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The efficacy of PD-1 monoclonals such as pembrolizumab can be modulated by the signals delivered via their Fc region. Tumour/inflammation associated proteases can generate F(ab')2 fragments of therapeutic monoclonals, and subsequent recognition of F(ab')2 epitopes by circulating anti-hinge antibodies (AHA) can then, potentially, link F(ab')2 binding to the target antigen with novel Fc signalling. Although elevated in inflammatory diseases, AHA levels in cancer patients have not been investigated and functional studies utilising the full repertoire of AHA present in sera have been limited. AHA levels in pembrolizumab treated melanoma patients (n = 23) were therefore compared to those of normal donors and adalimumab treated patients. A subset of melanoma patients and the majority of adalimumab patients had elevated levels of AHA reactive with F(ab')2 fragments of IgG4 anti-PD-1 monoclonals (nivolumab, pembrolizumab) and IgG1 therapeutic monoclonals (rituximab, adalimumab). Survival analysis was restricted by the small patient numbers but those melanoma patients with the highest levels (>75% percentile, n = 5) of pembrolizumab-F(ab')2 reactive AHA had significantly better overall survival post pembrolizumab treatment (p = 0.039). In vitro functional studies demonstrated that the presence of AHA+ sera restored the neutrophil activating capacity of pembrolizumab to its F(ab')2 fragment. Neither pembrolizumab nor its F(ab')2 fragments can induce NK cell or complement dependent cytotoxicity (CDC). However, AHA+ sera in combination with pembrolizumab-F(ab')2 provided Fc regions that could activate NK cells. The ability of AHA+ sera to restore CDC activity was more restricted and observed using only one pembrolizumab and one adalimumab patient serum in combination with rituximab- F(ab')2. This study reports the presence of elevated AHA levels in pembrolizumab treated melanoma patients and highlight the potential for AHA to provide additional Fc signaling. The issue of whether tumour associated proteolysis of PD-1 mAbs and subsequent AHA recognition impacts on treatment efficacy requires further study. [ABSTRACT FROM AUTHOR]

Purpose: Kaposi's sarcoma (KS) is a spindle cell tumor resulting from growth dysregulation in the setting of infection with human herpes virus-8 (also called KS herpes virus). Advanced KS is characterized by poor responses to antiretroviral therapy and some of the chemotherapy readily accessible to patients in low-resource areas. Gemcitabine induced partial and complete regression of AIDS-associated KS (AIDS-KS) in 11 of 24 patients in a pilot study. The current study compares the antimetabolite gemcitabine with the standard care bleomycin and vincristine (BV) in the treatment of chemotherapy-naïve patients with AIDS-KS in a resource-limited setting. Patients and Methods: Patients with persistent or progressive KS despite treatment with combined antiretroviral therapy were randomly assigned to receive gemcitabine 1,000 mg/m2 or bleomycin 15 IU/ m2 and vincristine 1.4 mg/m2 given twice weekly. The main end point was objective response by bidirectional measurement, adverse events, and quality of life after three cycles of chemotherapy. Results: Of 70 participants enrolled, 36 received gemcitabine and 34 received BV. Complete response was achieved in 12 patients (33.3%) in the gemcitabine arm and six (17.6%) in the BV arm (P =.175). The partial response rate was 52.8% (n = 19) in the gemcitabine arm and 58.8% (n = 20) in the BV arm. Both study arms reported similar neurologic and hematologic adverse events; there was statistically significant baseline to post-treatment improvement in health-related quality-of-life scores. Conclusion: The results of this randomized, phase IIA trial demonstrate gemcitabine activity in chemotherapy-naïve patients with AIDS-KS, on the basis of response rates, adverse events, and health-related quality-of-life scores. [ABSTRACT FROM AUTHOR]

