Wnt-pathway Activating Mutations Are Associated with Resistance to First-line Abiraterone and Enzalutamide in Castration-resistant Prostate Cancer.

BACKGROUND: Wnt signaling is a cellular pathway involved in embryogenesis, development, and neoplasia. Wnt-pathway activation may accelerate prostate cancer androgen-independent growth and mediate antiandrogen resistance. Since 10-20% of advanced prostate cancers harbor Wnt-activating mutations, we aimed to characterize the clinical features and response to novel antiandrogens in such patients. OBJECTIVE: To determine whether men with metastatic castration-resistant prostate cancer (mCRPC) who harbor Wnt-pathway mutations have poorer responses to first-line novel hormonal therapies: abiraterone/enzalutamide. DESIGN, SETTING, AND PARTICIPANTS: Patients with mCRPC who received first-line abiraterone or enzalutamide were retrospectively evaluated. Using tumor DNA analyses, we queried for activating mutations in CTNNB1 or inactivating mutations in APC or RNF43, all of which are predicted to stimulate Wnt signaling. Presence or absence of at least one Wnt-activating alteration was correlated with clinical-pathologic characteristics and treatment outcomes. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Time to prostate-specific antigen (PSA) progression, overall survival (OS), and PSA response were measured. Cox regression models were used to test associations between Wnt status and clinical-pathologic outcomes; Kaplan-Meier and log-rank analyses were used to compare time-to-event endpoints. RESULTS AND LIMITATIONS: Of 137 patients evaluated, 11% (n=15) had tumor DNA analysis showing at least one Wnt-stimulating alteration. Patients with Wnt-activating mutations had numerically fewer T3/T4 tumors than Wnt wild-type patients (31% vs 51%), but were otherwise generally balanced. Median time to PSA progression on first-line abiraterone/enzalutamide was shorter in Wnt-activated patients (6.5 vs 9.6mo, hazard ratio [HR] 2.34, p=0.003), as was OS (23.6 vs 27.7mo, HR 2.28, p=0.01). PSA responses were numerically worse in Wnt-activated patients (53% vs 75%, p=0.12). Presence of Wnt-activating alterations (adjusted HR [aHR] 2.33, p=0.007) and use of previous chemotherapy (aHR 1.83, p=0.004) were both independently associated with increased hazard of progression. CONCLUSIONS: Patients with somatic Wnt-pathway activating mutations have worse outcomes to first-line abiraterone/enzalutamide than Wnt wild-type patients. Our data suggest that additional genomically informed therapies are needed for this relevant subset of mCRPC patients. PATIENT SUMMARY: In this report, we retrospectively examined outcomes of metastatic prostate cancer patients with or without Wnt-pathway mutations who received abiraterone or enzalutamide for the first time, in order to examine whether these mutations affect the prognosis. Our study suggested that patients who have Wnt-pathway activating mutations derived less benefit from abiraterone and enzalutamide when compared to patients without these mutations. We conclude that Wnt-pathway mutations might decrease the effectiveness of abiraterone and enzalutamide, and we propose that the Wnt pathway might be a good therapeutic target for these patients, in order to potentially reverse or prolong resistance to abiraterone and enzalutamide in men with Wnt mutations.

Efficacy of Radium-223 in Bone-metastatic Castration-resistant Prostate Cancer with and Without Homologous Repair Gene Defects.

