or worsening of disease, was assessed by line and type of treatment, as was overall survival (OS). Patients with squamous NSCLC with NFE2L2/KEAP1 mutations had shorter real-world PFS to first-line treatment compared with patients whose tumors were wild-type for these mutations (4.54 months vs 6.25 months; P = .0027). Median OS was numerically shorter in patients with NFE2L2/KEAP1 mutations, but this was not statistically significant (13.59 vs 17.37 months; P = .41). This retrospective real-world analysis suggests that patients with squamous NSCLC and NFE2L2/KEAP1 mutations have inferior outcomes with systemic treatments and may have worsened OS; however, this was not statistically significant. Many of these patients were treated before the approval of the KEYNOTE-407 chemo-immunotherapy regimen in squamous NSCLC, so they did not have what we would consider contemporary standard treatment. Further studies are needed to evaluate the role of NRF2 activation in resistance to NSCLC treatments, and there is a need for therapeutics to target these common mutations in squamous NSCLC. Fortunately, there are current ongoing clinical trials.^[6]

Segmentectomy Is Noninferior to and Improves Overall Survival Compared With Lobectomy in Selected Cases of Small Peripheral Early-Stage NSCLC              

Lobectomy has been the standard of care for surgical treatment of early-stage NSCLC. Saji and colleagues investigated whether segmentectomy was noninferior to lobectomy in selected cases of small-sized peripheral NSCLC. This randomized, controlled, noninferiority trial was conducted at 70 institutions in Japan.

Patients with selected stage IA (American Joint Committee on Cancer [AJCC], seventh edition) NSCLC (peripheral tumors, £ 2 cm diameter, consolidation-to-tumor ratio > 0.5) were randomly assigned to undergo segmentectomy or lobectomy. The primary endpoint was OS. Pertinent secondary endpoints included postoperative respiratory function, relapse-free survival, and adverse events.

A total of 1106 patients were enrolled: 554 in the lobectomy group and 552 in the segmentectomy group. The 5-year OS was 94.3% for segmentectomy and 91.1% for lobectomy (hazard ratio 0.663; one-sided P < .001 for noninferiority; P = .0082 for superiority). In addition to the modestly improved OS observed, 5-year relapse-free survival was comparable between the groups (88% for segmentectomy and 87.9% for lobectomy). However, more local relapse was observed for segmentectomy (10.5%) than for lobectomy (5.4%) (P = .0018). Despite significantly more locoregional recurrences with segmentectomy compared with lobectomy, rates of combined distant and locoregional relapses were similar. Slightly more patients died in the lobectomy group than the segmentectomy group, and the rate of cancer-related deaths, including second primary lung cancers, was higher in the lobectomy group. Interestingly, although segmentectomy had better OS, the survival advantage was not cancer-specific.

The mechanism by which segmentectomy improved survival over lobectomy in these selected patients with small, peripheral stage IA NSCLC is still unclear. Limitations of the study included that all patients were from one geographic region (Japan) and that the study was unblinded, which can introduce bias. We await the results of CALGB 140503: A Randomized Phase III Trial of Lobectomy versus Sublobar Resection for Small (< 2cm) Peripheral Non-Small Cell Lung Cancer (NCT00499330). This study is being done in a US population and includes nonanatomic wedge in its sublobar resection cohort.

The study by Saji and colleagues suggests that surgeons should consider segmentectomy in appropriate patients (select small stage IA NSCLC [peripheral tumors, £ 2 cm diameter, consolidation-to-tumor ratio > 0.5]), based on the modest improvement in OS compared with lobectomy.

Immunotherapy Activity in Cachexic and Noncachexic Patients With Advanced NSCLC and Clinical Outcomes, by Adipose Tissue Loss on Treatment

There are emerging data that body mass index (BMI) and the presence or absence of cachexia in cancers, including NSCLC, may change the efficacy of programmed cell death-ligand 1 (PD-L1) immune checkpoint inhibitors. Nishioka and colleagues, in a single-center retrospective cohort, examined patients with advanced NSCLC (40 with cachexia and 34 without cachexia) who received PD-L1 inhibitors (pembrolizumab, nivolumab, or atezolizumab). Patients were excluded if they had poor performance status, EGFR/ALK/ROS1 oncogene drivers, unknown PD-L1 expression status, and unknown weight loss in the 6 months before immunotherapy administration. In addition to BMI, measurements of adipose tissue quantity and muscle mass were used.

The overall response rate was 28.4% in the 74 patients analyzed. Patients with cachexia had a lower overall response rate than those without cachexia (15.0% vs 44.1%; P < .05). Among the patients without cachexia, those with total adipose tissue loss had a significantly longer PFS than those with total adipose tissue maintenance (18.5 months vs 2.86 months; P = .037), including in a multivariate analyses (hazard ratio 0.34; P < .05), after adjustment for PD-L1 expression and performance status (Eastern Cooperative Oncology Group [ECOG] 0 vs. 1).

Mechanistically, a paradoxical effect of obesity on T-cell function that relates to leptin, which is secreted by adipose tissue, has been observed in preclinical studies.⁷ In a previously published study, obesity resulted in tumor progression and PD-1–mediated T-cell dysfunction, which can be overcome by PD-L1 blockade with improved clinical outcomes to these therapies in patients with obesity and cancer, including NSCLC.⁷ This "obesity paradox" may underlie some of the findings observed in Nishioka and colleagues' study. More research needs to be done regarding the activity of immune checkpoint inhibition in NSCLC as it relates to BMI, cachexia, and amount of adipose tissue.

Additional References

1.           Shibata T, Ohta T, Tong KI, et al. Cancer related mutations in NRF2 impair its recognition by Keap1-Cul3 E3 ligase and promote malignancy. Proc Natl Acad Sci U S A. 2008;105(36):13568-13573. doi: 10.1073/pnas.0806268105

2.           Frank R, Scheffler M, Merkelbach-Bruse S, et al. Clinical and pathological characteristics of KEAP1- and NFE2L2-mutated non-small cell lung carcinoma (NSCLC). Clin Cancer Res. 2018;24:3087-3096. doi: 10.1158/1078-0432.CCR-17-3416

3.           Binkley MS, Jeon YJ, Nesselbush M, et al. KEAP1/NFE2L2 mutations predict lung cancer radiation resistance that can be targeted by glutaminase inhibition. Cancer Discov. 2020;10(12):1826-1841. doi: 10.1158/2159-8290.CD-20-0282

4.           Hellyer JA, Padda SK, Diehn M, et al. Clinical implications of KEAP1-NFE2L2 mutations in NSCLC. J Thorac Oncol. 2021;16(3):395-403. doi: 10.1016/j.jtho.2020.11.015

5.           Jeong Y, Hellyer JA, Stehr H, et al. Role of KEAP1/NFE2L2 mutations in the chemotherapeutic response of patients with non-small cell lung cancer. Clin Cancer Res. 2020;26(1):274-281. doi: 10.1158/1078-0432.CCR-19-1237

6.           Riess JW, Frankel P, Shackelford D, et al. Phase 1 trial of MLN0128 (sapanisertib) and CB-839 HCl (telaglenastat) in patients with advanced NSCLC (NCI 10327): Rationale and study design. Clin Lung Cancer. 2021;22:67-70. doi: 10.1016/j.cllc.2020.10.006

Real-World Retrospective Study Suggests Inferior Outcomes to First-Line Systemic Treatment in Advanced NFE2L2 and KEAP1 Mutant Squamous NSCLC

Targeted therapies against oncogene-driven lung cancer, such as epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK), in lung adenocarcinoma have revolutionized lung cancer treatment. However, there are no US Food and Drug Administration–approved targeted therapies for commonly occurring mutations in advanced squamous non–small cell lung cancer (NSCLC).

NFE2L2 and KEAP1 mutations are molecular alterations that occur in about 25%-30% of squamous NSCLC. NFE2L2 encodes for the NRF2 transcription factor that is involved in the oxidative stress pathway and KEAP1 encodes for the KEAP1 protein, which is the negative regulator of NFE2L2.¹ When the NRF2-KEAP1 signaling pathway is disrupted, there is persistent activation of NRF2, which promotes cell proliferation and carcinogenesis and may contribute to resistance to cancer-directed treatments. Previous retrospective studies suggest that patients with lung cancers harboring NFE2L2 and KEAP1 mutations have a poorer prognosis and do worse with both systemic anticancer treatments and radiation.^2-5

Wu and colleagues, in a retrospective cohort study, identified 703 patients with squamous NSCLC from 2011 to 2018 who had NFE2L2 or KEAP1 mutations identified by comprehensive genomic profiling in the Flatiron Health-Foundation Medicine Clinico-Genomic Database. Real-world progression-free survival (PFS), defined as a distinct episode where the clinician concluded that there was growth or worsening of disease, was assessed by line and type of treatment, as was overall survival (OS). Patients with squamous NSCLC with NFE2L2/KEAP1 mutations had shorter real-world PFS to first-line treatment compared with patients whose tumors were wild-type for these mutations (4.54 months vs 6.25 months; P = .0027). Median OS was numerically shorter in patients with NFE2L2/KEAP1 mutations, but this was not statistically significant (13.59 vs 17.37 months; P = .41). This retrospective real-world analysis suggests that patients with squamous NSCLC and NFE2L2/KEAP1 mutations have inferior outcomes with systemic treatments and may have worsened OS; however, this was not statistically significant. Many of these patients were treated before the approval of the KEYNOTE-407 chemo-immunotherapy regimen in squamous NSCLC, so they did not have what we would consider contemporary standard treatment. Further studies are needed to evaluate the role of NRF2 activation in resistance to NSCLC treatments, and there is a need for therapeutics to target these common mutations in squamous NSCLC. Fortunately, there are current ongoing clinical trials.^[6]

Segmentectomy Is Noninferior to and Improves Overall Survival Compared With Lobectomy in Selected Cases of Small Peripheral Early-Stage NSCLC              

Lobectomy has been the standard of care for surgical treatment of early-stage NSCLC. Saji and colleagues investigated whether segmentectomy was noninferior to lobectomy in selected cases of small-sized peripheral NSCLC. This randomized, controlled, noninferiority trial was conducted at 70 institutions in Japan.

Patients with selected stage IA (American Joint Committee on Cancer [AJCC], seventh edition) NSCLC (peripheral tumors, £ 2 cm diameter, consolidation-to-tumor ratio > 0.5) were randomly assigned to undergo segmentectomy or lobectomy. The primary endpoint was OS. Pertinent secondary endpoints included postoperative respiratory function, relapse-free survival, and adverse events.