Ovarian cancer is a leading cause of cancer death for Kenyan women. Most women are diagnosed with an advanced stage of disease. The current North American standard of care includes surgery followed by carboplatin and paclitaxel. Neither drug is available for Kenyan women. We performed a literature search investigating chemotherapy in low-resource countries with the aim to write an evidence-based chemotherapy protocol for women diagnosed with ovarian cancer in Eldoret, Kenya, at the Moi Teaching and Referral Hospital.We systematically searched PubMed and EMBASE for articles describing chemotherapy treatment outcomes of ovarian epithelial cancer in low-resource settings. After data analysis, a secondary review was undertaken on randomized controlled trials (RCTs) aligning with chemotherapy availability in Kenya.We identified 1184 articles. Fourteen met our criteria: ovarian epithelial cancer, low resource, chemotherapy use, and survival or response data. No publications were RCTs or had a cohort larger than 100 patients. There was no consistency in drug choice between studies. After this search, we reviewed commonly quoted and relevant RCTs and meta-analyses conducted on ovarian cancer since the 1980s. Although RCTs in the developed world suggest carboplatin and taxol provide optimal survival benefit, these drugs are unavailable in Kenya. Cyclophosphamide and cisplatin provide the next most optimal survival benefit, with acceptable and manageable toxicity. Because these drugs are more available and affordable in Kenya, we have developed a protocol recommending their use, which has been accepted by the Moi Teaching and Referral Hospital.Currently, there is a paucity of published RCTs that may guide treatment in low-resource settings. One considerable barrier to establishing and evaluating chemotherapy protocols in low-resource settings may be the cost of chemotherapy drugs. There needs to be an international movement to make cancer chemotherapeutics available at lower prices in low-resource settings. [ABSTRACT FROM AUTHOR]

Background: Identifying methods to accurately measure the glomerular filtration rate (GFR) in obese individuals without kidney overt kidney disease is necessary to understanding the pathophysiology and natural history of obesity-related kidney disease. Methods: Using a cross-sectional design, iohexol clearance and disposition was measured, an optimal sampling schedule was identified, and the reliability of GFR-estimating methods was described in 29 obese individuals with normal serum creatinine levels. Iohexol disposition was measured using population pharmacokinetics. The agreement with GFR-estimating equations was assessed by intraclass coefficients. Results: Mean age was 44 ± 10 years, body mass index 45 ± 10, creatinine 0.7 ± 0.2 mg/dl (62 ± 18 μmol/l) , and cystatin C 0.83 ± 0.18 mg/dl (8.3 ± 1.8 mg/l). Iohexol disposition fit a two-compartment model and 5 sampling windows were identified over a 4-hour period to optimize model accuracy and minimize blood draws. Precision was not compromised with this sampling design. Neither creatinine nor cystatin C were linearly correlated with the measured GFR though cystatin C was independent of body composition. Agreement was fair to poor between the measured GFR and GFR-estimating equations. Conclusion: This study offers a rigorous method to study obesity-related kidney disease and improve upon suboptimal GFR-estimating methods. Copyright © 2010 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Advanced adenocarcinoma of the pancreas has a globally poor prognosis. One of the characteristic features of pancreatic cancer (PC) is pancreatic exocrine insufficiency (PEI). This leads to a malabsorption syndrome and subsequent digestive symptoms. Given the high prevalence of PEI and malabsorption in PC, empiric use of pancreatic enzyme replacement therapy (PERT) is recommended. The aim of this pilot study was to determine the potential efficacy of PERT in improving symptoms and quality of life in those with metastatic PC. The study recruited patients with advanced PC referred to a specialist palliative care service. Following an initial assessment, patients were commenced on pancrealipase 25,000IU (Creon) and reassessed after 1 week and 3 weeks post-initiation of supplementation. These assessments included demographics, malabsorption symptom checklist, and completion of two validated