A Phase I Trial of CT900, a Novel α-Folate Receptor-Mediated Thymidylate Synthase Inhibitor, in Patients with Solid Tumors with Expansion Cohorts in Patients with High-Grade Serous Ovarian Cancer.

PURPOSE: CT900 is a novel small molecule thymidylate synthase inhibitor that binds to α-folate receptor (α-FR) and thus is selectively taken up by α-FR-overexpressing tumors. PATIENTS AND METHODS: A 3+3 dose escalation design was used. During dose escalation, CT900 doses of 1-6 mg/m2 weekly and 2-12 mg/m2 every 2 weeks (q2Wk) intravenously were evaluated. Patients with high-grade serous ovarian cancer were enrolled in the expansion cohorts. RESULTS: 109 patients were enrolled: 42 patients in the dose escalation and 67 patients in the expansion cohorts. At the dose/schedule of 12 mg/m2/q2Wk (with and without dexamethasone, n = 40), the most common treatment-related adverse events were fatigue, nausea, diarrhea, cough, anemia, and pneumonitis, which were predominantly grade 1 and grade 2. Levels of CT900 more than 600 nmol/L needed for growth inhibition in preclinical models were achieved for >65 hours at a dose of 12 mg/m2. In the expansion cohorts, the overall response rate (ORR), was 14/64 (21.9%). Thirty-eight response-evaluable patients in the expansion cohorts receiving 12 mg/m2/q2Wk had tumor evaluable for quantification of α-FR. Patients with high or medium expression had an objective response rate of 9/25 (36%) compared with 1/13 (7.7%) in patients with negative/very low or low expression of α-FR. CONCLUSIONS: The dose of 12 mg/m2/q2Wk was declared the recommended phase II dose/schedule. At this dose/schedule, CT900 exhibited an acceptable side effect profile with clinical benefit in patients with high/medium α-FR expression and warrants further investigation.

Phase 1, dose-escalation study of guadecitabine (SGI-110) in combination with pembrolizumab in patients with solid tumors.

BACKGROUND: Data suggest that immunomodulation induced by DNA hypomethylating agents can sensitize tumors to immune checkpoint inhibitors. We conducted a phase 1 dose-escalation trial (NCT02998567) of guadecitabine and pembrolizumab in patients with advanced solid tumors. We hypothesized that guadecitabine will overcome pembrolizumab resistance. METHODS: Patients received guadecitabine (45 mg/m2 or 30 mg/m2, administered subcutaneously on days 1-4), with pembrolizumab (200 mg administered intravenously starting from cycle 2 onwards) every 3 weeks. Primary endpoints were safety, tolerability and maximum tolerated dose; secondary and exploratory endpoints included objective response rate (ORR), changes in methylome, transcriptome, immune contextures in pre-treatment and on-treatment tumor biopsies. RESULTS: Between January 2017 and January 2020, 34 patients were enrolled. The recommended phase II dose was guadecitabine 30 mg/m2, days 1-4, and pembrolizumab 200 mg on day 1 every 3 weeks. Two dose-limiting toxicities (neutropenia, febrile neutropenia) were reported at guadecitabine 45 mg/m2 with none reported at guadecitabine 30 mg/m2. The most common treatment-related adverse events (TRAEs) were neutropenia (58.8%), fatigue (17.6%), febrile neutropenia (11.8%) and nausea (11.8%). Common, grade 3+ TRAEs were neutropaenia (38.2%) and febrile neutropaenia (11.8%). There were no treatment-related deaths. Overall, 30 patients were evaluable for antitumor activity; ORR was 7% with 37% achieving disease control (progression-free survival) for ≥24 weeks. Of 12 evaluable patients with non-small cell lung cancer, 10 had been previously treated with immune checkpoint inhibitors with 5 (42%) having disease control ≥24 weeks (clinical benefit). Reduction in LINE-1 DNA methylation following treatment in blood (peripheral blood mononuclear cells) and tissue samples was demonstrated and methylation at transcriptional start site and 5' untranslated region gene regions showed enriched negative correlation with gene expression. Increases in intra-tumoural effector T-cells were seen in some responding patients. Patients having clinical benefit had high baseline inflammatory signature on RNAseq analyses. CONCLUSIONS: Guadecitabine in combination with pembrolizumab is tolerable with biological and anticancer activity. Reversal of previous resistance to immune checkpoint inhibitors is demonstrated.

A role for metabolism in determining neonatal immune function.

