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B Introduction: b PTCLs are aggressive hematologic malignancies often with poor prognoses; there is no standard of care therapy for patients with I R i / I R i PTCL. B Conclusion: b AFM13 monotherapy demonstrated robust clinical activity in heavily pretreated patients with I R i / I R i PTCL. [Extracted from the article]

Background: Patients with relapsed or refractory (R/R) peripheral T-cell lymphoma (PTCL) generally have poor prognoses and limited treatment options., Materials & Methods: This study evaluated the efficacy of a novel CD30/CD16A bispecific innate cell engager, acimtamig (AFM13), in patients with R/R PTCL. Patients included those with CD30 expression in ≥1% of tumor cells and who were R/R following ≥1 prior line of systemic therapy. Acimtamig (200 mg) was administered once weekly in 8-week cycles. The primary endpoint was overall response rate (ORR) by fluorodeoxyglucose-positron emission tomography per independent review committee; secondary and exploratory endpoints included duration of response (DoR), safety, progression-free survival, and overall survival., Results: The ORR in 108 patients was 32.4% (95% CI: 23.7, 42.1) with a complete response rate of 10.2% (95% CI: 5.2, 17.5); median DoR was 2.3 months (95% CI: 1.9, 6.5). Patients with R/R angioimmunoblastic T-cell lymphoma exhibited the greatest number of responses (53.3% [95% CI: 34.3, 71.7]). Responses were independent of CD30 expression level, prior brentuximab vedotin treatment, or steroid premedication. Acimtamig exhibited a tolerable safety profile; the most common treatment-related adverse events were infusion-related reactions in 27 patients (25.0%) and neutropenia in 11 patients (10.2%). No cases of cytokine release syndrome or acimtamig-related deaths were reported. Despite exhibiting promising clinical activity and tolerable safety in a heavily pretreated PTCL population, the study did not meet the criteria for the primary endpoint., Conclusions: The promising clinical efficacy observed warrants further investigation, and development of acimtamig for patients with R/R CD30+ lymphomas continues in combination with allogeneic natural killer cells.

Parkinson's disease (PD) is a progressive, neurodegenerative disorder of the central nervous system. While it primarily affects motor function, patients eventually develop non-motor symptoms including depression, anxiety, and eventually dementia. Although there is currently no cure, treatment is aimed largely at improving quality of life though medication or surgical techniques to reduce motor symptoms. However, there is vast evidence of the benefits of physical activity as adjunct therapy for Parkinson's disease. In this review, we analyze 31 studies or reviews and highlight the role of exercise and rehabilitation in PD treatment. This study serves to provide clinicians with a comprehensive resource of the wide variety of exercises with proven benefit for patients affected by Parkinson's disease. Specifically, patients report significant improvements in motor function, cognition, mood and sleep habits.

Background: In the intent-to-treat (ITT) population of the RAINBOW study, objective response rate (ORR) was 28% and 16% in the ramucirumab and control arms, respectively. To further characterize tumor response, we present details on timing and extent of tumor shrinkage, as well as associations with symptom palliation., Materials and Methods: Tumor response was assessed with RECIST v1.1, and quality of life (QoL) was assessed with the European Organization for Research and Treatment of Cancer Quality-of-Life Questionnaire-Core 30 (EORTC QLQ-C30) v3.0. Prespecified and post hoc analyses were conducted in the ITT population, patients with measurable disease, or responders, and included best overall response (BOR), ORR, disease control rate (DCR), duration of response, time to response (TtR), change in tumor size, and associations of QoL with tumor shrinkage and BOR., Results: In both treatment arms, median TtR was 1.5 months. Responses were more durable in the ramucirumab versus control arm (median 4.4 vs. 2.8 months). In patients with measurable disease (78% of ITT), ORR was 36% versus 20%; DCR was 81% versus 61% in the ramucirumab versus control arms. Waterfall plots demonstrated more tumor shrinkage in the ramucirumab versus control arm. Regardless of treatment, tumor response and stable disease were associated with improved or stable QoL, with more tumor shrinkage associated with greater symptom palliation., Conclusion: Treatment with ramucirumab plus paclitaxel yielded the highest ORR reported to date for patients with previously treated advanced gastric or gastroesophageal junction adenocarcinoma. Additional details demonstrate robustness of tumor response results. The extent of tumor shrinkage is directly associated with symptom palliation and should be considered when evaluating patient needs and treatment selection. Clinical trial identification number. NCT01170663., Implications for Practice: Ramucirumab plus paclitaxel is a recognized standard of care as it improves survival for patients with advanced gastric or gastroesophageal junction adenocarcinoma who have been previously treated with recommended first-line therapy. These additional data on tumor response demonstrate a positive association between tumor shrinkage and symptom palliation in a patient population that is often symptomatic. These observations included patients with nonmeasurable disease, a group of patients often underrepresented in clinical trials. This knowledge can inform treatment decisions, which align individual patient characteristics and needs with demonstrated benefits., (© 2020 AlphaMed Press.)