quality-of-life questionnaires, the European Organisation for Research and Treatment of Cancer QLQ-C30 and QLQ-PAN26. PERT was associated with statistically significant improvement of symptoms in both the general (QLQ-C30) and pancreatic cancer specific tool (PAN26). Within 1 week of PERT initiation, there was a reduction in diarrhoea scores (26 vs. 8, p <0.005), pancreatic and hepatic pain (47 vs. 33 and 24 vs. 11, respectively, p <0.05). After 3 weeks, there were significant improvements in pancreatic pain and bloating/gas symptoms (47 vs. 26 and 46 vs. 26, respectively, p < 0.005). PERT appears to have the potential to improve symptoms of malabsorption in patients with metastatic PC. [ABSTRACT FROM AUTHOR]

Obesity is associated with glomerular hyperfiltration and increased urinary protein excretion, as well as structural and functional changes that lead to kidney disease and failure. Dietary protein mimics obesity's effects on the glomerular filtration rate (GFR) and proteinuria and, in certain circumstances, may have the potential to adversely affect kidney function. Here we tested the hypothesis that dietary protein independently explains elevations in the GFR and proteinuria found in obese persons with a normal serum creatinine. Seventeen patients were randomized in a double-blind, crossover fashion for 1-week periods to high (140 g/day) and low (50 g/day) protein diets with a 1-week washout interval separating these periods. High protein consumption was associated with a very modest but significant increase in the GFR of 5±6 ml/min. Hence, while dietary protein does modulate kidney parameters, it is unlikely to fully account for the elevations in GFR and proteinuria found in obesity. [ABSTRACT FROM AUTHOR]

Purpose: To determine whether SD-101, a Toll-like receptor 9 agonist, potentiates the antitumor activity of anti-PD-1 antibodies in patients with anti-PD-1/PD-L1 naïve, recurrent/metastatic head and neck squamous cell carcinoma (HNSCC)., Patients and Methods: Patients with PD-1 Ab-naïve HNSCC received either 2 mg SD-101 injected in one to four lesions or 8 mg SD-101 injected into a single lesion weekly × 4 doses then every 3 weeks × 7 doses. Pembrolizumab was administered at 200 mg every 3 weeks., Results: A total of 28 patients received 2 mg and 23 received 8 mg per injection, respectively. A total of 76% of patients had received prior systemic therapy. Combined positive score was ≥1 to < 20 in 35 patients (70%) and ≥ 20 in 15 patients (30%) of 50 patients with available data. There were 12 patients with grade ≥3 treatment-related adverse events (24%), and no treatment-related deaths. The objective response rate was 24% including 2 complete and 10 partial responses. The median duration of response was 7.0 [95% confidence interval (CI): 2.1-11.1] months. The response rate was higher in human papillomavirus-positive (HPV+) patients (44%, N = 16). Responses were not associated with PD-L1 expression levels or IFNγ-related gene expression at baseline. Responses were observed both in injected (32%) and in noninjected lesions (29%). Progression-free and overall survival at 9 months were 19.0% (95% CI: 9.1-31.7) and 64.7% (95% CI: 45.3-78.7), respectively., Conclusions: SD-101 combined with pembrolizumab induced objective responses, especially in HPV+ tumors, which were frequently associated with increased intratumoral inflammation and effector immune cell activity., (©2021 The Authors; Published by the American Association for Cancer Research.)

Background: In the phase III double-blind European Organisation for Research and Treatment of Cancer 1325/KEYNOTE-054 trial, pembrolizumab improved recurrence-free and distant metastasis-free survival in patients with stage III cutaneous melanoma with complete resection of lymph nodes. In the pembrolizumab group, the incidence of grade I-V and of grade III-V immune-related adverse events (irAEs) was 37% and 7%, respectively., Methods: Patients were randomised to receive intravenous (i.v.) pembrolizumab 200 mg (N = 514) or placebo (N = 505) every 3 weeks, up to 1 year. On recurrence, patients could enter part 2 of the study: pembrolizumab 200 mg i.v. every 3 weeks up to 2 years, for