Immune responses of neonates differ markedly to those of adults, with skewed cytokine phenotypes, reduced inflammatory properties and drastically diminished memory function. Recent research efforts have started to unravel the role of cellular metabolism in determining immune cell fate and function. For studies in humans, much of the work on metabolic mechanisms underpinning innate and adaptive immune responses by different haematopoietic cell types is in adults. Studies investigating the contribution of metabolic adaptation in the unique setting of early life are just emerging, and much more work is needed to elucidate the contribution of metabolism to neonatal immune responses. Here, we discuss our current understanding of neonatal immune responses, examine some of the latest developments in neonatal immunometabolism and consider the possible role of altered metabolism to the distinctive immune phenotype of the neonate. Understanding the role of metabolism in regulating immune function at this critical stage in life has direct benefit for the child by affording opportunities to maximize immediate and long-term health. Additionally, gaining insight into the diversity of human immune function and naturally evolved immunometabolic strategies that modulate immune function could be harnessed for a wide range of opportunities including new therapeutic approaches.

Health system challenges to integration of mental health delivery in primary care in Kenya--perspectives of primary care health workers.

BACKGROUND: Health system weaknesses in Africa are broadly well known, constraining progress on reducing the burden of both communicable and non-communicable disease (Afr Health Monitor, Special issue, 2011, 14-24), and the key challenges in leadership, governance, health workforce, medical products, vaccines and technologies, information, finance and service delivery have been well described (Int Arch Med, 2008, 1:27). This paper uses focus group methodology to explore health worker perspectives on the challenges posed to integration of mental health into primary care by generic health system weakness. METHODS: Two ninety minute focus groups were conducted in Nyanza province, a poor agricultural region of Kenya, with 20 health workers drawn from a randomised controlled trial to evaluate the impact of a mental health training programme for primary care, 10 from the intervention group clinics where staff had received the training programme, and 10 health workers from the control group where staff had not received the training). RESULTS: These focus group discussions suggested that there are a number of generic health system weaknesses in Kenya which impact on the ability of health workers to care for clients with mental health problems and to implement new skills acquired during a mental health continuing professional development training programmes. These weaknesses include the medicine supply, health management information system, district level supervision to primary care clinics, the lack of attention to mental health in the national health sector targets, and especially its absence in district level targets, which results in the exclusion of mental health from such district level supervision as exists, and the lack of awareness in the district management team about mental health. The lack of mental health coverage included in HIV training courses experienced by the health workers was also striking, as was the intensive focus during district supervision on HIV to the detriment of other health issues. CONCLUSION: Generic health system weaknesses in Kenya impact on efforts for horizontal integration of mental health into routine primary care practice, and greatly frustrate health worker efforts.Improvement of medicine supplies, information systems, explicit inclusion of mental health in district level targets, management and supervision to primary care are likely to greatly improve primary care health worker effectiveness, and enable training programmes to be followed by better use in the field of newly acquired skills. A major lever for horizontal integration of mental health into the health system would be the inclusion of mental health in the national health sector reform strategy at community, primary care and district levels rather than just at the higher provincial and national levels, so that supportive supervision from the district level to primary care would become routine practice rather than very scarce activity. TRIAL REGISTRATION: Trial registration ISRCTN 53515024.

Exploring the perspectives and experiences of health workers at primary health facilities in Kenya following training.

BACKGROUND: A cluster randomised controlled trial (RCT) of a national Kenyan mental health primary care training programme demonstrated a significant impact for health workers on the health, disability and quality of life of their clients, despite a severe shortage of medicines in the clinics. In order to better understand the potential reasons for the improved outcomes in the intervention group, the experiences of the participating health workers were explored through qualitative focus group discussions, as focus group methodology has been found to be a useful method of obtaining a detailed understanding of client and health worker perspectives within health systems. METHODS: Two ninety minute focus groups were conducted in Nyanza province, a poor agricultural region of Kenya, with 10 health workers from the intervention group clinics where staff had received the training programme, and 10 health workers from the control group where staff had not received the training during the earlier randomised controlled trial. RESULTS: These focus group discussions suggest that the health workers in the intervention group perceived an increase in their communication, diagnostic and counselling skills, and that the clients in the intervention group noticed and appreciated these enhanced skills, while health workers and clients in the control group were both aware of the lack of these skills. CONCLUSION: Enhanced health worker skills conferred by the mental health training programme may be responsible for the significant improvement in outcome of patients in the intervention clinics found in the randomised controlled trial, despite the general shortage of medicines and other health system weaknesses. These findings suggest that strengthening mental health training for primary care staff is worthwhile even where health systems are not strong and where the medicine supply cannot be guaranteed. TRIAL REGISTRATION: ISRCTN 53515024.