Background: Panic disorder (PD), frequently occurring with agoraphobia (AG), and depression are common mental disorders in primary care and associated with considerable individual and societal costs. Early detection and effective treatment of depression and PD/AG are of major importance. Cognitive behavioural exposure exercises have been shown to be effective in reducing anxiety and depressive symptoms. Practice team-based case management can improve clinical outcomes for patients with chronic diseases in primary care. The present study aims at evaluating the effects and cost-effectiveness of a primary care team-based intervention using behavioural therapy elements and case management supported by eHealth components in patients with PD/AG or depression compared to treatment as usual., Methods/design: This is a two-arm cluster-randomized, controlled trial (cRCT). General practices represent the units of randomisation. General practitioners recruit adult patients with depression and PD ± AG according to the International Classification of Diseases, version 10 (ICD-10). In the intervention group, patients receive cognitive behaviour therapy-oriented psychoeducation and instructions to self-managed exposure exercises in four manual-based appointments with the general practitioner. A trained health care assistant from the practice team delivers case management and is continuously monitoring symptoms and treatment progress in ten protocol-based telephone contacts with patients. Practice teams and patients are supported by eHealth components. In the control group, patients receive usual care from general practitioners. Outcomes are measured at baseline (T0), at follow-up after 6 months (T1), and at follow-up after 12 months (T2). The primary outcome is the mental health status of patients as measured by the Mental Health Index (MHI-5). Effect sizes of 0.2 standard deviation (SD) are regarded as relevant. Assuming a drop-out rate of 20% of practices and patients each, we aim at recruiting 1844 patients in 148 primary care practices. This corresponds to 12.5 patients on average per primary care practice. Secondary outcomes include depression and anxiety-related clinical parameters and health-economic costs., Discussion: If the intervention is more effective than treatment as usual, the three-component (cognitive behaviour therapy, case-management, eHealth) primary care-based intervention for patients suffering from PD/AG or depression could be a valuable low-threshold option that benefits patients and primary care practice teams., Trial Registration: German clinical trials register, DRKS00016622. Registered on February 22nd, 2019.

Background and Aim: REGARD and RAINBOW were global, phase 3, randomized, double-blind trials of second-line ramucirumab for metastatic gastric or gastroesophageal junction adenocarcinoma. Exploratory subgroup analyses were described to assess the efficacy and safety of ramucirumab in REGARD and RAINBOW in young (≤ 45 and < 65 years) and elderly (≥ 65, ≥ 70, and ≥ 75 years) patients., Methods: Patients were randomized 2:1 to receive ramucirumab plus best supportive care or placebo plus best supportive care (REGARD) or 1:1 to ramucirumab plus paclitaxel or placebo plus paclitaxel (RAINBOW). Subpopulation Treatment Effect Pattern Plots assessed efficacy and adverse events by age groups for ramucirumab versus placebo., Results: The hazard ratios (HRs) for overall survival favored treatment with ramucirumab: REGARD ≤ 45 years (HR: 0.59, 95% confidence interval: 0.27-1.26), < 65 years (0.80, 0.59-1.10), ≥ 65 years (0.72, 0.48-1.08), ≥ 70 years (0.73, 0.44-1.23), and ≥ 75 years (0.59, 0.25-1.37); and RAINBOW ≤ 45 years (0.56, 0.33-0.93), < 65 years (0.78, 0.63-0.97), ≥ 65 years (0.88, 0.66-1.18), and ≥ 70 years (0.88, 0.60-1.28). The exception was elderly patients aged ≥ 75 years in RAINBOW (0.97, 0.47-2.01); however, patient numbers were low in this subgroup (n = 36). Similar findings were observed for progression-free survival, for which HRs numerically favored ramucirumab-treated patients. Adverse events (including grade ≥ 3) were not associated with age., Conclusions: In comparison with placebo, ramucirumab conferred improvements in efficacy across age groups with a tolerable safety profile. Despite some limitations, these exploratory analyses support the use of ramucirumab in advanced gastric cancer, irrespective of age., (© 2017 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)

