Search

128 Background: LuPSMA, a radioligand therapy targeting the cell surface protein PSMA, is approved for men with PSMA-positive mCRPC previously treated with androgen receptor signaling inhibitor (ARSI) and taxane chemotherapy. Several PARP inhibitors (PARPi) are also currently approved for patients with mCRPC harboring alterations in genes associated with DNA damage repair (DDR). Given that both therapeutics result in DNA damage, we hypothesized that there would be clinical evidence of cross-resistance between the two classes of agents, with decreased efficacy in patients receiving LuPSMA following a PARPi. Methods: We abstracted retrospective data from patients at three centers who received at least one cycle of LuPSMA per the FDA label and had panel-based tumor sequencing performed. Patients with PARPi qualifying mutations were included in the analysis. PSA50 responses (i.e. ≥50% decline in PSA from baseline), PSA progression free survival (PFS) and overall survival (OS) following treatment with LuPSMA were compared between patients who received prior PARPi (PARPi-T cohort) and those who did not (PARPi-NT cohort). Results: Forty-nine patients with a PARPi qualifying alteration who received at least one cycle of LuPSMA were identified. Baseline characteristics (Gleason score, visceral metastases, race, ECOG PS, PSMA SUVmean/max) were similar between cohorts. Prior non-PARPi lines of therapy, including receipt of radium-223 (14% vs 21%), carboplatin (33% vs 36%), ≥ 2 prior ARSI (67% vs 68%), and ≥ 2 prior taxanes (43% vs 47%) were also similar between the PARP-NT and PARP-T cohorts respectively. Median PSA PFS and OS were both significantly increased in the PARPi-NT cohort as compared to the PARPi-T cohort (Table). PSA50 responses were numerically increased in the PARP-NT cohort, although this did not reach statistical significance. The most common PARPi qualifying alteration was BRCA2 (N=15). PARP-NT patients with BRCA2 alterations had significantly increased PSA PFS and OS as well as PSA50 response rates compared to the PARP-T patients. Conclusions: Prior receipt of PARPi therapy appears to negatively associate with the clinical activity of LuPSMA, with the largest difference in outcomes observed in patients with BRCA2 mutations. These data support the hypothesis that PARPi therapy may lead to clinically significant cross-resistance with LuPSMA. Prospective studies to evaluate the optimal sequence of LuPSMA and PARPi therapy are justified. [Table: see text]

PURPOSE: While 177Lu-PSMA-617 (LuPSMA) is an effective therapy for many patients with metastatic castration-resistant prostate cancer (mCRPC), biomarkers associated with outcomes are not well defined. We hypothesized that prostate cancer mutational profile may associate with clinical activity of LuPSMA. We devised a study to evaluate associations between mCRPC mutational profile with LuPSMA clinical outcomes. METHODS: This was a multicenter retrospective analysis of patients with mCRPC with next-generation sequencing (NGS) who received LuPSMA. PSA50 response (ie, ≥50% decline in prostate-specific antigen [PSA]) rate, PSA progression free survival (PSA PFS), and overall survival (OS) were compared between genetically defined subgroups. RESULTS: One hundred twenty-six patients with NGS results who received at least one cycle of LuPSMA were identified. The median age was 73 (IQR, 68-78) years, 124 (98.4%) received ≥1 prior androgen receptor-signaling inhibitor, and 121 (96%) received ≥1 taxane-based chemotherapy regimen. Fifty-eight (46%) patients with a DNA damage repair gene mutation (DNA damage response group) and 59 (46.8%) with a mutation in TP53 , RB1 , or PTEN tumor suppressor genes (TSG group) were identified. After adjusting for relevant confounders, the presence of ≥1 TSG mutation was associated with shorter PSA PFS (hazard ratio [HR], 1.93 [95% CI, 1.05 to 3.54]; P =.034) and OS (HR, 2.65 [95% CI, 1.15 to 6.11]; P =.023). There was improved OS favoring the DNA damage response group (HR, 0.37 [95% CI, 0.14 to 0.97]; P =.044) on multivariable analysis. Univariate analysis of patients with ATM mutations had significantly higher rates of PSA50 response, PSA PFS, and OS. CONCLUSION: Outcomes on LuPSMA varied on the basis of mutational profile. Prospective studies to define the clinical activity of LuPSMA in predefined genomic subgroups are justified. Mutations in DNA damage repair genes are associated with improved clinical activity of 177Lu-PSMA617 [ABSTRACT FROM AUTHOR]