A total of 1106 patients were enrolled: 554 in the lobectomy group and 552 in the segmentectomy group. The 5-year OS was 94.3% for segmentectomy and 91.1% for lobectomy (hazard ratio 0.663; one-sided P < .001 for noninferiority; P = .0082 for superiority). In addition to the modestly improved OS observed, 5-year relapse-free survival was comparable between the groups (88% for segmentectomy and 87.9% for lobectomy). However, more local relapse was observed for segmentectomy (10.5%) than for lobectomy (5.4%) (P = .0018). Despite significantly more locoregional recurrences with segmentectomy compared with lobectomy, rates of combined distant and locoregional relapses were similar. Slightly more patients died in the lobectomy group than the segmentectomy group, and the rate of cancer-related deaths, including second primary lung cancers, was higher in the lobectomy group. Interestingly, although segmentectomy had better OS, the survival advantage was not cancer-specific.

The mechanism by which segmentectomy improved survival over lobectomy in these selected patients with small, peripheral stage IA NSCLC is still unclear. Limitations of the study included that all patients were from one geographic region (Japan) and that the study was unblinded, which can introduce bias. We await the results of CALGB 140503: A Randomized Phase III Trial of Lobectomy versus Sublobar Resection for Small (< 2cm) Peripheral Non-Small Cell Lung Cancer (NCT00499330). This study is being done in a US population and includes nonanatomic wedge in its sublobar resection cohort.

The study by Saji and colleagues suggests that surgeons should consider segmentectomy in appropriate patients (select small stage IA NSCLC [peripheral tumors, £ 2 cm diameter, consolidation-to-tumor ratio > 0.5]), based on the modest improvement in OS compared with lobectomy.

Immunotherapy Activity in Cachexic and Noncachexic Patients With Advanced NSCLC and Clinical Outcomes, by Adipose Tissue Loss on Treatment

There are emerging data that body mass index (BMI) and the presence or absence of cachexia in cancers, including NSCLC, may change the efficacy of programmed cell death-ligand 1 (PD-L1) immune checkpoint inhibitors. Nishioka and colleagues, in a single-center retrospective cohort, examined patients with advanced NSCLC (40 with cachexia and 34 without cachexia) who received PD-L1 inhibitors (pembrolizumab, nivolumab, or atezolizumab). Patients were excluded if they had poor performance status, EGFR/ALK/ROS1 oncogene drivers, unknown PD-L1 expression status, and unknown weight loss in the 6 months before immunotherapy administration. In addition to BMI, measurements of adipose tissue quantity and muscle mass were used.

The overall response rate was 28.4% in the 74 patients analyzed. Patients with cachexia had a lower overall response rate than those without cachexia (15.0% vs 44.1%; P < .05). Among the patients without cachexia, those with total adipose tissue loss had a significantly longer PFS than those with total adipose tissue maintenance (18.5 months vs 2.86 months; P = .037), including in a multivariate analyses (hazard ratio 0.34; P < .05), after adjustment for PD-L1 expression and performance status (Eastern Cooperative Oncology Group [ECOG] 0 vs. 1).

Mechanistically, a paradoxical effect of obesity on T-cell function that relates to leptin, which is secreted by adipose tissue, has been observed in preclinical studies.⁷ In a previously published study, obesity resulted in tumor progression and PD-1–mediated T-cell dysfunction, which can be overcome by PD-L1 blockade with improved clinical outcomes to these therapies in patients with obesity and cancer, including NSCLC.⁷ This "obesity paradox" may underlie some of the findings observed in Nishioka and colleagues' study. More research needs to be done regarding the activity of immune checkpoint inhibition in NSCLC as it relates to BMI, cachexia, and amount of adipose tissue.

Additional References

1.           Shibata T, Ohta T, Tong KI, et al. Cancer related mutations in NRF2 impair its recognition by Keap1-Cul3 E3 ligase and promote malignancy. Proc Natl Acad Sci U S A. 2008;105(36):13568-13573. doi: 10.1073/pnas.0806268105

2.           Frank R, Scheffler M, Merkelbach-Bruse S, et al. Clinical and pathological characteristics of KEAP1- and NFE2L2-mutated non-small cell lung carcinoma (NSCLC). Clin Cancer Res. 2018;24:3087-3096. doi: 10.1158/1078-0432.CCR-17-3416

3.           Binkley MS, Jeon YJ, Nesselbush M, et al. KEAP1/NFE2L2 mutations predict lung cancer radiation resistance that can be targeted by glutaminase inhibition. Cancer Discov. 2020;10(12):1826-1841. doi: 10.1158/2159-8290.CD-20-0282

4.           Hellyer JA, Padda SK, Diehn M, et al. Clinical implications of KEAP1-NFE2L2 mutations in NSCLC. J Thorac Oncol. 2021;16(3):395-403. doi: 10.1016/j.jtho.2020.11.015

5.           Jeong Y, Hellyer JA, Stehr H, et al. Role of KEAP1/NFE2L2 mutations in the chemotherapeutic response of patients with non-small cell lung cancer. Clin Cancer Res. 2020;26(1):274-281. doi: 10.1158/1078-0432.CCR-19-1237

6.           Riess JW, Frankel P, Shackelford D, et al. Phase 1 trial of MLN0128 (sapanisertib) and CB-839 HCl (telaglenastat) in patients with advanced NSCLC (NCI 10327): Rationale and study design. Clin Lung Cancer. 2021;22:67-70. doi: 10.1016/j.cllc.2020.10.006

Infections have long been identified as possible triggers for psoriasis and psoriatic arthritis (PsA) onset. Thrastardottir and colleagues evaluated the association between sites where the culture sample was obtained, the culture result, and pathogens and incident PsA and psoriasis. They obtained data on all samples sent for bacterial culture in the Stockholm region of Sweden (313,235 bacterial cultures from 128,982 individuals) from January 1, 2004, to December 31, 2006. Among all samples sent for culture, a pharyngeal sample was associated with a higher risk for PsA onset within the next 50 days compared with urine (hazard ratio [HR] 8.78; 95% CI 3.23-23.91), nasopharyngeal (HR 8.26; 95% CI 2.23-30.63), or blood (HR 25.22; 95% CI 3.12-204.13) samples. Streptococcal infections in the pharynx or at any other site were not associated with an increased risk for PsA. Similar associations were found for psoriasis, but not for rheumatoid arthritis. These results indicate that having sent a pharyngeal sample for culture was associated with an increased risk for psoriatic disease onset, suggesting that the site of infection—rather than the pathogen—is associated with the increased risk. These intriguing results support the need to further study the role of site and type of infection and antibiotic use on psoriatic disease onset.

With regard to other risk factors for PsA, a meta-analysis by Pouw and colleagues looked at 29 studies including adult patients with psoriasis with or without concurrent PsA or adult patients with psoriasis who developed PsA. The analysis showed that the body surface area affected by psoriasis was significantly higher in patients with psoriasis and concurrent PsA vs patients with only psoriasis (mean difference 5.31; 95% CI 1.78-8.83). Severe psoriasis was a significant predictor of concurrent PsA (odds ratio 3.34; P < .001). Thus, optimum care of patients with PsA requires excellent collaboration between rheumatologists and dermatologists.

Factors such as sex and body mass index (BMI) are likely to have a role in PsA treatment response but have not been extensively evaluated. To address this issue, Mease and colleagues conducted a post hoc analysis of the phase 3 SEAM-PsA trial including 851 patients who were methotrexate (MTX)/biologics naive and had early PsA. They were randomly assigned to receive MTX + placebo, etanercept + placebo, or MTX + etanercept. The study demonstrated that at week 24 a higher proportion of men vs women receiving MTX + etanercept achieved the American College of Rheumatology 20% criteria (ACR20) (71.5% vs 58.3%; P = .0194) and minimal disease activity (MDA) (45.8% vs 25.2%; P = .0003). A higher proportion of patients with a BMI ≤ 30 vs > 30 in all treatment groups achieved MDA (all P < .05), and those in the MTX + etanercept group achieved ACR20 (P = .0241). Thus, men (vs women) and those with lower BMI experience significantly better outcomes with treatment. When counseling patients about response to treatment, sex and BMI need to be taken into consideration. Moreover, further research is required to confirm and identify the reasons underlying these findings and to optimize treatment outcomes.

Another post hoc study explored the association between baseline disease activity and achieving the treatment target in PsA. Mease and colleagues analysed data from the phase 3 PALACE 4 study including 175 patients who were disease-modifying antirheumatic drug (DMARD)–naive and had active PsA. They received 30 mg apremilast twice daily. The study found that at week 52, remission or low disease activity according to the Clinical Disease Activity Index for Psoriatic Arthritis was achieved in 61.7% of patients with moderate disease activity vs 28.2% of these with high disease activity at baseline. Thus, DMARD-naive patients with moderate (vs high) disease activity at baseline are more likely to achieve low disease activity after apremilast therapy.

Infections have long been identified as possible triggers for psoriasis and psoriatic arthritis (PsA) onset. Thrastardottir and colleagues evaluated the association between sites where the culture sample was obtained, the culture result, and pathogens and incident PsA and psoriasis. They obtained data on all samples sent for bacterial culture in the Stockholm region of Sweden (313,235 bacterial cultures from 128,982 individuals) from January 1, 2004, to December 31, 2006. Among all samples sent for culture, a pharyngeal sample was associated with a higher risk for PsA onset within the next 50 days compared with urine (hazard ratio [HR] 8.78; 95% CI 3.23-23.91), nasopharyngeal (HR 8.26; 95% CI 2.23-30.63), or blood (HR 25.22; 95% CI 3.12-204.13) samples. Streptococcal infections in the pharynx or at any other site were not associated with an increased risk for PsA. Similar associations were found for psoriasis, but not for rheumatoid arthritis. These results indicate that having sent a pharyngeal sample for culture was associated with an increased risk for psoriatic disease onset, suggesting that the site of infection—rather than the pathogen—is associated with the increased risk. These intriguing results support the need to further study the role of site and type of infection and antibiotic use on psoriatic disease onset.

With regard to other risk factors for PsA, a meta-analysis by Pouw and colleagues looked at 29 studies including adult patients with psoriasis with or without concurrent PsA or adult patients with psoriasis who developed PsA. The analysis showed that the body surface area affected by psoriasis was significantly higher in patients with psoriasis and concurrent PsA vs patients with only psoriasis (mean difference 5.31; 95% CI 1.78-8.83). Severe psoriasis was a significant predictor of concurrent PsA (odds ratio 3.34; P < .001). Thus, optimum care of patients with PsA requires excellent collaboration between rheumatologists and dermatologists.