Purpose: To identify baseline prognostic factors for survival in patients with disease progression, during or after chemotherapy for the treatment of advanced gastric or gastroesophageal junction (GEJ) cancer., Materials and Methods: We pooled data from patients randomized between 2009 and 2012 in 2 phase III, global double-blind studies of ramucirumab for the treatment of advanced gastric or GEJ adenocarcinoma following disease progression on first-line platinum- and/or fluoropyrimidine-containing therapy (REGARD and RAINBOW). Forty-one key baseline clinical and laboratory factors common in both studies were examined. Model building started with covariate screening using univariate Cox models (significance level=0.05). A stepwise multivariable Cox model identified the final prognostic factors (entry+exit significance level=0.01). Cox models were stratified by treatment and geographic region. The process was repeated to identify baseline prognostic quality of life (QoL) parameters., Results: Of 1,020 randomized patients, 953 (93%) patients without any missing covariates were included in the analysis. We identified 12 independent prognostic factors of poor survival: 1) peritoneal metastases; 2) Eastern Cooperative Oncology Group (ECOG) performance score 1; 3) the presence of a primary tumor; 4) time to progression since prior therapy <6 months; 5) poor/unknown tumor differentiation; abnormally low blood levels of 6) albumin, 7) sodium, and/or 8) lymphocytes; and abnormally high blood levels of 9) neutrophils, 10) aspartate aminotransferase (AST), 11) alkaline phosphatase (ALP), and/or 12) lactate dehydrogenase (LDH). Factors were used to devise a 4-tier prognostic index (median overall survival [OS] by risk [months]: high=3.4, moderate=6.4, medium=9.9, and low=14.5; Harrell's C-index=0.66; 95% confidence interval [CI], 0.64-0.68). Addition of QoL to the model identified patient-reported appetite loss as an independent prognostic factor., Conclusions: The identified prognostic factors and the reported prognostic index may help clinical decision-making, patient stratification, and planning of future clinical studies., Competing Interests: Conflict of Interest: Drs. Emig, Ferry, Chandrawansa, Hsu, Sashegyi, and Liepa are full-time employees and stockholders of Eli Lilly and Company. Dr. Ferry additionally received honoraria from Eli Lilly and Company, Sanofi, and Roche; he also held an advisory role for Eli Lilly and Company, Sanofi, and Roche; he received research funding from Eli Lilly and Company and Sanofi; he gave expert testimony for Eli Lilly and Company; he received travel support from Sanofi and Roche. Dr. Fuchs served as a consultant for Eli Lilly and Company, Pfizer, Entrinsic Health, Genentech, Merck, Gilead Sciences, Macrogenics, Sanofi, Dicerna, Frive Prime Therapeutics, Bristol Myers Squibb, Bayer, Merrimack, and Celgene. Dr. Muro received honoraria from Takeda, Chugai Pharma, Yakult Honsha, Merck Serono, and Taiho Pharmaceutical. Dr. Tomasek received honoraria from Roche, Bayer, Merck, Amgen, and Eli Lilly and Company; he served in an advisory role for Ipsen, Amgen, and Roche; he received research funding from Amgen, Novartis, and Eli Lilly and Company; and he received travel support from Pfizer, Eli Lily and Company, Novartis, and Roche. Dr. Van Cutsem received research support from Amgen, Bayer, Boehringer Ingelheim, Eli Lilly and Company, Merck Serono, Novartis, Roche, Sanofi, Celgene, and Ipsen. Dr. Chau would like to acknowledge United Kingdom National Health Service funding to the National Institute for Health Research Biomedical Research Centre at the Royal Marsden NHS Foundation Trust and The Institute of Cancer Research. Dr. Shimada received research funding from Eli Lilly and Company, Taiho Pharmaceutical, and Chugai Pharma. Dr. Al-Batran received honoraria and served as an advisor for Eli Lilly and Company. Dr. Passalacqua received honoraria from Eli Lilly and Company, Roche, and Novartis; he served as an advisor for Eli Lilly and Company; he is on the Speakers' bureau for Astellas Pharma; and he receives research funding from Amgen. Dr. Ohtsu is related to an employee of Celgene and he receives research funding from Bristol-Myers Squibb. Dr. Wilke received honoraria from Eli Lilly and Company and served as an advisor for Eli Lilly and Company.