Chimeric antigen receptor (CAR) T-cell therapy produces high response rates in refractory B-cell non-Hodgkin lymphoma, but long-term data are minimal to date. In this study, we present long-term follow-up of a pilot trial testing a CD20-targeting third-generation CAR in patients with relapsed B-cell lymphomas following cyclophosphamide-only lymphodepletion. Two of the three patients in the trial, with mantle cell lymphoma and follicular lymphoma, had remissions lasting more than 7 years, though they ultimately relapsed. The absence of B-cell aplasia in both patients suggested a lack of functional CAR T-cell persistence, leading to the hypothesis that endogenous immune responses were responsible for these long-term remissions. Correlative immunologic analyses supported this hypothesis, with evidence of new humoral and cellular antitumor immune responses proximal to clinical response time points. Collectively, our results suggest that CAR T-cell therapy may facilitate epitope spreading and endogenous immune response formation in lymphomas. Significance: Two of three patients treated with CD20-targeted CAR T-cell therapy had long-term remissions, with evidence of endogenous antitumor immune response formation. Further investigation is warranted to develop conditions that promote epitope spreading in lymphomas., (©2024 American Association for Cancer Research.)

Purpose: One third of patients with triple-negative breast cancer (TNBC) achieve pathologic complete response (pCR) with standard neoadjuvant chemotherapy (NACT). CALGB 40603 (Alliance), a 2 × 2 factorial, open-label, randomized phase II trial, evaluated the impact of adding carboplatin and/or bevacizumab., Patients and Methods: Patients (N = 443) with stage II to III TNBC received paclitaxel 80 mg/m(2) once per week (wP) for 12 weeks, followed by doxorubicin plus cyclophosphamide once every 2 weeks (ddAC) for four cycles, and were randomly assigned to concurrent carboplatin (area under curve 6) once every 3 weeks for four cycles and/or bevacizumab 10 mg/kg once every 2 weeks for nine cycles. Effects of adding these agents on pCR breast (ypT0/is), pCR breast/axilla (ypT0/isN0), treatment delivery, and toxicities were analyzed., Results: Patients assigned to either carboplatin or bevacizumab were less likely to complete wP and ddAC without skipped doses, dose modification, or early discontinuation resulting from toxicity. Grade ≥ 3 neutropenia and thrombocytopenia were more common with carboplatin, as were hypertension, infection, thromboembolic events, bleeding, and postoperative complications with bevacizumab. Employing one-sided P values, addition of either carboplatin (60% v 44%; P = .0018) or bevacizumab (59% v 48%; P = .0089) significantly increased pCR breast, whereas only carboplatin (54% v 41%; P = .0029) significantly raised pCR breast/axilla. More-than-additive interactions between the two agents could not be demonstrated., Conclusion: In stage II to III TNBC, addition of either carboplatin or bevacizumab to NACT increased pCR rates, but whether this will improve relapse-free or overall survival is unknown. Given results from recently reported adjuvant trials, further investigation of bevacizumab in this setting is unlikely, but the role of carboplatin could be evaluated in definitive studies, ideally limited to biologically defined patient subsets most likely to benefit from this agent., (© 2014 by American Society of Clinical Oncology.)