crossover (those who received placebo) or rechallenge (those who had recurrence ≥6 months after completing 1-year adjuvant pembrolizumab therapy). For these patients, we present the safety profile and efficacy outcomes., Results: At the clinical cut-off (16-Oct-2020), in the placebo group, 298 patients had a disease recurrence, in which 155 (52%) crossed over ('crossover'). In the pembrolizumab group, 297 patients completed the 1-year treatment period; 47 had a recurrence ≥6 months later, in which 20 (43%) entered the rechallenge part 2 ('rechallenge'). In the crossover group, the median progression-free survival (PFS) was 8.5 months (95% confidence interval [CI] 5.7-15.2) and the 3-year PFS rate was 32% (95% CI 25-40%). Among 80 patients with stage IV evaluable disease, 31 (39%) had an objective response: 14 (18%) patients with complete response (CR) and 17 (21%) patients with partial response. The 2-year PFS rate from response was 69% (95% CI 48-83%). In the rechallenge group, the median PFS was 4.1 months (95% CI 2.6-NE). Among 9 patients with stage IV evaluable disease, 1 had an objective response (CR). Among the 175 patients, 51 (29%) had a grade I-IV irAE and 11 (6%) had a grade III-IV irAE., Conclusions: Pembrolizumab treatment after crossover yielded an overall 3-year PFS rate of 32% and a 39% ORR in evaluable patients, but the efficacy (11% ORR) was lower in those rechallenged., Competing Interests: Conflict of interest statement A.M.M.E.—consulting fees: Biocad, BioInvent, BioNTech, BMS, CatalYm, Ellipses, GSK, IO Biotech, ISA Pharmaceuticals, Merck/MSD, Nektar, Novartis, Pfizer, SAiRoPA, Sellas, SkylineDx, TigaTx, TTxDiscovery; payment or honoraria: Biocad, BMS, Merck/MSD, Novartis; payment for expert testimony: Novartis; support for attending meetings and/or travel: BMS; participation on a Data Safety Monitoring Board or Advisory Board: GSK, Novartis and Pfizer; leadership or fiduciary role in other board, society, committee or advocacy group, paid or unpaid: European Academy Cancer Sciences Gerrman Cancer Aid; stock or stock options: SkylineDx and SAiRoPA P.L.—personal fees, advisory, speaker, trial grants: BMS, Merck, Novartis, GSK, Amgen, Chugai, Pierre Fabre, NeraCare, Roche and Oncology Education Canada. N.I.—stock or stock options: Merck stock; other financial interest: employee Merck & Co. M.K.—study funding from Merck to institution; grants or contacts: Pierre Fabre; sponsor and provider of an academic grant for different melanoma studies (money paid to the author’s institution); BMS Sponsor and provider of an academic grant for different melanoma studies (money paid to the author’s institution). S.S.—Merck is the sponsor of this study; payment was made to the author’s institution; grants or contracts: BMS, Pierre Fabre—sponsor and provider of academic grants to other EORTC melanoma studies; payments were made to the author’s institution. C.R.—consulting fees: occasional consultant for Roche, Novartis, Pierre Fabre, MSD, BMS, Sanofi, Pfizer; payment or honoraria: occasional consultant for Roche, Novartis, Pierre Fabre, MSD, BMS, Sanofi and Pfizer. A.M.—grants or contracts: Merck Sharp Dohme Pharmaceuticals and Bristol Myers Squibb; payment or honoraria: Merck Sharp Dohme Pharmaceuticals and Bristol Myers Squibb; support for attending meetings: Merck Sharp Dohme Pharmaceuticals and Bristol Myers Squibb. V.A.—payment or honoraria: BMS, MSD, Nektar, Novartis, Pierre Fabre, Q Biotics, Roche and Limbic Ad Boards. C.K.—stock or stock options: Merck & Co. C.B.—grants or contracts: BMS, Novartis and NanoString Payments were made to the author’s institution; consulting fees: BMS, MSD, Roche, Novartis, Lilly, Pfizer, GSK, GenMab and Pierre Fabre; payments were made to the author’s institution. Third Rock Venture: payments were made to the author; stock or stock options: Unity Cars—Stocks; Immagene BV - Co-founder. A.C.J.v.A.—grants or contracts from any entity: Amgen, Merck-Pfizer, all paid to the institute and unrelated to current work; participation on a Data Safety Monitoring Board or Advisory Board: Amgen, Bristol Myers Squibb, Novartis, MSD-Merck, Merck-Pfizer, Pierre Fabre, Sanofi, Sirius Medical, 4SC, all paid to the institute and unrelated to current work M.M.