Background: Angiogenesis inhibition is an important strategy for cancer treatment. Ramucirumab, a human IgG1 monoclonal antibody that targets VEGF receptor 2 (VEGFR2), inhibits VEGF-A, -C, -D binding and endothelial cell proliferation. To attempt to identify prognostic and predictive biomarkers, retrospective analyses were used to assess tumour (HER2, VEGFR2) and serum (VEGF-C and -D, and soluble (s) VEGFR1 and 3) biomarkers in phase 3 REGARD patients with metastatic gastric/gastroesophageal junction carcinoma., Methods: A total of 152 out of 355 (43%) patients randomised to ramucirumab or placebo had ⩾1 evaluable biomarker result using VEGFR2 immunohistochemistry or HER2, immunohistochemistry or FISH, of blinded baseline tumour tissue samples. Serum samples (32 patients, 9%) were assayed for VEGF-C and -D, and sVEGFR1 and 3., Results: None of the biomarkers tested were associated with ramucirumab efficacy at a level of statistical significance. High VEGFR2 endothelial expression was associated with a non-significant prognostic trend toward shorter progression-free survival (high vs low HR=1.65, 95% CI=0.84,3.23). Treatment with ramucirumab was associated with a trend toward improved survival in both high (HR=0.69, 95% CI=0.38, 1.22) and low (HR=0.73, 95% CI=0.42, 1.26) VEGFR2 subgroups. The benefit associated with ramucirumab did not appear to differ by tumoural HER2 expression., Conclusions: REGARD exploratory analyses did not identify a strong potentially predictive biomarker of ramucirumab efficacy; however, statistical power was limited., Competing Interests: IC, BM, MAT, JT report speaker honoraria from Lilly and non-Lilly pharmaceutical companies. JAA, IC report a commercial research grant. IC, CSF, JTa, MAT, JTo report serving on the Advisory Board for Eli Lilly and/or other companies. CWC, ME, DF, RRH, SAM are employees of Eli Lilly and Company. The remaining authors declare no conflict of interest.

Background: We evaluated the safety and efficacy of ramucirumab plus paclitaxel versus placebo plus paclitaxel in patients previously treated for advanced gastric or gastroesophageal junction adenocarcinoma in Japanese and Western subgroups from the RAINBOW trial., Methods: Patients received ramucirumab at 8 mg/kg or placebo (days 1 and 15) plus paclitaxel at 80 mg/m(2) (days 1, 8, and 15 of a 28-day cycle). End points were compared between treatment arms within Japanese (N = 140) and Western (N = 398) populations., Results: The incidence of adverse events of grade 3 or higher was higher for ramucirumab plus paclitaxel in both populations (Japanese population, 83.8 % vs 52.1 %; Western population, 79.1 % vs 61.9 %). Neutropenia was the commonest adverse event of grade 3 or higher, with a higher incidence for ramucirumab plus paclitaxel (Japanese population, 66.2 % vs 25.4 %; Western population, 32.1 % vs 14.7 %). The incidence of febrile neutropenia was low and was similar between treatment arms in both populations. The overall survival hazard ratio was 0.88 (95 % confidence interval, 0.60-1.28) in the Japanese population and 0.73 (95 % confidence interval, 0.58-0.91) in the Western population. The progression-free survival hazard ratio was 0.50 (95 % confidence interval, 0.35-0.73) in the Japanese population and 0.63 (95 % confidence interval, 0.51-0.79) in the Western population. The objective response rate was higher for ramucirumab plus paclitaxel in both populations (Japanese population, 41.2 % vs 19.4 %; Western population, 26.8 % vs 13.0 %), as was the 6-month survival rate (Japanese population, 94.1 % vs 71.4 %; Western population, 66.0 % vs 49.0 %)., Conclusions: Safety profiles of the ramucirumab plus paclitaxel arm were similar between populations, though there was a higher incidence of neutropenia in Japanese patients. Progression-free survival and objective response rate improvements were observed for ramucirumab plus paclitaxel in both populations. CLINICALTRIALS., Gov Identifier: NCT01170663.