Background: The Government of Ghana has been implementing various health sector reforms (e.g. user fees in public health facilities, decentralization, sector-wide approaches to donor coordination) in a bid to improve efficiency in health care. However, to date, except for the pilot study reported in this paper, no attempt has been made to make an estimate of the efficiency of hospitals and/or health centres in Ghana. The objectives of this study, based on data collected in 2000, were: (i) to estimate the relative technical efficiency (TE) and scale efficiency (SE) of a sample of public hospitals and health centres in Ghana; and (ii) to demonstrate policy implications for health sector policy-makers., Methods: The Data Envelopment Analysis (DEA) approach was used to estimate the efficiency of 17 district hospitals and 17 health centres. This was an exploratory study., Results: Eight (47%) hospitals were technically inefficient, with an average TE score of 61% and a standard deviation (STD) of 12%. Ten (59%) hospitals were scale inefficient, manifesting an average SE of 81% (STD = 25%). Out of the 17 health centres, 3 (18%) were technically inefficient, with a mean TE score of 49% (STD = 27%). Eight health centres (47%) were scale inefficient, with an average SE score of 84% (STD = 16%)., Conclusion: This pilot study demonstrated to policy-makers the versatility of DEA in measuring inefficiencies among individual facilities and inputs. There is a need for the Planning and Budgeting Unit of the Ghana Health Services to continually monitor the productivity growth, allocative efficiency and technical efficiency of all its health facilities (hospitals and health centres) in the course of the implementation of health sector reforms.

Background and Purpose: There are no previously published studies of the long-term outcome of stroke in sub-Saharan Africa. Our goal was to determine the case fatality, time to and cause of death, and recovery in a hospital cohort of stroke patients in The Gambia., Methods: For 1 year beginning April 1, 1990, any patient presenting to the Royal Victoria Hospital (Banjul) with a diagnosis of stroke or having a stroke as an inpatient was recruited. After a standardized assessment, patients were followed up at 1 month, 6 months, and 3 to 4 years to assess recovery or, for those who died, record the date and likely cause of death., Results: Mean age of the 106 patients (70 men) was 58 years (range, 20 to 93 years). By 1 and 6 months, 29 (27%) and 47 (44%), respectively, had died, with only 27 (25%) surviving to final follow-up (4 patients not traced). Death occurred in hospital in 43 patients (57%). Cause of death was the initial stroke in 46 (61%), further stroke in 5 (7%), infection in 9 (12%), miscellaneous in 8 (11%) (only 1 vascular), and unknown in 7 (9%). On Cox regression analysis, incontinence in the first 24 hours, sensory inattention, and impaired gag reflex on admission were significant predictors of mortality. Predictors of recovery were similar to those of developed countries., Conclusions: Despite the young mean age, there was a high case fatality rate. The main cause of death was the stroke itself, and ischemic heart disease was very rare.

A community trial was conducted in rural Gambia in order to determine whether a community-based intervention designed to mobilize latent demand for contraception would increase use of modern contraceptives, even in the absence of improved availability of family planning services. Analysis of trial data indicates that the demand-mobilization intervention had a statistically significant positive effect on nonusers' adoption of modern contraception and that coterminous implementation of an intervention designed to improve access to services offered no additional benefit. The program component found to have the greatest impact was the "kabilo approach," in which village women provide basic health and family planning counseling to other women in their extended families. These results suggest that the principal barriers to increased contraceptive use in rural Gambia are psychosocial and that these barriers can be overcome through village-based interventions designed to provide socially appropriate counseling to potential contraceptive users.

Objective: The aim of the pathfinder survey was to assess the periodontal status and treatment needs in The Gambia., Methods: A multistage stratified random sampling technique was used to obtain a sample of 1,235 (or 0.1% of the national population). The study was conducted according to the World Health Organisation's criteria (WHO, 1987). The WHO J2 software programme was used to analyse the data., Results: Not more than 12% of subjects in any age group had healthy periodontal tissues. Two to three sextants were healthy among those under the age of 35 years. Shallow (4-5 mm) pockets were present in all ages. However, less than one sextant was involved among subjects younger than 25 years. Despite the high prevalence of pockets, few sextants were edentulous. The majority of subjects needed oral hygiene instructions and oral prophylaxis. Of the subjects between the ages of 8 and 29 years, 5-28% needed complex treatment in only half of a sextant. Similarly, 38% and 80% of older subjects needed complex treatment in 0.8-1.9 sextants., Conclusion: A national oral health plan in The Gambia should focus on health education and provision of oral prophylaxis by trained auxiliary health care workers. In conclusion, there is a need to develop a functional district oral health services system in The Gambia.