—payment or honoraria: BMS, MSD, Novartis, Pierre Fabre and Sanofi. G.V.L. is a consultant advisor for Aduro Biotech Inc, Amgen Inc, Array Biopharma inc, Boehringer Ingelheim International GmbH, Bristol Myers Squibb, Hexel AG, Highlight Therapeutics S.L., Merck Sharpe & Dohme, Novartis Pharma AG, OncoSec, Pierre Fabre, QBiotics Group Limited, Regeneron Pharmaceuticals Inc, SkylineDX B.V., specialised Therapeutics Australia Pty Ltd; payment or honoraria: Bristol Myers Squibb—personal—one hour lecture of the author’s own slides; Pierre Fabre—personal—one hour lecture of the author’s own slides. A.M.D.G.—payment or honoraria: BMS, MSD, Sanofi, Pierre Fabre; compensated educational activities; support for attending meetings and/or travel: Pierre Fabre and BMS; participation on a Data Safety Monitoring Board or Advisory Board: BMS, MSD, Pierre Fabre, Sanofi, Incyte, GSK and Novartis. S.S.—grants or contracts from any entity: Advanced Accelerators Applications (a Novartis company), Amgen, Merck Sharp & Dohme, Merck Serono, Genentech, AstraZeneca; funding to the institution; consulting fees: Amgen, Merck Sharp & Dohme, Merck Serono, AstraZeneca and Bristol Myer Squibb (funding to the institution). R.K.—consulting fees: Merck, Array/Pfizer, BMS and Regeneron; participation on a Data Safety Monitoring Board or Advisory Board: Merck, Array/Pfizer, Regeneron and BMS P.L.O.R.—patents planned, issued or pending: PLCG1 for T-cell lymphoma. Participation on a Data Safety Monitoring Board or Advisory Board: Novartis, Takeda, Kyowa, 4SC, Helsinn, Recordati Rare Diseases, Innate Pharma, MIRAGEN advisory boards; payments to the author, receipt of equipment, materials, drugs, medical writing, gifts or other services: MEDA (Viatris) support for the investigator-initiated clinical trial. I.M.S.—all support for the present manuscript: MSD/EORTC partly covering of trial-associated expenses to the author’s institution; consulting fees: MSD - Webpage text, personal fee; support for attending meetings and/or travel: MSD—Conference in oncology; participation on a Data Safety Monitoring Board or Advisory Board: Roche/Genentech—IDSM, personal fee, Pierre Fabre; Novartis—Adv board, personal fee. S.P.—grants or contracts from any entity: Almirall—to the author’s institution; ISDIN—to the author’s institution; La Roche-Posay—to the author’s institution; consulting fees: ISDIN, Almirall—to the author; Sanofi, Sun Pharma—to the author; Pfizer, Roche and Regeneron—to the author; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events: ISDIN, La Roche-Posay—to the author; Pfizer, Roche and Regeneron—to the author. BMS, Sun Pharma—to the author; support for attending meetings and/or travel: Almirall—to the author; participation on a Data Safety Monitoring Board orAdvisory Board: Roche and Sanofi—to the author; Sun Pharma and Almirall—to the author; ISDIN, Pfizer and Novartis—to the author. Pi.Q.—payment or honoraria: BMS, MSD, Pierre Fabre, Novartis and Roche; support for attending meetings and/or travel: BMS, MSD, Pierre Fabre, Novartis and Roche. Pa.Q.—payment or honoraria: Roche, Novartis, Sun Pharma, Sanofi, BMS, MSD, Merck Serono and Pierre Fabre. P.M.—payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events: Amgen, Allmiral-Hermal, Beiersdorf, BMS, Medac, MSD, Pierre Fabre, Novartis, Roche and Sanofi Genzyme; support for attending meetings and/or travel: Amgen, Allmiral-Hermal, Beiersdorf, BMS, Medac, MSD, Pierre Fabre, Novartis, Roche and Sanofi Genzyme; participation on a Data Safety Monitoring Board or Advisory Board: CureVac AG. M.H.—payment or honoraria: MSD, BMS, Novartis; lecture at MSD symposium; payment for expert testimony: Pierre Fabre—A written statement to the Finnish Pricing Board; Participation on a Data Safety Monitoring Board or Advisory Board: MSD, BMS, Novartis, Varian—Participation on National and Nordic advisory boards A.H.