Factors such as sex and body mass index (BMI) are likely to have a role in PsA treatment response but have not been extensively evaluated. To address this issue, Mease and colleagues conducted a post hoc analysis of the phase 3 SEAM-PsA trial including 851 patients who were methotrexate (MTX)/biologics naive and had early PsA. They were randomly assigned to receive MTX + placebo, etanercept + placebo, or MTX + etanercept. The study demonstrated that at week 24 a higher proportion of men vs women receiving MTX + etanercept achieved the American College of Rheumatology 20% criteria (ACR20) (71.5% vs 58.3%; P = .0194) and minimal disease activity (MDA) (45.8% vs 25.2%; P = .0003). A higher proportion of patients with a BMI ≤ 30 vs > 30 in all treatment groups achieved MDA (all P < .05), and those in the MTX + etanercept group achieved ACR20 (P = .0241). Thus, men (vs women) and those with lower BMI experience significantly better outcomes with treatment. When counseling patients about response to treatment, sex and BMI need to be taken into consideration. Moreover, further research is required to confirm and identify the reasons underlying these findings and to optimize treatment outcomes.

Another post hoc study explored the association between baseline disease activity and achieving the treatment target in PsA. Mease and colleagues analysed data from the phase 3 PALACE 4 study including 175 patients who were disease-modifying antirheumatic drug (DMARD)–naive and had active PsA. They received 30 mg apremilast twice daily. The study found that at week 52, remission or low disease activity according to the Clinical Disease Activity Index for Psoriatic Arthritis was achieved in 61.7% of patients with moderate disease activity vs 28.2% of these with high disease activity at baseline. Thus, DMARD-naive patients with moderate (vs high) disease activity at baseline are more likely to achieve low disease activity after apremilast therapy.

Infections have long been identified as possible triggers for psoriasis and psoriatic arthritis (PsA) onset. Thrastardottir and colleagues evaluated the association between sites where the culture sample was obtained, the culture result, and pathogens and incident PsA and psoriasis. They obtained data on all samples sent for bacterial culture in the Stockholm region of Sweden (313,235 bacterial cultures from 128,982 individuals) from January 1, 2004, to December 31, 2006. Among all samples sent for culture, a pharyngeal sample was associated with a higher risk for PsA onset within the next 50 days compared with urine (hazard ratio [HR] 8.78; 95% CI 3.23-23.91), nasopharyngeal (HR 8.26; 95% CI 2.23-30.63), or blood (HR 25.22; 95% CI 3.12-204.13) samples. Streptococcal infections in the pharynx or at any other site were not associated with an increased risk for PsA. Similar associations were found for psoriasis, but not for rheumatoid arthritis. These results indicate that having sent a pharyngeal sample for culture was associated with an increased risk for psoriatic disease onset, suggesting that the site of infection—rather than the pathogen—is associated with the increased risk. These intriguing results support the need to further study the role of site and type of infection and antibiotic use on psoriatic disease onset.

With regard to other risk factors for PsA, a meta-analysis by Pouw and colleagues looked at 29 studies including adult patients with psoriasis with or without concurrent PsA or adult patients with psoriasis who developed PsA. The analysis showed that the body surface area affected by psoriasis was significantly higher in patients with psoriasis and concurrent PsA vs patients with only psoriasis (mean difference 5.31; 95% CI 1.78-8.83). Severe psoriasis was a significant predictor of concurrent PsA (odds ratio 3.34; P < .001). Thus, optimum care of patients with PsA requires excellent collaboration between rheumatologists and dermatologists.

Factors such as sex and body mass index (BMI) are likely to have a role in PsA treatment response but have not been extensively evaluated. To address this issue, Mease and colleagues conducted a post hoc analysis of the phase 3 SEAM-PsA trial including 851 patients who were methotrexate (MTX)/biologics naive and had early PsA. They were randomly assigned to receive MTX + placebo, etanercept + placebo, or MTX + etanercept. The study demonstrated that at week 24 a higher proportion of men vs women receiving MTX + etanercept achieved the American College of Rheumatology 20% criteria (ACR20) (71.5% vs 58.3%; P = .0194) and minimal disease activity (MDA) (45.8% vs 25.2%; P = .0003). A higher proportion of patients with a BMI ≤ 30 vs > 30 in all treatment groups achieved MDA (all P < .05), and those in the MTX + etanercept group achieved ACR20 (P = .0241). Thus, men (vs women) and those with lower BMI experience significantly better outcomes with treatment. When counseling patients about response to treatment, sex and BMI need to be taken into consideration. Moreover, further research is required to confirm and identify the reasons underlying these findings and to optimize treatment outcomes.

Another post hoc study explored the association between baseline disease activity and achieving the treatment target in PsA. Mease and colleagues analysed data from the phase 3 PALACE 4 study including 175 patients who were disease-modifying antirheumatic drug (DMARD)–naive and had active PsA. They received 30 mg apremilast twice daily. The study found that at week 52, remission or low disease activity according to the Clinical Disease Activity Index for Psoriatic Arthritis was achieved in 61.7% of patients with moderate disease activity vs 28.2% of these with high disease activity at baseline. Thus, DMARD-naive patients with moderate (vs high) disease activity at baseline are more likely to achieve low disease activity after apremilast therapy.

Chemotherapy plays a critical role in the management of patients with advanced gastroesophageal adenocarcinoma, and a fluoropyrimidine and platinum doublet (either oxaliplatin or cisplatin) is the standard regimen used. Chemotherapy is associated with toxicity, which is particularly concerning in frail and older adult patients.¹ A study by Chinen and colleagues specifically looked at the use of platinum chemotherapy agents in the older adult patient population. This retrospective cohort study analyzed survival outcomes and granulocyte colony–stimulating factor (G-CSF) use in 242 patients with advanced gastric cancer who were at least 70 years old and who were treated with either an oxaliplatin- or cisplatin-containing regimen. After propensity score weighting, the study demonstrated that treatment with these agents resulted in similar overall survival, but G-CSF use was more frequent with oxaliplatin use. These results are in line with previous data regarding these agents. In a prospective noninferiority study with a two-by-two design (REAL-2), an oxaliplatin-containing regimen had similar activity to a cisplatin-containing regimen.² However, oxaliplatin use was associated with less neutropenia. Going forward, the use of oxaliplatin should be preferred over cisplatin in older adult patients given its more favorable toxicity profile.

A study by Sotelo and colleagues looked at the presence of gastric preneoplastic lesions in the first-degree relatives of patients with gastric cancer. In this cross-sectional study conducted in Chile, endoscopic evaluation was performed in 110 people eligible for evaluation. Among the participants, 95 cases (86.4%) of preneoplastic lesions were identified, most commonly atrophic gastritis (86.4%) and intestinal metaplasia (82.7%). There was no association with sex, age, or Helicobacter pylori infection. The high rates of these lesions in the study are probably reflective of a high prevalence of gastric cancer in this geographic area. Although the data interpretation is limited by the small study size, these results suggest that endoscopic surveillance of first-degree relatives is warranted in areas of high gastric cancer incidence, and that optimal surveillance protocols, as well as management of these precancerous conditions, should be defined further.

The role of hyperthermic intraperitoneal chemotherapy (HIPEC) has been controversial in the management of gastric cancer. Thus far, there has not been a definitive study demonstrating a positive impact of HIPEC on survival in patients with this disease. A study by Lee and colleagues looked at the role of prophylactic HIPEC in patients with clinical stage T4 gastric cancer who do not have evidence of distant metastasis. Retrospective analysis included 132 patients with clinical stage T4 gastric cancer who underwent gastrectomy and D2 lymphadenectomy. After propensity score matching to reduce selection bias, the outcomes of 35 patients per cohort (gastrectomy vs gastrectomy plus prophylactic HIPEC) were analyzed. The two groups were well matched in regard to histology, pathologic T and N stage, perioperative therapy, and the type of resection. There was no difference in the incidence of postoperative complications. While the rate of peritoneal recurrences was lower in the HIPEC cohort, there was no difference in the rate of distant metastasis between the two groups. In terms of survival outcomes, the study demonstrated that disease-free survival and overall survival were improved with prophylactic HIPEC. Although firm conclusions cannot be drawn from this small retrospective study, these results suggest that it may be worth further investigating the role of prophylactic HIPEC in a subset of patients with high-risk early-stage disease.

Additional References

1. Hwang IG, Ji JH, Kang JH, et al. A multi-center, open-label, randomized phase III trial of first-line chemotherapy with capecitabine monotherapy versus capecitabine plus oxaliplatin in elderly patients with advanced gastric cancer. J Geriatr Oncol. 2017;8(3):170-175. Doi: 10.1016/j.jgo.2017.01.002

2. Cunningham D, Starling N, Rao S, et al. Capecitabine and oxaliplatin for advanced esophagogastric cancer. N Engl J Med. 2008;358:36-46. Doi:  10.1056/NEJMoa073149

Chemotherapy plays a critical role in the management of patients with advanced gastroesophageal adenocarcinoma, and a fluoropyrimidine and platinum doublet (either oxaliplatin or cisplatin) is the standard regimen used. Chemotherapy is associated with toxicity, which is particularly concerning in frail and older adult patients.¹ A study by Chinen and colleagues specifically looked at the use of platinum chemotherapy agents in the older adult patient population. This retrospective cohort study analyzed survival outcomes and granulocyte colony–stimulating factor (G-CSF) use in 242 patients with advanced gastric cancer who were at least 70 years old and who were treated with either an oxaliplatin- or cisplatin-containing regimen. After propensity score weighting, the study demonstrated that treatment with these agents resulted in similar overall survival, but G-CSF use was more frequent with oxaliplatin use. These results are in line with previous data regarding these agents. In a prospective noninferiority study with a two-by-two design (REAL-2), an oxaliplatin-containing regimen had similar activity to a cisplatin-containing regimen.² However, oxaliplatin use was associated with less neutropenia. Going forward, the use of oxaliplatin should be preferred over cisplatin in older adult patients given its more favorable toxicity profile.

A study by Sotelo and colleagues looked at the presence of gastric preneoplastic lesions in the first-degree relatives of patients with gastric cancer. In this cross-sectional study conducted in Chile, endoscopic evaluation was performed in 110 people eligible for evaluation. Among the participants, 95 cases (86.4%) of preneoplastic lesions were identified, most commonly atrophic gastritis (86.4%) and intestinal metaplasia (82.7%). There was no association with sex, age, or Helicobacter pylori infection. The high rates of these lesions in the study are probably reflective of a high prevalence of gastric cancer in this geographic area. Although the data interpretation is limited by the small study size, these results suggest that endoscopic surveillance of first-degree relatives is warranted in areas of high gastric cancer incidence, and that optimal surveillance protocols, as well as management of these precancerous conditions, should be defined further.