BACKGROUND: Pathogenic mutations in genes mediating homologous recombination (HR) DNA repair are present in 20-30% of men with metastatic castrate-resistant prostate cancer (mCRPC). Radium-223 is a bone-seeking α-emitter that induces double-strand DNA breaks, thereby killing cancer cells in the bone microenvironment. OBJECTIVE: To evaluate the potential impact of germline or somatic HR-deficiency (HRD) mutations on radium-223 efficacy in mCRPC with bone metastasis. DESIGN, SETTING, AND PARTICIPANTS: This is a retrospective single-institution study. Medical records of 190 mCRPC patients for whom germline and/or somatic DNA sequencing data were available were reviewed. Of these patients, 28 had received standard-of-care radium-223 at Johns Hopkins between February 2013 and February 2018. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Alkaline phosphatase (ALP) responses and time-to-ALP-progression were the coprimary endpoints. Prostate-specific antigen (PSA) responses, overall survival (OS), and time to next systemic therapy were also evaluated. RESULTS AND LIMITATIONS: Of the 28 patients included, 10 men (35.7%) had a germline/somatic HRD mutation (three in BRCA2, and one each in ATM, ATR, CHEK2, FANCG, FANCI, FANCL, and PALB2) and 18 (64.3%) did not. Men with HRD mutations (HRD+) had numerically lower ages (66 vs 73yr, p=0.25), more soft-tissue metastases (50% vs 38%, p=0.43), and higher baseline ALP levels (130 vs 108 U/l, p=0.84). Compared with HRD(-) men, HRD(+) patients showed greater ALP responses (80% vs 39%, p=0.04), longer time to ALP progression (median10.4 vs 5.8mo, hazard ratio [HR] 6.4, p=0.005), and a trend toward longer OS (median 36.9 vs 19.0mo, HR 3.3, p=0.11). PSA responses (0% vs 0%, p>0.99) and time to next systemic therapy (HR 1.5, p=0.39) were similar between the two groups. Results are limited by the retrospective nature of the analysis and the small sample size. CONCLUSIONS: In this exploratory study, bone-metastatic CRPC patients with inactivating HRD mutations demonstrated significantly improved ALP responses and time to ALP progression. These results should motivate prospective validation of the "synthetic lethality" hypothesis between HRD mutations and radium-223 activity. PATIENT SUMMARY: In this report, we retrospectively examined outcomes to metastatic prostate cancer in patients with and without DNA repair mutations who received radium-223, a therapy that kills cancer cells by causing direct DNA damage. Our study suggested that patients who have inherited or acquired DNA repair gene mutations derived greater benefit from radium-223 when compared with patients without these mutations. We concluded that radium-223 might have an important role in this setting; however, prospective studies are needed to confirm whether DNA repair mutations truly make radium-223 work better or not.

Good quality locally procured drugs can be as effective as internationally quality assured drugs in treating multi-drug resistant tuberculosis.

BACKGROUND: Owing toGiven the high costs of drugs to treat multi-drug resistant tuberculosis (MDR-TB), the Green Light Committee (GLC) initiative enables TB programs to procure quality-assured drugs at reduced prices. Despite price reductions, internationally quality assured (IQA) drugs can be more expensive than locally procured drugs. There is little evidence to inform decision-makers about whether IQA drugs are more effective than local drugs. This is the first study to compare outcomes between MDR-TB patients treated using IQA, and locally procured drugs in the same hospitals during the same time period. METHODS/FINDINGS: A retrospective cohort study was conducted in three hospitals across Pakistan. Data on baseline characteristics and treatment outcomes during the first six months of treatment were extracted from hospital records of adult culture-positive pulmonary MDR-TB patients starting treatment between January 2011 and June 2012. Two cohorts were defined: patients receiving IQA drugs, and patients receiving locally procured non-IQA drugs. Data were analysed using Kaplan-Meier curves and Cox proportional hazards regression. The primary outcome compared between cohorts was time to culture conversion. Of 231 patients, 90 were in the IQA and 141 in the non-IQA cohorts. Baseline characteristics were similar except for higher frequency of quinolone resistance in the IQA cohort. Overall, 193 patients (84%) culture converted. Culture conversion was not faster in the IQA cohort; the median time was 81 and 68 days in the IQA and non-IQA cohorts, respectively. Unadjusted and adjusted hazard ratios for culture conversion in IQA verses non-IQA cohorts were 0.82 (95%-CI, 0.62-1.10) and 0.95 (95%-CI, 0.66-1.36) respectively. CONCLUSIONS: Use of good quality, locally procured drugs can be effective in treating MDR-TB, may involve lower costs than using IQA drugs and could strengthen developing country drug quality assurance systems. This may be a suitable alternative in lieu of or whilst awaiting arrival of internationally procured medicines.

Quantitatively evaluating the effect of social barriers: a case-control study of family members' opposition and women's intention to use contraception in Pakistan.