—Grants or contracts from any entity: clinical trial support (grant to the institution): MSD/Merck, Philogen, Pierre Fabre, Regeneron, Roche, Sanofi-Genzyme, Novartis Pharma and Eisai; consulting fees: clinical trial support (grant to the institution): MSD/Merck, Philogen, Pierre Fabre, Regeneron, Roche, Sanofi-Genzyme, Novartis Pharma and Eisai; Payment or honoraria: MSD/Merck, Pierre Fabre, Regeneron, Roche, Sanofi-Genzyme, Novartis Pharma and Eisai; Participation on a Data Safety Monitoring Board or Advisory Board: MSD/Merck, Pierre Fabre, Regeneron, Roche, Sanofi-Genzyme, Novartis Pharma, Eisai, Immunocore, Replimune and Seagen. N.Y.—grants or contracts from any entity: ONO Pharmaceuticals, Bristol Myers Squibb, Novartis Pharma K.K.，MSD K.K, Merck Serono Co., Ltd.; payment or honoraria: ONO Pharmaceuticals, Bristol-Myers Squibb, Novartis Pharma K.K.，MSD K.K., Merck Serono Co., Ltd. and Takeda Pharmaceutical Co., Ltd. The other authors have no disclosures., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Purpose: Kaposi's sarcoma (KS) is a spindle cell tumor resulting from growth dysregulation in the setting of infection with human herpes virus-8 (also called KS herpes virus). Advanced KS is characterized by poor responses to antiretroviral therapy and some of the chemotherapy readily accessible to patients in low-resource areas. Gemcitabine induced partial and complete regression of AIDS-associated KS (AIDS-KS) in 11 of 24 patients in a pilot study. The current study compares the antimetabolite gemcitabine with the standard care bleomycin and vincristine (BV) in the treatment of chemotherapy-naïve patients with AIDS-KS in a resource-limited setting., Patients and Methods: Patients with persistent or progressive KS despite treatment with combined antiretroviral therapy were randomly assigned to receive gemcitabine 1,000 mg/m 2 or bleomycin 15 IU/ m 2 and vincristine 1.4 mg/m 2 given twice weekly. The main end point was objective response by bidirectional measurement, adverse events, and quality of life after three cycles of chemotherapy., Results: Of 70 participants enrolled, 36 received gemcitabine and 34 received BV. Complete response was achieved in 12 patients (33.3%) in the gemcitabine arm and six (17.6%) in the BV arm ( P = .175). The partial response rate was 52.8% (n = 19) in the gemcitabine arm and 58.8% (n = 20) in the BV arm. Both study arms reported similar neurologic and hematologic adverse events; there was statistically significant baseline to post-treatment improvement in health-related quality-of-life scores., Conclusion: The results of this randomized, phase IIA trial demonstrate gemcitabine activity in chemotherapy-naïve patients with AIDS-KS, on the basis of response rates, adverse events, and health-related quality-of-life scores.

Publicly funded cancer medicines listed on the New Zealand Pharmaceutical Schedule were compared with those listed on the Australian Pharmaceutical Benefits Scheme. To quantify the health gains offered by the cancer medicines funded in Australia but not in New Zealand, clinical trial data reporting median progression-free survival (PFS) and overall survival (OS) were sought. The differences in the median PFS and OS for the unfunded medicines, relative to the comparator medicine funded in NZ, were then assessed against the American Society of Clinical Oncology Cancer Research Committee (ASCO-CRC) recommended targets for clinically meaningful health gains. Our analysis confirms that, whilst New Zealand funds fewer cancer medicines than Australia, most of the additional medicines funded in Australia do not deliver clinically meaningful health gains as defined by the ASCO-CRC guidance. This suggests that New Zealand is not missing substantive opportunities for improvements to New Zealand's cancer survival rates through additional medicines funding. A policy of funding more new cancer medicines in order to achieve numerical parity with Australia or other countries would not result in substantive health improvement and would cost significantly more, and investing the millions of dollars needed to achieve funding parity with other countries would not represent good value for money in terms of delivering the best health outcomes for all New Zealanders, rather selective funding of new medicines that demonstrate clear clinical benefit and that are cost-effective and affordable is the sensible approach., (Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.)