The role of hyperthermic intraperitoneal chemotherapy (HIPEC) has been controversial in the management of gastric cancer. Thus far, there has not been a definitive study demonstrating a positive impact of HIPEC on survival in patients with this disease. A study by Lee and colleagues looked at the role of prophylactic HIPEC in patients with clinical stage T4 gastric cancer who do not have evidence of distant metastasis. Retrospective analysis included 132 patients with clinical stage T4 gastric cancer who underwent gastrectomy and D2 lymphadenectomy. After propensity score matching to reduce selection bias, the outcomes of 35 patients per cohort (gastrectomy vs gastrectomy plus prophylactic HIPEC) were analyzed. The two groups were well matched in regard to histology, pathologic T and N stage, perioperative therapy, and the type of resection. There was no difference in the incidence of postoperative complications. While the rate of peritoneal recurrences was lower in the HIPEC cohort, there was no difference in the rate of distant metastasis between the two groups. In terms of survival outcomes, the study demonstrated that disease-free survival and overall survival were improved with prophylactic HIPEC. Although firm conclusions cannot be drawn from this small retrospective study, these results suggest that it may be worth further investigating the role of prophylactic HIPEC in a subset of patients with high-risk early-stage disease.

Additional References

1. Hwang IG, Ji JH, Kang JH, et al. A multi-center, open-label, randomized phase III trial of first-line chemotherapy with capecitabine monotherapy versus capecitabine plus oxaliplatin in elderly patients with advanced gastric cancer. J Geriatr Oncol. 2017;8(3):170-175. Doi: 10.1016/j.jgo.2017.01.002

2. Cunningham D, Starling N, Rao S, et al. Capecitabine and oxaliplatin for advanced esophagogastric cancer. N Engl J Med. 2008;358:36-46. Doi:  10.1056/NEJMoa073149

Chemotherapy plays a critical role in the management of patients with advanced gastroesophageal adenocarcinoma, and a fluoropyrimidine and platinum doublet (either oxaliplatin or cisplatin) is the standard regimen used. Chemotherapy is associated with toxicity, which is particularly concerning in frail and older adult patients.¹ A study by Chinen and colleagues specifically looked at the use of platinum chemotherapy agents in the older adult patient population. This retrospective cohort study analyzed survival outcomes and granulocyte colony–stimulating factor (G-CSF) use in 242 patients with advanced gastric cancer who were at least 70 years old and who were treated with either an oxaliplatin- or cisplatin-containing regimen. After propensity score weighting, the study demonstrated that treatment with these agents resulted in similar overall survival, but G-CSF use was more frequent with oxaliplatin use. These results are in line with previous data regarding these agents. In a prospective noninferiority study with a two-by-two design (REAL-2), an oxaliplatin-containing regimen had similar activity to a cisplatin-containing regimen.² However, oxaliplatin use was associated with less neutropenia. Going forward, the use of oxaliplatin should be preferred over cisplatin in older adult patients given its more favorable toxicity profile.

A study by Sotelo and colleagues looked at the presence of gastric preneoplastic lesions in the first-degree relatives of patients with gastric cancer. In this cross-sectional study conducted in Chile, endoscopic evaluation was performed in 110 people eligible for evaluation. Among the participants, 95 cases (86.4%) of preneoplastic lesions were identified, most commonly atrophic gastritis (86.4%) and intestinal metaplasia (82.7%). There was no association with sex, age, or Helicobacter pylori infection. The high rates of these lesions in the study are probably reflective of a high prevalence of gastric cancer in this geographic area. Although the data interpretation is limited by the small study size, these results suggest that endoscopic surveillance of first-degree relatives is warranted in areas of high gastric cancer incidence, and that optimal surveillance protocols, as well as management of these precancerous conditions, should be defined further.

The role of hyperthermic intraperitoneal chemotherapy (HIPEC) has been controversial in the management of gastric cancer. Thus far, there has not been a definitive study demonstrating a positive impact of HIPEC on survival in patients with this disease. A study by Lee and colleagues looked at the role of prophylactic HIPEC in patients with clinical stage T4 gastric cancer who do not have evidence of distant metastasis. Retrospective analysis included 132 patients with clinical stage T4 gastric cancer who underwent gastrectomy and D2 lymphadenectomy. After propensity score matching to reduce selection bias, the outcomes of 35 patients per cohort (gastrectomy vs gastrectomy plus prophylactic HIPEC) were analyzed. The two groups were well matched in regard to histology, pathologic T and N stage, perioperative therapy, and the type of resection. There was no difference in the incidence of postoperative complications. While the rate of peritoneal recurrences was lower in the HIPEC cohort, there was no difference in the rate of distant metastasis between the two groups. In terms of survival outcomes, the study demonstrated that disease-free survival and overall survival were improved with prophylactic HIPEC. Although firm conclusions cannot be drawn from this small retrospective study, these results suggest that it may be worth further investigating the role of prophylactic HIPEC in a subset of patients with high-risk early-stage disease.

Additional References

1. Hwang IG, Ji JH, Kang JH, et al. A multi-center, open-label, randomized phase III trial of first-line chemotherapy with capecitabine monotherapy versus capecitabine plus oxaliplatin in elderly patients with advanced gastric cancer. J Geriatr Oncol. 2017;8(3):170-175. Doi: 10.1016/j.jgo.2017.01.002

2. Cunningham D, Starling N, Rao S, et al. Capecitabine and oxaliplatin for advanced esophagogastric cancer. N Engl J Med. 2008;358:36-46. Doi:  10.1056/NEJMoa073149

Tirzepatide, recently approved by the US Food and Drug Administration, is a unique dual gastric inhibitory peptide/glucagon-like peptide 1 (GLP-1) receptor agonist that has been formulated as a once-weekly injection. The results from the phase 3 SURPASS program demonstrated its efficacy for type 2 diabetes management. Glycosylated hemoglobin reduction ranged from 1.9%-2.6%; up to 97% of participants achieved an A1c< 7% and up to 62% achieved an A1c < 5.7%, and weight loss ranged from 6 to 13 kg. Tirzepatide was superior to 1 mg semaglutide, insulin degludec, and insulin glargine for A1c lowering and weight loss.

In a subgroup of SURPASS-3, Battelino and colleagues compared tirzepatide to insulin degludec using continuous glucose monitoring. Patients treated with tirzepatide at doses of 5 mg and 10 mg achieved a mean time in tight range (71-140 mg/dL) of 72.4% and 72.6%, respectively, which was significantly better than the 48.0% for patients treated with insulin degludec. Remarkably, time in range (71-180 mg/dL) was 91% for the 10- and 15-mg doses of tirzepatide compared with 75% for insulin degludec. Time spent in hypoglycemia and glycemic variability were lower with tirzepatide vs insulin degludec. This analysis shows the superiority of tirzepatide in achieving clinically meaningful improvements in the percentage of time spent within a tight target range and target range for tirzepatide compared with insulin degludec, further supporting the use of this dual Incretin before starting basal insulin.

Cotadutide is a GLP-1 receptor/glucagon dual agonist currently in phase 2b/3 trials in patients with either nonalcoholic steatohepatitis (NASH) or type 2 diabetes with chronic kidney disease. In a recent meta-analysis of early cotadutide trials vs placebo, Ali and colleagues reported a significant 3.3 kg weight loss and a 0.68% reduction in A1c, as well as reductions in glucose area under the plasma concentration curve and fasting plasma glucose. Although we will have to await the results of further studies, these and other early data with cotadutide suggests that this GLP-1 receptor/glucagon co-agonist may offer benefits in patients with type 2 diabetes or NASH.

It has been over 60 years since the first clinical use of metformin, yet we continue to learn about potential uses beyond just glycemic control in type 2 diabetes. In a Chinese prospective cohort study of 7587 patients with type 2 diabetes who were hospitalized with a first stroke, Tu and colleagues found lower rates of in-hospital mortality, 12-month mortality, and disability in those treated with metformin vs those not treated with metformin. The authors speculate that metformin has antioxidant, anti-inflammatory, and neuroprotective effects that may lead to better stroke outcomes. Of course, this study is limited by its observational design, and randomized controlled studies are required to determine whether metformin use may have a protective effect against the poor functional outcome in first-ever stroke patients with type 2 diabetes.

In another study of metformin, Jiang and colleagues reported that among patients with long-standing type 2 diabetes, metformin users were 83% less likely than metformin nonusers to develop early age-related macular degeneration (AMD). This was a small retrospective study from which conclusions cannot be made. Given that AMD is a leading cause of vision loss for older adults, future prospective studies of metformin in the treatment of AMD would be helpful in determining the impact of metformin in this common eye condition.

Tirzepatide, recently approved by the US Food and Drug Administration, is a unique dual gastric inhibitory peptide/glucagon-like peptide 1 (GLP-1) receptor agonist that has been formulated as a once-weekly injection. The results from the phase 3 SURPASS program demonstrated its efficacy for type 2 diabetes management. Glycosylated hemoglobin reduction ranged from 1.9%-2.6%; up to 97% of participants achieved an A1c< 7% and up to 62% achieved an A1c < 5.7%, and weight loss ranged from 6 to 13 kg. Tirzepatide was superior to 1 mg semaglutide, insulin degludec, and insulin glargine for A1c lowering and weight loss.

In a subgroup of SURPASS-3, Battelino and colleagues compared tirzepatide to insulin degludec using continuous glucose monitoring. Patients treated with tirzepatide at doses of 5 mg and 10 mg achieved a mean time in tight range (71-140 mg/dL) of 72.4% and 72.6%, respectively, which was significantly better than the 48.0% for patients treated with insulin degludec. Remarkably, time in range (71-180 mg/dL) was 91% for the 10- and 15-mg doses of tirzepatide compared with 75% for insulin degludec. Time spent in hypoglycemia and glycemic variability were lower with tirzepatide vs insulin degludec. This analysis shows the superiority of tirzepatide in achieving clinically meaningful improvements in the percentage of time spent within a tight target range and target range for tirzepatide compared with insulin degludec, further supporting the use of this dual Incretin before starting basal insulin.