BACKGROUND: Uptake of family planning services in Pakistan has remained slow over the past decade despite a rapid increase in availability and awareness, indicating that social barriers may be preventing uptake. Social barriers such as opposition by family members have largely been studied qualitatively; there is a lack of quantitative evidence about the effect of different family members' opposition on women's intention to use contraceptives. The objective of this study was to quantitatively evaluate the effect of family members' opposition to family planning on intention to use contraception amongst poor women in Pakistan who have physical access to family planning services. METHODS: An unmatched case control study (nested within a larger cohort study) was conducted in two public hospitals in Karachi, Pakistan. Univariable and multivariable logistic regression analyses were conducted to compare risk factors between women that were not intending to use any contraceptive methods in the future (cases) and women that were planning to use contraceptive methods (controls). RESULTS: 248 cases and 496 controls were included in the study. Negative contraceptive intent was associated with no knowledge of contraception (AOR = 3.79 [2.43-5.90]; p < 0.001), husband's opposition (AOR = 21.87 [13.21-36.21]; p < 0.001) and mother-in-law's opposition (AOR = 4.06 [1.77-9.30]; p < 0.001). CONCLUSIONS: This study is the first to quantitatively assess the effect of opposition by different family members on women's contraceptive intent in Pakistan. Our results indicate that of all family members, husband's opposition has the strongest effect on women's intention to use contraception, even when the women have knowledge of and physical access to family planning services.

Prospective cohort study of a new vacuum delivery device to assist with complicated labour in low-resource settings.

OBJECTIVES: Currently available vacuum devices used to assist women undergoing complicated labour are unsuitable for use in low-resource settings. The objective of this study was to evaluate the safety and feasibility of a new low-cost vacuum device, named Koohi Goth Vacuum Delivery System (KGVDS), designed for use in low-resource settings. METHODS: A hospital-based, multicentre, prospective cohort study with no control group was conducted in Karachi, Pakistan. After training, KGVDS devices were made available for use by labour room staff at their discretion when instrumental delivery was indicated. Women to whom KGVDS was applied were followed from the start of labour until discharge. Feasibility was assessed in terms of successful expulsion of the foetal head following application of KGVDS and ease of use ratings. Safety was assessed by observing maternal and newborn post-delivery outcomes prior to discharge. RESULTS: Koohi Goth Vacuum Delivery System was applied to 137 women requiring instrumental delivery, of whom 111 (81%; 95% CI = 74-88%) successfully expelled the foetal head assisted by KGVDS and 103 (75%) stated that they would agree to use KGVDS again. There were no serious maternal or neonatal injuries or infections related to KGVDS use. The mean score for 'ease of use' given by doctors and midwives using the device was 8 of 10. CONCLUSIONS: Koohi Goth Vacuum Delivery System was feasible and safe to use for assisting complicated deliveries in low-resource hospitals in this initial evaluation. Our results indicate that this new device may have the potential to improve birth outcomes in settings where most mortality occurs and that further evaluations should be conducted.

Novel methodology to assess sputum smear microscopy quality in private laboratories.

BACKGROUND: In South Asia, it is estimated that 80% of patients choose to attend a private facility for their healthcare needs. Although patients generally believe that the private-sector provides high quality services, private diagnostic laboratories are largely unregulated and little is known about the accuracy of results provided. This study assesses the accuracy of sputum smear microscopy for pulmonary tuberculosis diagnosis in private laboratories operating in Karachi, Pakistan. A novel evaluation methodology was designed in which patient-actors submitted sputum specimens spiked with cultured Mycobacterium tuberculosis (Mtb) for testing such that laboratories were not aware that they were being assessed. METHODS: Smear-negative sputum specimens from Indus Hospital TB Program patients were collected and combined with an attenuated, cultured Mtb strain to create Mtb-spiked samples; for negative standards, no Mtb was added to the smear-negative sputum specimens. Seven of the largest private laboratories across Karachi were chosen for evaluation and were sent six Mtb-spiked and one Mtb-negative sputum specimens. Patient-actors pretending to be laboratory customers submitted these specimens to each laboratory for testing over a three day period. RESULTS: Only three laboratories accurately classified all the Mtb-spiked specimens which were submitted. A further three misclassified all the Mtb-spiked specimens as smear-negative, thus providing the 'patients' with false negative results. CONCLUSIONS: TB sputum smear microscopy services are highly variable across private laboratories and are often of extremely poor quality. Engagement, capacity building and rigorous monitoring of standards at private laboratories are of vital importance for the control of TB. Our findings, while specific for TB diagnostic tests, could be symptomatic of other tests performed in private laboratories and warrant further investigation.

Engaging the private sector to increase tuberculosis case detection: an impact evaluation study.