Objective: The aim of this study was to assess dental caries status and treatment needs in The Gambia for the purpose of national planning., Materials and Methods: 1,235 subjects were obtained with a multi-stage stratified random sampling technique. Clinical examinations were carried out using the criteria suggested in WHO Basic Methods (WHO 1987). The WHO J2 software programme was used for data analysis., Results: More than half of the subjects had caries. Mean DMFT increased from 1.7 in the 7-year-old group to 8.8 in 65-99-year-olds. Mean DT peaked at 5.1 in the 30-34-year-old group before declining to 3.2 among the 65-99-year-olds. Mean filled teeth (FT) was zero in all ages. Missing teeth (MT) increased from 0.1 in 13-year-olds to 5.6 among the 65-99-year group. Mean DMFT was 2.3, 2.8, and 6.6 in 12-year-olds, 15-year-olds and 35-44-year-olds respectively. Unmet treatment need (DT/DMFT) was 90-100% in subjects below 25 years. Need for dental extraction increased from 15% to 63% in 65-99-year-olds. Between 0.3 and 2.8 teeth required extraction, and 46-79% of subjects needed conservative treatment. Dental auxiliaries should be trained to carry out extractions and fillings using the atraumatic restorative treatment (ART).

SPf66 malaria vaccine is a synthetic protein with aminoacid sequences derived from pre-erythrocytic and asexual blood-stage proteins of Plasmodium falciparum. SPf66 was found to have a 31% protective efficacy in an area of intensive malaria transmission in Tanzanian children, 1-5 years old. We report a randomised, double-blind, placebo-controlled trial of SPf66 against clinical P falciparum malaria in Gambian infants. 630 children, aged 6-11 months at time of the first dose, received three doses of SPf66 or injected polio vaccine (IPV). Morbidity was monitored during the following rainy season by means of active and passive case detection. Cross-sectional surveys were carried out at the beginning and at the end of the rainy season. An episode of clinical malaria was defined as fever (> or = 37.5 degrees C) and a parasite density of 6000/microL or more. Analysis of efficacy was done on 547 children (316 SPf66/231 IPV). No differences in mortality or in health centre admissions were found between the two groups of children. 347 clinical episodes of malaria were detected during the three and a half months of surveillance. SPf66 vaccine was associated with a protective efficacy against the first or only clinical episode of 8% (95% CI -18 to 29, p = 0.50) and against the overall incidence of clinical episodes of malaria of 3% (95% CI -24 to 24, p = 0.81). No significant differences in parasite rates or in any other index of malaria were found between the two groups of children. The findings of this study differ from previous reports on SPf66 efficacy from South America and from Tanzania. In The Gambia, protection against clinical attacks of malaria during the rainy season after immunisation in children 6-11 months old at time of the first dose was not achieved.

We review the development of anaesthesia in The Gambia from 1977 to 1992 and the role of nurse anaesthetists. The anaesthetists service provided over a one year period at the Royal Victoria Hospital, Banjul shows that 58.3% are for Obstetrics and Gynaecology (O & G) procedures, 38.06% for Surgical and Dental while 3.164% was Ophthalmology. Nurse anaesthetists administered anaesthesia for 94.4% of the O & G Procedures with minimal complication. However anaesthesia for 65.6% of the general surgical and dental procedures required the expertise of a physician anaesthetist. The major problems associated with anaesthetic service delivery in The Gambia are highlighted and suggestions made on the future development of the specialty of anaesthesia.

Because of the high prevalence of hepatitis B virus (HBV) infection in The Gambia, HBV vaccination has been incorporated into the national expanded programme on immunisation. We have assessed the efficacy of the vaccine against HBV infection and chronic carriage by examining 720 3-4-year-old children who had received the vaccine in infancy and 816 who had not received it. The vaccine was 84% (95% CI 78-89%) effective against infection and 94% (84-98%) effective against chronic carriage. Vaccinated infants of mothers positive for hepatitis B surface and e antigens were at greater risk of breakthrough infection and chronic carriage than infants of uninfected mothers. The high vaccine efficacy against the HBV carrier state, the main risk factor for the development of chronic liver disease and liver cancer, offers hope that the prevalence of these diseases may be reduced in the future.