Cotadutide is a GLP-1 receptor/glucagon dual agonist currently in phase 2b/3 trials in patients with either nonalcoholic steatohepatitis (NASH) or type 2 diabetes with chronic kidney disease. In a recent meta-analysis of early cotadutide trials vs placebo, Ali and colleagues reported a significant 3.3 kg weight loss and a 0.68% reduction in A1c, as well as reductions in glucose area under the plasma concentration curve and fasting plasma glucose. Although we will have to await the results of further studies, these and other early data with cotadutide suggests that this GLP-1 receptor/glucagon co-agonist may offer benefits in patients with type 2 diabetes or NASH.

It has been over 60 years since the first clinical use of metformin, yet we continue to learn about potential uses beyond just glycemic control in type 2 diabetes. In a Chinese prospective cohort study of 7587 patients with type 2 diabetes who were hospitalized with a first stroke, Tu and colleagues found lower rates of in-hospital mortality, 12-month mortality, and disability in those treated with metformin vs those not treated with metformin. The authors speculate that metformin has antioxidant, anti-inflammatory, and neuroprotective effects that may lead to better stroke outcomes. Of course, this study is limited by its observational design, and randomized controlled studies are required to determine whether metformin use may have a protective effect against the poor functional outcome in first-ever stroke patients with type 2 diabetes.

In another study of metformin, Jiang and colleagues reported that among patients with long-standing type 2 diabetes, metformin users were 83% less likely than metformin nonusers to develop early age-related macular degeneration (AMD). This was a small retrospective study from which conclusions cannot be made. Given that AMD is a leading cause of vision loss for older adults, future prospective studies of metformin in the treatment of AMD would be helpful in determining the impact of metformin in this common eye condition.

Tirzepatide, recently approved by the US Food and Drug Administration, is a unique dual gastric inhibitory peptide/glucagon-like peptide 1 (GLP-1) receptor agonist that has been formulated as a once-weekly injection. The results from the phase 3 SURPASS program demonstrated its efficacy for type 2 diabetes management. Glycosylated hemoglobin reduction ranged from 1.9%-2.6%; up to 97% of participants achieved an A1c< 7% and up to 62% achieved an A1c < 5.7%, and weight loss ranged from 6 to 13 kg. Tirzepatide was superior to 1 mg semaglutide, insulin degludec, and insulin glargine for A1c lowering and weight loss.

In a subgroup of SURPASS-3, Battelino and colleagues compared tirzepatide to insulin degludec using continuous glucose monitoring. Patients treated with tirzepatide at doses of 5 mg and 10 mg achieved a mean time in tight range (71-140 mg/dL) of 72.4% and 72.6%, respectively, which was significantly better than the 48.0% for patients treated with insulin degludec. Remarkably, time in range (71-180 mg/dL) was 91% for the 10- and 15-mg doses of tirzepatide compared with 75% for insulin degludec. Time spent in hypoglycemia and glycemic variability were lower with tirzepatide vs insulin degludec. This analysis shows the superiority of tirzepatide in achieving clinically meaningful improvements in the percentage of time spent within a tight target range and target range for tirzepatide compared with insulin degludec, further supporting the use of this dual Incretin before starting basal insulin.

Cotadutide is a GLP-1 receptor/glucagon dual agonist currently in phase 2b/3 trials in patients with either nonalcoholic steatohepatitis (NASH) or type 2 diabetes with chronic kidney disease. In a recent meta-analysis of early cotadutide trials vs placebo, Ali and colleagues reported a significant 3.3 kg weight loss and a 0.68% reduction in A1c, as well as reductions in glucose area under the plasma concentration curve and fasting plasma glucose. Although we will have to await the results of further studies, these and other early data with cotadutide suggests that this GLP-1 receptor/glucagon co-agonist may offer benefits in patients with type 2 diabetes or NASH.

It has been over 60 years since the first clinical use of metformin, yet we continue to learn about potential uses beyond just glycemic control in type 2 diabetes. In a Chinese prospective cohort study of 7587 patients with type 2 diabetes who were hospitalized with a first stroke, Tu and colleagues found lower rates of in-hospital mortality, 12-month mortality, and disability in those treated with metformin vs those not treated with metformin. The authors speculate that metformin has antioxidant, anti-inflammatory, and neuroprotective effects that may lead to better stroke outcomes. Of course, this study is limited by its observational design, and randomized controlled studies are required to determine whether metformin use may have a protective effect against the poor functional outcome in first-ever stroke patients with type 2 diabetes.

In another study of metformin, Jiang and colleagues reported that among patients with long-standing type 2 diabetes, metformin users were 83% less likely than metformin nonusers to develop early age-related macular degeneration (AMD). This was a small retrospective study from which conclusions cannot be made. Given that AMD is a leading cause of vision loss for older adults, future prospective studies of metformin in the treatment of AMD would be helpful in determining the impact of metformin in this common eye condition.

NEW ORLEANS – A single dose of a synthetic formulation of psilocybin provides rapid improvement in treatment-resistant depression, with benefits sustained for up to 12 weeks, according to results from the largest randomized controlled study of psilocybin to date.

“This is easily the largest study of a psychedelic drug employing modern randomized controlled trial methodology [with] 22 sites and 10 countries, so it’s not your typical phase 2 trial,” the study’s lead author, Guy M. Goodwin, MD, emeritus professor of psychiatry at the University of Oxford, England, said in an interview.

“Importantly, 94% of the patients in the study were psilocybin naive, which is very important for generalizability,” Dr. Goodwin noted.

Long used as psychedelic ‘magic mushrooms,’ psilocybin has gained increased interest in psychiatry in recent years as a potential treatment for severe depression after showing benefits in patients with life-threatening cancers and others with major depressive disorder (MDD).

To put the therapy to test in a more rigorous, randomized trial, Dr. Goodwin and colleagues conducted the phase 2b study of a proprietary synthetic formulation of psilocybin, COMP360 (COMPASS Pathways), recruiting 233 patients with treatment-resistant depression at 22 centers.

The study was presented at the annual meeting of the American Psychiatric Association.

After a 2-week washout period following the discontinuation of antidepressants, the patients were randomized to one of three groups: A single dose of 25 mg (n = 79), 10 mg (n = 75), or a subtherapeutic comparison of 1 mg (n = 79).

The psilocybin was administered in the presence of specially trained therapists who provided psychological support before, during, and after the 6- to 8-hour session.

Patients were then asked to refrain from antidepressant use for at least 3 weeks following the session, and had periodic follow-up for 12 weeks.

For the primary endpoint, those in the 25-mg group, but not the 10-mg dose, showed a significantly greater reduction in depression from baseline versus the 1-mg group on the Montgomery-Åsberg Depression Rating Scale at week 3 (MADRS; -6.6; P < .001).

The benefit was observed at day 2 and week 1 following administration, “confirming the rapid-acting character of the effect,” the investigators reported.

Sustained responses, defined as at least a 50% change from baseline in MADRS total score, were further observed up to week 12 among 20.3% in the 25-mg group and among 5.3% in the 10-mg groups versus 10.1% in the 1-mg group.

On the day of psilocybin treatment, the treatment-emergent side effects that were reported were headache, nausea, and dizziness, with event rates of 83.5% in the 25-mg group, 74.7% in the 10-mg group, and 72.2% in the 1-mg group.

One participant in the 25-mg group experienced acute anxiety and was treated with lorazepam.

The incidence of treatment-emergent serious adverse events from day 2 to week 3 was 6.3% (five patients) in the 25-mg group, 8.0% (six patients) in the 10-mg group, and 1.3% (one patient) in the 1-mg group.

Serious AEs included suicidal ideation and intentional self-injury among two patients each in the 25-mg group, while in the 10-mg group, two had suicidal ideation and one had hospitalization for severe depression.

There were no significant differences between the groups in terms of vital signs or clinical laboratory tests.

Of note, two patients in the 25-mg group had a change from baseline in QTcF >60 msec on day 2. For one patient, the increase was within normal range, and the other had a QTcF interval duration >500 msec on day 2, but levels returned to normal by day 9.
 

Improvements in context

Dr. Goodwin noted that the improvements were swift and impressive when compared with those of the STAR*D trial, which is the largest prospective study of treatment outcomes in patients with MDD.

“In the STAR*D trial, third- and fourth-step treatments showed low response rates of under 15% and high relapse rates,” Dr. Goodwin said. “By comparison, our response rates at 12 weeks were 20%-25%, so almost double that seen for probably equivalent treatment steps in STAR*D, with a single treatment with 25 mg, and no additional antidepressant, so no side effect burden.

“We hope to follow up enough of these patients [in the new study] to get some idea of relapse rates,” Dr. Goodwin added. “These have been low in comparable studies with MDD patients: We will see.”

Commenting on the research, Balwinder Singh, MD, of the department of psychiatry and psychology, Mayo Clinic, Rochester, Minn., said the study represents a valuable addition to needed evidence on psilocybin – with some caveats.

“This study adds to the emerging evidence base of psilocybin for treatment-resistant depression, at least in the short term,” he said in an interview. “I think the challenge in the real world would be to have access to 6-8 hours of therapy with psilocybin when patients struggle to find good therapists who could provide even weekly therapy for an hour.”

In addition, Dr. Singh questioned the durability of a single dose of psilocybin in the long term, noting a recent study (N Engl J Med. 2021 Apr 15. doi: 10.1056/NEJMoa2032994) that evaluated two doses of psilocybin (25 mg) 3 weeks apart, and failed to show any significant difference compared with the serotonergic antidepressant escitalopram at 6 weeks.

He further expressed concern about the emergence of suicidal behaviors in some patients, as well as the prolongation of QTc > 60 msec reported in the two patients.

“This is something to be carefully assessed in future studies, due to the risk of arrhythmias,” Dr. Singh said.

The study was sponsored by COMPASS Pathfinder Limited. Dr. Goodwin is chief medical officer for COMPASS Pathways. Dr. Singh had no disclosures to report.

NEW ORLEANS – A single dose of a synthetic formulation of psilocybin provides rapid improvement in treatment-resistant depression, with benefits sustained for up to 12 weeks, according to results from the largest randomized controlled study of psilocybin to date.

“This is easily the largest study of a psychedelic drug employing modern randomized controlled trial methodology [with] 22 sites and 10 countries, so it’s not your typical phase 2 trial,” the study’s lead author, Guy M. Goodwin, MD, emeritus professor of psychiatry at the University of Oxford, England, said in an interview.

“Importantly, 94% of the patients in the study were psilocybin naive, which is very important for generalizability,” Dr. Goodwin noted.

Long used as psychedelic ‘magic mushrooms,’ psilocybin has gained increased interest in psychiatry in recent years as a potential treatment for severe depression after showing benefits in patients with life-threatening cancers and others with major depressive disorder (MDD).