BACKGROUND: In many countries with a high burden of tuberculosis, most patients receive treatment in the private sector. We evaluated a multifaceted case-detection strategy in Karachi, Pakistan, targeting the private sector. METHODS: A year-long communications campaign advised people with 2 weeks or more of productive cough to seek care at one of 54 private family medical clinics or a private hospital that was also a national tuberculosis programme (NTP) reporting centre. Community laypeople participated as screeners, using an interactive algorithm on mobile phones to assess patients and visitors in family-clinic waiting areas and the hospital's outpatient department. Screeners received cash incentives for case detection. Patients with suspected tuberculosis also came directly to the hospital's tuberculosis clinic (self-referrals) or were referred there (referrals). The primary outcome was the change (from 2010 to 2011) in tuberculosis notifications to the NTP in the intervention area compared with that in an adjacent control area. FINDINGS: Screeners assessed 388,196 individuals at family clinics and 81,700 at Indus Hospital's outpatient department from January-December, 2011. A total of 2416 tuberculosis cases were detected and notified via the NTP reporting centre at Indus Hospital: 603 through family clinics, 273 through the outpatient department, 1020 from self-referrals, and 520 from referrals. In the intervention area overall, tuberculosis case notification to the NTP increased two times (from 1569 to 3140 cases) from 2010 to 2011--a 2·21 times increase (95% CI 1·93-2·53) relative to the change in number of case notifications in the control area. From 2010 to 2011, pulmonary tuberculosis notifications at Indus Hospital increased by 3·77 times for adults and 7·32 times for children. INTERPRETATION: Novel approaches to tuberculosis case-finding involving the private sector and using laypeople, mobile phone software and incentives, and communication campaigns can substantially increase case notification in dense urban settings. FUNDING: TB REACH, Stop TB Partnership.

Assessing the need for training: general practitioners' knowledge, attitude and practice concerning dengue and malaria in Karachi, Pakistan.

Changing environmental conditions have increased the transmission period for both dengue and malaria. Annual incidence of malaria in 2006 alone was 247 million cases leading to nearly 881 000 deaths; whereas another 50 to 100 million dengue infections, associated with an overall mortality of 2.5%, are expected each year. In Pakistan, like many developing nations with endemic malaria, an empirical clinical diagnosis is usually made, due to a lack of resources and availability of diagnostic facilities. Since both diseases are endemic in the same population and presenting symptoms are similar a thorough knowledge of both diseases is essential for improving diagnosis on clinical grounds. Thus our study aims were to evaluate knowledge, attitudes and practices of family medicine practitioners with regard to dengue and malaria and thereby assess the need for further training. Ninety consenting general practitioners (GPs) in different towns of Karachi, Pakistan were administered an extensive questionnaire of 50 questions regarding their knowledge, attitudes and practices on management of dengue and malaria. The authors concluded that despite possessing basic knowledge of the disease, the majority of GPs in the area needed training regarding both diseases and their management. Key targets identified for training programs included clinical diagnosis and management of endemic vector borne diseases.

Prevalence of mistreatment or belittlement among medical students--a cross sectional survey at a private medical school in Karachi, Pakistan.

BACKGROUND: Mistreatment or belittlement of medical students either by faculty or fellow students has often been reported. Perception of mistreatment has also been associated with increased degree of psychological morbidity. There is a lack of such studies being conducted amongst the medical students of Pakistan. The aim of this study was to determine the prevalence and forms of perceived mistreatment and presence of mental health morbidity in a private medical school in Pakistan. Also, any association between mental health morbidity and mistreatment was to be identified. METHODS: A cross sectional study was carried out on medical students from Aga Khan University Hospital, Karachi, Pakistan during the period of June-September 2007. A self administered questionnaire, adapted from Frank et al and Baldwin et al was distributed to a total of 350 students. The questionnaire consisted of three parts: the first dealing with the demographics of the population, the second concerning the various forms of mistreatment, while the third assessed the mental health of students using the General Health Questionnaire 12(GHQ12). Descriptive statistics were performed. The Chi-square test and Fisher's exact tests were applied. RESULTS: A total of 350 students were approached out of which 232 completed the questionnaire giving a response rate of 66.2%. Mistreatment was reported by 62.5% (145/232) of the respondents. Of these, 69.7% (83/145) were males and 54.9% (62/145) were females. There was a significant relationship between gender, year division, stress at medical school and possible use of drugs/alcohol and reported mistreatment but no statistical relationship was seen with psychiatric morbidity. The overall prevalence of psychological morbidity was 34.8% (77/221). CONCLUSION: This study suggests high prevalence of perceived mistreatment and psychological morbidity among Pakistani medical students. However, no association was found between these two aspects of medical student education. There is a need to bring about changes to make the medical education environment conducive to learning. Increased student feedback, support systems and guidance about progress throughout the year and the provision of adequate learning resources may provide help with resolving both of these issues.