Perspectives and concerns of clients at primary health care facilities involved in evaluation of a national mental health training programme for primary care in Kenya.

BACKGROUND: A cluster randomised controlled trial (RCT) of a national Kenyan mental health primary care training programme demonstrated a significant impact on the health, disability and quality of life of clients, despite a severe shortage of medicines in the clinics (Jenkins et al. Submitted 2012). As focus group methodology has been found to be a useful method of obtaining a detailed understanding of client and health worker perspectives within health systems (Sharfritz and Roberts. Health Transit Rev 4:81-85, 1994), the experiences of the participating clients were explored through qualitative focus group discussions in order to better understand the potential reasons for the improved outcomes in the intervention group. METHODS: Two ninety minute focus groups were conducted in Nyanza province, a poor agricultural region of Kenya, with 10 clients from the intervention group clinics where staff had received the training programme, and 10 clients from the control group where staff had not received the training during the earlier randomised controlled trial. RESULTS: These focus group discussions suggest that the clients in the intervention group noticed and appreciated enhanced communication, diagnostic and counselling skills in their respective health workers, whereas clients in the control group were aware of the lack of these skills. Confidentiality emerged from the discussions as a significant client concern in relation to the volunteer cadre of community health workers, whose only training comes from their respective primary care health workers. CONCLUSION: Enhanced health worker skills conferred by the mental health training programme may be responsible for the significant improvement in outcomes for clients in the intervention clinics found in the randomised controlled trial, despite the general shortage of medicines and other health system weaknesses. These findings suggest that strengthening mental health training for primary care staff is worthwhile even where health systems are not strong and where the medicine supply cannot be guaranteed. TRIAL REGISTRATION: ISRCTN 53515024.

UK practice regarding reversal of vasectomy 2001-2010: relevance to best contemporary patient management.

UNLABELLED: Study Type - Practice trends (survey) Level of Evidence 2c What's known on the subject? and What does the study add? Approximately 6% of men who have had a vasectomy subsequently decide to have it reversed. For such men there are various options available, including vasal reconstruction, surgical sperm retrieval with assisted reproductive techniques, use of donated sperm or adoption. The decision-making process with regard to the most appropriate management is challenging and the urologist requires both an intimate knowledge of the advantages and disadvantages of each of the available options and the opportunity to counsel a couple appropriately. The study confirms that patient management after previous vasectomy is a complex process, demanding detailed knowledge about the availability and outcomes of alternatives to vasectomy reversal. It recommends that couples should not be seen by urologists with diverse interests but by those with appropriate knowledge of all of the factors influencing outcome and the available management options and their costs. Urologists should also have appropriate facilities to offer intra-operative demonstration of and, potentially, storage of sperm. OBJECTIVES: To review the management of men presenting for reversal of vasectomy amongst consultant members of the British Association of Urological Surgeons (BAUS) between 2001 and 2010. • To make recommendations for contemporary practice. SUBJECTS AND METHODS: Three consecutive questionnaire-based surveys were undertaken by BAUS consultant members in 2001, 2005 and 2010. • Standard questionnaires were sent on each occasion asking urologists about their counselling of couples regarding options in achieving a conception, expectation of outcome from reconstructive surgery and the techniques of vaso-vasostomy used. • In 2005 additional information was obtained about the availability of fertility treatments and sub-specialization of the urologist and in 2010 about the eligibility criteria for in-vitro fertilization (IVF) treatment and synchronous sperm retrieval. RESULTS: Overall there was a 47% response rate with >80% of respondents still performing vaso-vasostomy. • More than 75% of respondents were doing <15 procedures a year and <50% of respondents counselled couples about other management options. • Only 41% gave their personalized outcomes from vaso-vasostomy, whilst >80% were using some form of magnification intra-operatively. • Members of the BAUS section of andrology were more likely to discuss options for becoming a parent and criteria for IVF treatment, to present their individualized outcomes from vaso-vasotomy and to carry out >15 procedures a year than urologists with no andrological affiliation. CONCLUSIONS: • Patient management after previous vasectomy is a complex process necessitating detailed knowledge concerning the availability and outcomes of alternatives to vaso-vasostomy. • Couples should not be seen by urologists with diverse interests but by those with appropriate knowledge of all of the factors influencing outcome. • Vaso-vasostomy should no longer be seen as a procedure within the remit of any adequately trained urologist but as one option to be considered by a sub-specialist with access to appropriate micro-surgical training and assisted reproductive technologies.