To put the therapy to test in a more rigorous, randomized trial, Dr. Goodwin and colleagues conducted the phase 2b study of a proprietary synthetic formulation of psilocybin, COMP360 (COMPASS Pathways), recruiting 233 patients with treatment-resistant depression at 22 centers.

The study was presented at the annual meeting of the American Psychiatric Association.

After a 2-week washout period following the discontinuation of antidepressants, the patients were randomized to one of three groups: A single dose of 25 mg (n = 79), 10 mg (n = 75), or a subtherapeutic comparison of 1 mg (n = 79).

The psilocybin was administered in the presence of specially trained therapists who provided psychological support before, during, and after the 6- to 8-hour session.

Patients were then asked to refrain from antidepressant use for at least 3 weeks following the session, and had periodic follow-up for 12 weeks.

For the primary endpoint, those in the 25-mg group, but not the 10-mg dose, showed a significantly greater reduction in depression from baseline versus the 1-mg group on the Montgomery-Åsberg Depression Rating Scale at week 3 (MADRS; -6.6; P < .001).

The benefit was observed at day 2 and week 1 following administration, “confirming the rapid-acting character of the effect,” the investigators reported.

Sustained responses, defined as at least a 50% change from baseline in MADRS total score, were further observed up to week 12 among 20.3% in the 25-mg group and among 5.3% in the 10-mg groups versus 10.1% in the 1-mg group.

On the day of psilocybin treatment, the treatment-emergent side effects that were reported were headache, nausea, and dizziness, with event rates of 83.5% in the 25-mg group, 74.7% in the 10-mg group, and 72.2% in the 1-mg group.

One participant in the 25-mg group experienced acute anxiety and was treated with lorazepam.

The incidence of treatment-emergent serious adverse events from day 2 to week 3 was 6.3% (five patients) in the 25-mg group, 8.0% (six patients) in the 10-mg group, and 1.3% (one patient) in the 1-mg group.

Serious AEs included suicidal ideation and intentional self-injury among two patients each in the 25-mg group, while in the 10-mg group, two had suicidal ideation and one had hospitalization for severe depression.

There were no significant differences between the groups in terms of vital signs or clinical laboratory tests.

Of note, two patients in the 25-mg group had a change from baseline in QTcF >60 msec on day 2. For one patient, the increase was within normal range, and the other had a QTcF interval duration >500 msec on day 2, but levels returned to normal by day 9.
 

Improvements in context

Dr. Goodwin noted that the improvements were swift and impressive when compared with those of the STAR*D trial, which is the largest prospective study of treatment outcomes in patients with MDD.

“In the STAR*D trial, third- and fourth-step treatments showed low response rates of under 15% and high relapse rates,” Dr. Goodwin said. “By comparison, our response rates at 12 weeks were 20%-25%, so almost double that seen for probably equivalent treatment steps in STAR*D, with a single treatment with 25 mg, and no additional antidepressant, so no side effect burden.

“We hope to follow up enough of these patients [in the new study] to get some idea of relapse rates,” Dr. Goodwin added. “These have been low in comparable studies with MDD patients: We will see.”

Commenting on the research, Balwinder Singh, MD, of the department of psychiatry and psychology, Mayo Clinic, Rochester, Minn., said the study represents a valuable addition to needed evidence on psilocybin – with some caveats.

“This study adds to the emerging evidence base of psilocybin for treatment-resistant depression, at least in the short term,” he said in an interview. “I think the challenge in the real world would be to have access to 6-8 hours of therapy with psilocybin when patients struggle to find good therapists who could provide even weekly therapy for an hour.”

In addition, Dr. Singh questioned the durability of a single dose of psilocybin in the long term, noting a recent study (N Engl J Med. 2021 Apr 15. doi: 10.1056/NEJMoa2032994) that evaluated two doses of psilocybin (25 mg) 3 weeks apart, and failed to show any significant difference compared with the serotonergic antidepressant escitalopram at 6 weeks.

He further expressed concern about the emergence of suicidal behaviors in some patients, as well as the prolongation of QTc > 60 msec reported in the two patients.

“This is something to be carefully assessed in future studies, due to the risk of arrhythmias,” Dr. Singh said.

The study was sponsored by COMPASS Pathfinder Limited. Dr. Goodwin is chief medical officer for COMPASS Pathways. Dr. Singh had no disclosures to report.

NEW ORLEANS – A single dose of a synthetic formulation of psilocybin provides rapid improvement in treatment-resistant depression, with benefits sustained for up to 12 weeks, according to results from the largest randomized controlled study of psilocybin to date.

“This is easily the largest study of a psychedelic drug employing modern randomized controlled trial methodology [with] 22 sites and 10 countries, so it’s not your typical phase 2 trial,” the study’s lead author, Guy M. Goodwin, MD, emeritus professor of psychiatry at the University of Oxford, England, said in an interview.

“Importantly, 94% of the patients in the study were psilocybin naive, which is very important for generalizability,” Dr. Goodwin noted.

Long used as psychedelic ‘magic mushrooms,’ psilocybin has gained increased interest in psychiatry in recent years as a potential treatment for severe depression after showing benefits in patients with life-threatening cancers and others with major depressive disorder (MDD).

To put the therapy to test in a more rigorous, randomized trial, Dr. Goodwin and colleagues conducted the phase 2b study of a proprietary synthetic formulation of psilocybin, COMP360 (COMPASS Pathways), recruiting 233 patients with treatment-resistant depression at 22 centers.

The study was presented at the annual meeting of the American Psychiatric Association.

After a 2-week washout period following the discontinuation of antidepressants, the patients were randomized to one of three groups: A single dose of 25 mg (n = 79), 10 mg (n = 75), or a subtherapeutic comparison of 1 mg (n = 79).

The psilocybin was administered in the presence of specially trained therapists who provided psychological support before, during, and after the 6- to 8-hour session.

Patients were then asked to refrain from antidepressant use for at least 3 weeks following the session, and had periodic follow-up for 12 weeks.

For the primary endpoint, those in the 25-mg group, but not the 10-mg dose, showed a significantly greater reduction in depression from baseline versus the 1-mg group on the Montgomery-Åsberg Depression Rating Scale at week 3 (MADRS; -6.6; P < .001).

The benefit was observed at day 2 and week 1 following administration, “confirming the rapid-acting character of the effect,” the investigators reported.

Sustained responses, defined as at least a 50% change from baseline in MADRS total score, were further observed up to week 12 among 20.3% in the 25-mg group and among 5.3% in the 10-mg groups versus 10.1% in the 1-mg group.

On the day of psilocybin treatment, the treatment-emergent side effects that were reported were headache, nausea, and dizziness, with event rates of 83.5% in the 25-mg group, 74.7% in the 10-mg group, and 72.2% in the 1-mg group.

One participant in the 25-mg group experienced acute anxiety and was treated with lorazepam.

The incidence of treatment-emergent serious adverse events from day 2 to week 3 was 6.3% (five patients) in the 25-mg group, 8.0% (six patients) in the 10-mg group, and 1.3% (one patient) in the 1-mg group.

Serious AEs included suicidal ideation and intentional self-injury among two patients each in the 25-mg group, while in the 10-mg group, two had suicidal ideation and one had hospitalization for severe depression.

There were no significant differences between the groups in terms of vital signs or clinical laboratory tests.

Of note, two patients in the 25-mg group had a change from baseline in QTcF >60 msec on day 2. For one patient, the increase was within normal range, and the other had a QTcF interval duration >500 msec on day 2, but levels returned to normal by day 9.
 

Improvements in context

Dr. Goodwin noted that the improvements were swift and impressive when compared with those of the STAR*D trial, which is the largest prospective study of treatment outcomes in patients with MDD.

“In the STAR*D trial, third- and fourth-step treatments showed low response rates of under 15% and high relapse rates,” Dr. Goodwin said. “By comparison, our response rates at 12 weeks were 20%-25%, so almost double that seen for probably equivalent treatment steps in STAR*D, with a single treatment with 25 mg, and no additional antidepressant, so no side effect burden.

“We hope to follow up enough of these patients [in the new study] to get some idea of relapse rates,” Dr. Goodwin added. “These have been low in comparable studies with MDD patients: We will see.”

Commenting on the research, Balwinder Singh, MD, of the department of psychiatry and psychology, Mayo Clinic, Rochester, Minn., said the study represents a valuable addition to needed evidence on psilocybin – with some caveats.

“This study adds to the emerging evidence base of psilocybin for treatment-resistant depression, at least in the short term,” he said in an interview. “I think the challenge in the real world would be to have access to 6-8 hours of therapy with psilocybin when patients struggle to find good therapists who could provide even weekly therapy for an hour.”

In addition, Dr. Singh questioned the durability of a single dose of psilocybin in the long term, noting a recent study (N Engl J Med. 2021 Apr 15. doi: 10.1056/NEJMoa2032994) that evaluated two doses of psilocybin (25 mg) 3 weeks apart, and failed to show any significant difference compared with the serotonergic antidepressant escitalopram at 6 weeks.

He further expressed concern about the emergence of suicidal behaviors in some patients, as well as the prolongation of QTc > 60 msec reported in the two patients.

“This is something to be carefully assessed in future studies, due to the risk of arrhythmias,” Dr. Singh said.

The study was sponsored by COMPASS Pathfinder Limited. Dr. Goodwin is chief medical officer for COMPASS Pathways. Dr. Singh had no disclosures to report.

After years going on and off medications for occasional asthma symptoms, things went downhill for Brian Blome in November 2020. The retired carpenter started feeling short of breath and wheezing during bike rides. At home, he struggled with chores.

“I was having a hard time climbing a flight of stairs, just doing laundry,” said Mr. Blome, who lives in the Chicago suburb of Palatine.

To get things under control, he saw an allergist and started regular medications – two tablets, two nasal sprays, and inhaled corticosteroids each day, plus an albuterol inhaler for flare-ups.

The inhalers have an extra feature: an electronic monitor that attaches to the device and automatically tracks where and when the medication is used. Bluetooth sends this information to an app on the patient’s mobile phone and to a dashboard where the medical team can see, at a glance, when symptoms are popping up and how regularly medications are taken – leading to the devices often being called “smart inhalers.”

At the 2022 American Academy of Allergy, Asthma, and Immunology conference in Phoenix, researchers explained how digital monitoring devices can help diagnose and treat hard-to-control asthma, potentially reducing the need for oral steroids or biologic therapies.

Even though electric monitors have been on the market for years, their use has been slow to catch on because of uncertainties around insurance coverage, liability, and how to manage and best use the data. One recent study said these devices cost $100-$500, but that price depends on many things, such as insurance.