Background: VEGFR-2 has a role in gastric cancer pathogenesis and progression. We assessed whether ramucirumab, a monoclonal antibody VEGFR-2 antagonist, in combination with paclitaxel would increase overall survival in patients previously treated for advanced gastric cancer compared with placebo plus paclitaxel., Methods: This randomised, placebo-controlled, double-blind, phase 3 trial was done at 170 centres in 27 countries in North and South America, Europe, Asia, and Australia. Patients aged 18 years or older with advanced gastric or gastro-oesophageal junction adenocarcinoma and disease progression on or within 4 months after first-line chemotherapy (platinum plus fluoropyrimidine with or without an anthracycline) were randomly assigned with a centralised interactive voice or web-response system in a 1:1 ratio to receive ramucirumab 8 mg/kg or placebo intravenously on days 1 and 15, plus paclitaxel 80 mg/m(2) intravenously on days 1, 8, and 15 of a 28-day cycle. A permuted block randomisation, stratified by geographic region, time to progression on first-line therapy, and disease measurability, was used. The primary endpoint was overall survival. Efficacy analysis was by intention to treat, and safety analysis included all patients who received at least one treatment with study drug. This trial is registered with ClinicalTrials.gov, number NCT01170663, and has been completed; patients who are still receiving treatment are in the extension phase., Findings: Between Dec 23, 2010, and Sept 23, 2012, 665 patients were randomly assigned to treatment-330 to ramucirumab plus paclitaxel and 335 to placebo plus paclitaxel. Overall survival was significantly longer in the ramucirumab plus paclitaxel group than in the placebo plus paclitaxel group (median 9·6 months [95% CI 8·5-10·8] vs 7·4 months [95% CI 6·3-8·4], hazard ratio 0·807 [95% CI 0·678-0·962]; p=0·017). Grade 3 or higher adverse events that occurred in more than 5% of patients in the ramucirumab plus paclitaxel group versus placebo plus paclitaxel included neutropenia (133 [41%] of 327 vs 62 [19%] of 329), leucopenia (57 [17%] vs 22 [7%]), hypertension (46 [14%] vs eight [2%]), fatigue (39 [12%] vs 18 [5%]), anaemia (30 [9%] vs 34 [10%]), and abdominal pain (20 [6%] vs 11 [3%]). The incidence of grade 3 or higher febrile neutropenia was low in both groups (ten [3%] vs eight [2%])., Interpretation: The combination of ramucirumab with paclitaxel significantly increases overall survival compared with placebo plus paclitaxel, and could be regarded as a new standard second-line treatment for patients with advanced gastric cancer., Funding: Eli Lilly and Company., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Heretofore, Campylobacter infections have been predominantly associated with gastrointestinal manifestations. Over the past two decades, an increasing number of case reports have suggested that the spectrum of disease is much broader. To date, only 10 cases of myocarditis/pericarditis in patients with C. fetus have been reported in the English literature out of which at least 4 patients have died. We describe here a further case to include as we review the literature.

Background: Use of cetuximab, a monoclonal antibody targeting the epidermal growth factor receptor (EGFR), has the potential to increase survival in patients with advanced non-small-cell lung cancer. We therefore compared chemotherapy plus cetuximab with chemotherapy alone in patients with advanced EGFR-positive non-small-cell lung cancer., Methods: In a multinational, multicentre, open-label, phase III trial, chemotherapy-naive patients (>or=18 years) with advanced EGFR-expressing histologically or cytologically proven stage wet IIIB or stage IV non-small-cell lung cancer were randomly assigned in a 1:1 ratio to chemotherapy plus cetuximab or just chemotherapy. Chemotherapy was cisplatin 80 mg/m(2) intravenous infusion on day 1, and vinorelbine 25 mg/m(2) intravenous infusion on days 1 and 8 of every 3-week cycle) for up to six cycles. Cetuximab-at a starting dose of 400 mg/m(2) intravenous infusion over 2 h on day 1, and from day 8 onwards at 250 mg/m(2) over 1 h per week-was continued after the end of chemotherapy until disease progression or unacceptable toxicity had occurred. The primary endpoint was overall survival. Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00148798., Findings: Between October, 2004, and January, 2006, 1125 patients were randomly assigned to chemotherapy plus cetuximab (n=557) or chemotherapy alone (n=568). Patients given chemotherapy plus cetuximab survived longer than those in the chemotherapy-alone group (median 11.3 months vs 10.1 months; hazard ratio for death 0.871 [95% CI 0.762-0.996]; p=0.044). The main cetuximab-related adverse event was acne-like rash (57 [10%] of 548, grade 3)., Interpretation: Addition of cetuximab to platinum-based chemotherapy represents a new treatment option for patients with advanced non-small-cell lung cancer., Funding: Merck KGaA.