About 17% of adult asthma patients have “difficult-to-control” asthma, meaning they limit their activity because of breathing symptoms and use reliever medications multiple times a week.

But research suggests that correcting inhaling technique and sticking to the use of the medications can cut that 17% down to just 3.7%, said Mr. Blome’s allergist, Giselle Mosnaim, MD, of NorthShore University HealthSystem in Glenview, Ill. Dr. Mosnaim spoke about digital monitoring at a conference session on digital technologies for asthma management.

A study of more than 5,000 asthma patients “showed that, if you have critical errors in inhaler technique, this leads to worse asthma outcomes and increased asthma exacerbations,” she said. It also shows that, despite new devices and new technologies, “we still have poor inhaler technique.”

Yet adherence is poorly gauged by doctors and patient self-reporting. “The ideal measure of adherence should be objective, accurate, and unobtrusive to minimize impact on patient behavior and allow reliable data collection in real-world settings,” Dr. Mosnaim said. “So electronic medication monitors are the gold standard.”
 

Improving use

Patients not following instructions or guidelines “is something we saw nonstop with kids,” said Caroline Moassessi, founder of the allergy and asthma blog Gratefulfoodie.com who formerly served on a regional board of the American Lung Association. She’s also the mother of two asthmatic children, now in college, who years ago used electronic medication monitors as part of a research trial.

They were “unimpressed – mostly since I think they thought their asthma was controlled,” she said. “When patients are not in crisis, they don’t manage their asthma well.”

Even in research studies such as the one Rachelle Ramsey, PhD, presented at the conference, it’s not only hard to determine if better adherence leads to improved health, but when.

“For example, does your adherence this week impact your asthma control this week, or does it impact your asthma control next week? Or is it even further out? Do you need to have some level of adherence over the course of a month in order to have better outcomes at the end of that month?” said Dr. Ramsey, a pediatric research psychologist at Cincinnati Children’s Hospital Medical Center. “I think it’s a little complicated.”

That said, results from several small studies do show a connection between remote monitoring and better clinical outcomes. One study enrolled asthma patients in the United Kingdom, and another was done by Dr. Mosnaim with Chicago-area patients.

In the U.K. quality improvement project, nurses asked patients with difficult-to-control asthma if they knew how to use their inhalers and were following treatment guidelines.

Those who said “yes” were invited to swap their steroid/inhalers for a controller fitted with a device that tracks use and measures acoustics to test inhaler technique. After 28 days of monitoring, many people in the study had better clinical outcomes.

And after 3 months of digital monitoring, patients didn’t use their rescue medication quite as often.

Mr. Blome has seen a marked improvement in his asthma since starting regular appointments and getting back on daily medications a year and a half ago. He says that now and then, he has wheezing and shortness of breath, usually while biking or exercising. But those symptoms aren’t as severe or frequent as before.

From a doctor’s perspective, “digital inhaler systems allow me to discern patterns in order to determine what triggers his asthma symptoms and to adjust medications at different times of the year,” Dr. Mosnaim said.

Electronic systems can monitor pollen counts and air quality as well as how often a patient uses a quick reliever medication. Thus, she said, tracking these measures year-round could raise attention to impending asthma attacks and suggest when to increase the dose of controller medications or add other treatments.

A version of this article first appeared on WebMD.com.

After years going on and off medications for occasional asthma symptoms, things went downhill for Brian Blome in November 2020. The retired carpenter started feeling short of breath and wheezing during bike rides. At home, he struggled with chores.

“I was having a hard time climbing a flight of stairs, just doing laundry,” said Mr. Blome, who lives in the Chicago suburb of Palatine.

To get things under control, he saw an allergist and started regular medications – two tablets, two nasal sprays, and inhaled corticosteroids each day, plus an albuterol inhaler for flare-ups.

The inhalers have an extra feature: an electronic monitor that attaches to the device and automatically tracks where and when the medication is used. Bluetooth sends this information to an app on the patient’s mobile phone and to a dashboard where the medical team can see, at a glance, when symptoms are popping up and how regularly medications are taken – leading to the devices often being called “smart inhalers.”

At the 2022 American Academy of Allergy, Asthma, and Immunology conference in Phoenix, researchers explained how digital monitoring devices can help diagnose and treat hard-to-control asthma, potentially reducing the need for oral steroids or biologic therapies.

Even though electric monitors have been on the market for years, their use has been slow to catch on because of uncertainties around insurance coverage, liability, and how to manage and best use the data. One recent study said these devices cost $100-$500, but that price depends on many things, such as insurance.

About 17% of adult asthma patients have “difficult-to-control” asthma, meaning they limit their activity because of breathing symptoms and use reliever medications multiple times a week.

But research suggests that correcting inhaling technique and sticking to the use of the medications can cut that 17% down to just 3.7%, said Mr. Blome’s allergist, Giselle Mosnaim, MD, of NorthShore University HealthSystem in Glenview, Ill. Dr. Mosnaim spoke about digital monitoring at a conference session on digital technologies for asthma management.

A study of more than 5,000 asthma patients “showed that, if you have critical errors in inhaler technique, this leads to worse asthma outcomes and increased asthma exacerbations,” she said. It also shows that, despite new devices and new technologies, “we still have poor inhaler technique.”

Yet adherence is poorly gauged by doctors and patient self-reporting. “The ideal measure of adherence should be objective, accurate, and unobtrusive to minimize impact on patient behavior and allow reliable data collection in real-world settings,” Dr. Mosnaim said. “So electronic medication monitors are the gold standard.”
 

Improving use

Patients not following instructions or guidelines “is something we saw nonstop with kids,” said Caroline Moassessi, founder of the allergy and asthma blog Gratefulfoodie.com who formerly served on a regional board of the American Lung Association. She’s also the mother of two asthmatic children, now in college, who years ago used electronic medication monitors as part of a research trial.

They were “unimpressed – mostly since I think they thought their asthma was controlled,” she said. “When patients are not in crisis, they don’t manage their asthma well.”

Even in research studies such as the one Rachelle Ramsey, PhD, presented at the conference, it’s not only hard to determine if better adherence leads to improved health, but when.

“For example, does your adherence this week impact your asthma control this week, or does it impact your asthma control next week? Or is it even further out? Do you need to have some level of adherence over the course of a month in order to have better outcomes at the end of that month?” said Dr. Ramsey, a pediatric research psychologist at Cincinnati Children’s Hospital Medical Center. “I think it’s a little complicated.”

That said, results from several small studies do show a connection between remote monitoring and better clinical outcomes. One study enrolled asthma patients in the United Kingdom, and another was done by Dr. Mosnaim with Chicago-area patients.

In the U.K. quality improvement project, nurses asked patients with difficult-to-control asthma if they knew how to use their inhalers and were following treatment guidelines.

Those who said “yes” were invited to swap their steroid/inhalers for a controller fitted with a device that tracks use and measures acoustics to test inhaler technique. After 28 days of monitoring, many people in the study had better clinical outcomes.

And after 3 months of digital monitoring, patients didn’t use their rescue medication quite as often.

Mr. Blome has seen a marked improvement in his asthma since starting regular appointments and getting back on daily medications a year and a half ago. He says that now and then, he has wheezing and shortness of breath, usually while biking or exercising. But those symptoms aren’t as severe or frequent as before.

From a doctor’s perspective, “digital inhaler systems allow me to discern patterns in order to determine what triggers his asthma symptoms and to adjust medications at different times of the year,” Dr. Mosnaim said.

Electronic systems can monitor pollen counts and air quality as well as how often a patient uses a quick reliever medication. Thus, she said, tracking these measures year-round could raise attention to impending asthma attacks and suggest when to increase the dose of controller medications or add other treatments.

A version of this article first appeared on WebMD.com.

After years going on and off medications for occasional asthma symptoms, things went downhill for Brian Blome in November 2020. The retired carpenter started feeling short of breath and wheezing during bike rides. At home, he struggled with chores.

“I was having a hard time climbing a flight of stairs, just doing laundry,” said Mr. Blome, who lives in the Chicago suburb of Palatine.

To get things under control, he saw an allergist and started regular medications – two tablets, two nasal sprays, and inhaled corticosteroids each day, plus an albuterol inhaler for flare-ups.

The inhalers have an extra feature: an electronic monitor that attaches to the device and automatically tracks where and when the medication is used. Bluetooth sends this information to an app on the patient’s mobile phone and to a dashboard where the medical team can see, at a glance, when symptoms are popping up and how regularly medications are taken – leading to the devices often being called “smart inhalers.”

At the 2022 American Academy of Allergy, Asthma, and Immunology conference in Phoenix, researchers explained how digital monitoring devices can help diagnose and treat hard-to-control asthma, potentially reducing the need for oral steroids or biologic therapies.

Even though electric monitors have been on the market for years, their use has been slow to catch on because of uncertainties around insurance coverage, liability, and how to manage and best use the data. One recent study said these devices cost $100-$500, but that price depends on many things, such as insurance.

About 17% of adult asthma patients have “difficult-to-control” asthma, meaning they limit their activity because of breathing symptoms and use reliever medications multiple times a week.

But research suggests that correcting inhaling technique and sticking to the use of the medications can cut that 17% down to just 3.7%, said Mr. Blome’s allergist, Giselle Mosnaim, MD, of NorthShore University HealthSystem in Glenview, Ill. Dr. Mosnaim spoke about digital monitoring at a conference session on digital technologies for asthma management.

A study of more than 5,000 asthma patients “showed that, if you have critical errors in inhaler technique, this leads to worse asthma outcomes and increased asthma exacerbations,” she said. It also shows that, despite new devices and new technologies, “we still have poor inhaler technique.”

Yet adherence is poorly gauged by doctors and patient self-reporting. “The ideal measure of adherence should be objective, accurate, and unobtrusive to minimize impact on patient behavior and allow reliable data collection in real-world settings,” Dr. Mosnaim said. “So electronic medication monitors are the gold standard.”
 

Improving use

Patients not following instructions or guidelines “is something we saw nonstop with kids,” said Caroline Moassessi, founder of the allergy and asthma blog Gratefulfoodie.com who formerly served on a regional board of the American Lung Association. She’s also the mother of two asthmatic children, now in college, who years ago used electronic medication monitors as part of a research trial.

They were “unimpressed – mostly since I think they thought their asthma was controlled,” she said. “When patients are not in crisis, they don’t manage their asthma well.”

Even in research studies such as the one Rachelle Ramsey, PhD, presented at the conference, it’s not only hard to determine if better adherence leads to improved health, but when.

“For example, does your adherence this week impact your asthma control this week, or does it impact your asthma control next week? Or is it even further out? Do you need to have some level of adherence over the course of a month in order to have better outcomes at the end of that month?” said Dr. Ramsey, a pediatric research psychologist at Cincinnati Children’s Hospital Medical Center. “I think it’s a little complicated.”

That said, results from several small studies do show a connection between remote monitoring and better clinical outcomes. One study enrolled asthma patients in the United Kingdom, and another was done by Dr. Mosnaim with Chicago-area patients.

In the U.K. quality improvement project, nurses asked patients with difficult-to-control asthma if they knew how to use their inhalers and were following treatment guidelines.

Those who said “yes” were invited to swap their steroid/inhalers for a controller fitted with a device that tracks use and measures acoustics to test inhaler technique. After 28 days of monitoring, many people in the study had better clinical outcomes.

And after 3 months of digital monitoring, patients didn’t use their rescue medication quite as often.

Mr. Blome has seen a marked improvement in his asthma since starting regular appointments and getting back on daily medications a year and a half ago. He says that now and then, he has wheezing and shortness of breath, usually while biking or exercising. But those symptoms aren’t as severe or frequent as before.

From a doctor’s perspective, “digital inhaler systems allow me to discern patterns in order to determine what triggers his asthma symptoms and to adjust medications at different times of the year,” Dr. Mosnaim said.

Electronic systems can monitor pollen counts and air quality as well as how often a patient uses a quick reliever medication. Thus, she said, tracking these measures year-round could raise attention to impending asthma attacks and suggest when to increase the dose of controller medications or add other treatments.

A version of this article first appeared on WebMD.com.

Using adjunctive reflectance confocal microscopy (RCM) for examining suspect skin lesions reduced the number of unnecessary skin excisions by 43%, results from a large randomized clinical trial showed.

“Skin cancer management exerts a sizable burden on health systems,” researchers led by Giovanni Pellacani, MD, wrote in an article published in JAMA Dermatology. “The systematic application of RCM in the triage of high-risk patients should improve diagnostic accuracy and reduce unnecessary excisions for histopathological diagnostic confirmation, thereby reducing costs, surgical waiting lists, and delayed diagnoses.”

However, they added, “the clinical application of RCM has mainly been limited to retrospective and prospective observational studies producing hypothetical estimates of clinical applicability without intention to affect clinical and therapeutic patient pathways.”

For the current study, Dr. Pellacani, who chairs the department of dermatology at Sapienza University, Rome, and colleagues hypothesized that RCM would reduce unnecessary excisions by more than 30% and would identify all melanoma lesions 0.5 mm or thinner at baseline. They enrolled 3,165 patients with suspect lesions from three dermatology referral centers between January 2017 and December 2019, with a mean follow-up of 9.6 months in the study. Participants were randomly assigned 1:1 to standard therapeutic care, which consisted of clinical and dermoscopy evaluation with or without adjunctive RCM, a novel noninvasive technology that provides in vivo imaging of the skin, with a high diagnostic accuracy.

Histopathologic examination of all excised lesions was performed at the pathology department of the referral center. Resulting information guided prospective clinical decision-making (excision or follow-up). The mean age of patients was 49 years, 49% were women, 21% had a personal history of melanoma, and 51% had Fitzpatrick phototype 2 skin.

When compared with standard therapeutic care only, adjunctive RCM was associated with a higher positive predictive value (18.9 vs. 33.3, respectively), lower benign to malignant ratio (3.7:1.0 vs. 1.8:1.0), and a reduction in the number needed to excise of 43.4% (5.3 vs. 3.0). In addition, all 15 lesions with delayed melanoma diagnoses were thinner than 0.5 mm. Of these, eight were diagnosed as melanoma in situ.

Christine Ko, MD, professor of dermatology and pathology at Yale University, New Haven, Conn., who was asked to comment on the study, said that a strength of the analysis was its follow-up and histopathologic evaluation, “which are both essentially forms of feedback. Good, relevant feedback is necessary for all of us to improve.”

She pointed out that, while RCM does appear to reduce the number of benign lesions unnecessarily removed and increase the number of skin cancers appropriately excised, the authors acknowledged that they had at least 4 years of experience with RCM. “The study also does not address the time factor (the procedure takes about 7 minutes per lesion) and the financial cost of reflectance confocal microscopy, as compared to the cost of standard follow-up alone with an increased number of excisions.”

She added that the findings “are not yet applicable to general dermatology across the world, as the authors comment, given that reflectance confocal microscopy is not yet widely available.”

The Italian Ministry of Health supported the study. Neither the researchers nor Dr. Ko reported having relevant financial conflicts.

Using adjunctive reflectance confocal microscopy (RCM) for examining suspect skin lesions reduced the number of unnecessary skin excisions by 43%, results from a large randomized clinical trial showed.

“Skin cancer management exerts a sizable burden on health systems,” researchers led by Giovanni Pellacani, MD, wrote in an article published in JAMA Dermatology. “The systematic application of RCM in the triage of high-risk patients should improve diagnostic accuracy and reduce unnecessary excisions for histopathological diagnostic confirmation, thereby reducing costs, surgical waiting lists, and delayed diagnoses.”

However, they added, “the clinical application of RCM has mainly been limited to retrospective and prospective observational studies producing hypothetical estimates of clinical applicability without intention to affect clinical and therapeutic patient pathways.”

For the current study, Dr. Pellacani, who chairs the department of dermatology at Sapienza University, Rome, and colleagues hypothesized that RCM would reduce unnecessary excisions by more than 30% and would identify all melanoma lesions 0.5 mm or thinner at baseline. They enrolled 3,165 patients with suspect lesions from three dermatology referral centers between January 2017 and December 2019, with a mean follow-up of 9.6 months in the study. Participants were randomly assigned 1:1 to standard therapeutic care, which consisted of clinical and dermoscopy evaluation with or without adjunctive RCM, a novel noninvasive technology that provides in vivo imaging of the skin, with a high diagnostic accuracy.

Histopathologic examination of all excised lesions was performed at the pathology department of the referral center. Resulting information guided prospective clinical decision-making (excision or follow-up). The mean age of patients was 49 years, 49% were women, 21% had a personal history of melanoma, and 51% had Fitzpatrick phototype 2 skin.

When compared with standard therapeutic care only, adjunctive RCM was associated with a higher positive predictive value (18.9 vs. 33.3, respectively), lower benign to malignant ratio (3.7:1.0 vs. 1.8:1.0), and a reduction in the number needed to excise of 43.4% (5.3 vs. 3.0). In addition, all 15 lesions with delayed melanoma diagnoses were thinner than 0.5 mm. Of these, eight were diagnosed as melanoma in situ.

Christine Ko, MD, professor of dermatology and pathology at Yale University, New Haven, Conn., who was asked to comment on the study, said that a strength of the analysis was its follow-up and histopathologic evaluation, “which are both essentially forms of feedback. Good, relevant feedback is necessary for all of us to improve.”

She pointed out that, while RCM does appear to reduce the number of benign lesions unnecessarily removed and increase the number of skin cancers appropriately excised, the authors acknowledged that they had at least 4 years of experience with RCM. “The study also does not address the time factor (the procedure takes about 7 minutes per lesion) and the financial cost of reflectance confocal microscopy, as compared to the cost of standard follow-up alone with an increased number of excisions.”

She added that the findings “are not yet applicable to general dermatology across the world, as the authors comment, given that reflectance confocal microscopy is not yet widely available.”

The Italian Ministry of Health supported the study. Neither the researchers nor Dr. Ko reported having relevant financial conflicts.

Using adjunctive reflectance confocal microscopy (RCM) for examining suspect skin lesions reduced the number of unnecessary skin excisions by 43%, results from a large randomized clinical trial showed.

“Skin cancer management exerts a sizable burden on health systems,” researchers led by Giovanni Pellacani, MD, wrote in an article published in JAMA Dermatology. “The systematic application of RCM in the triage of high-risk patients should improve diagnostic accuracy and reduce unnecessary excisions for histopathological diagnostic confirmation, thereby reducing costs, surgical waiting lists, and delayed diagnoses.”

However, they added, “the clinical application of RCM has mainly been limited to retrospective and prospective observational studies producing hypothetical estimates of clinical applicability without intention to affect clinical and therapeutic patient pathways.”

For the current study, Dr. Pellacani, who chairs the department of dermatology at Sapienza University, Rome, and colleagues hypothesized that RCM would reduce unnecessary excisions by more than 30% and would identify all melanoma lesions 0.5 mm or thinner at baseline. They enrolled 3,165 patients with suspect lesions from three dermatology referral centers between January 2017 and December 2019, with a mean follow-up of 9.6 months in the study. Participants were randomly assigned 1:1 to standard therapeutic care, which consisted of clinical and dermoscopy evaluation with or without adjunctive RCM, a novel noninvasive technology that provides in vivo imaging of the skin, with a high diagnostic accuracy.

Histopathologic examination of all excised lesions was performed at the pathology department of the referral center. Resulting information guided prospective clinical decision-making (excision or follow-up). The mean age of patients was 49 years, 49% were women, 21% had a personal history of melanoma, and 51% had Fitzpatrick phototype 2 skin.

When compared with standard therapeutic care only, adjunctive RCM was associated with a higher positive predictive value (18.9 vs. 33.3, respectively), lower benign to malignant ratio (3.7:1.0 vs. 1.8:1.0), and a reduction in the number needed to excise of 43.4% (5.3 vs. 3.0). In addition, all 15 lesions with delayed melanoma diagnoses were thinner than 0.5 mm. Of these, eight were diagnosed as melanoma in situ.

Christine Ko, MD, professor of dermatology and pathology at Yale University, New Haven, Conn., who was asked to comment on the study, said that a strength of the analysis was its follow-up and histopathologic evaluation, “which are both essentially forms of feedback. Good, relevant feedback is necessary for all of us to improve.”

She pointed out that, while RCM does appear to reduce the number of benign lesions unnecessarily removed and increase the number of skin cancers appropriately excised, the authors acknowledged that they had at least 4 years of experience with RCM. “The study also does not address the time factor (the procedure takes about 7 minutes per lesion) and the financial cost of reflectance confocal microscopy, as compared to the cost of standard follow-up alone with an increased number of excisions.”

She added that the findings “are not yet applicable to general dermatology across the world, as the authors comment, given that reflectance confocal microscopy is not yet widely available.”

The Italian Ministry of Health supported the study. Neither the researchers nor Dr. Ko reported having relevant financial conflicts.