A phase II study (AARDVARC) of AZD4635 in combination with durvalumab and cabazitaxel in patients with progressive, metastatic, castration-resistant prostate cancer.

BACKGROUND: This phase II nonrandomized study evaluated the efficacy and safety of AZD4635 in combination with durvalumab (Arm A) or durvalumab plus cabazitaxel (Arm B) in patients with metastatic castration-resistant prostate cancer (mCRPC) previously treated with docetaxel and ≥1 novel hormonal agent. PATIENTS AND METHODS: The primary endpoint was radiographic progression-free survival (rPFS) per RECIST v1.1 (soft tissue) or the Prostate Cancer Clinical Trials Working Group 3 (bone). Secondary endpoints included safety, tolerability, overall survival, confirmed prostate-specific antigen (PSA50) response, pharmacokinetics, and objective response rate. Enrollment in Arm A was stopped following a sponsor decision unrelated to safety. The study was stopped based on the planned futility analysis due to low PSA50 response in Arm B. RESULTS: In the final analysis (1 November 2021), 30 patients were treated (Arm A, n = 2; Arm B, n = 28). The median rPFS in Arm B was 5.8 months (95% confidence interval 4.2-not calculable). Median rPFS was 5.8 months versus 4.2 months for patients with high versus low blood-based adenosine signature. The most common treatment-related adverse events in Arm B were nausea (50.0%), diarrhea (46.4%), anemia and neutropenia (both 35.7%), asthenia (32.1%), and vomiting (28.6%). Overall, AZD4635 in combination with durvalumab or AZD4635 in combination with cabazitaxel and durvalumab showed limited efficacy in patients with mCRPC. CONCLUSIONS: Although the safety profile of both combinations was consistent with known safety data of the individual agents, the results of this trial do not support further development of the combinations.

Standards of Care for the Health of Transgender and Gender Diverse People, Version 8.

Background: Transgender healthcare is a rapidly evolving interdisciplinary field. In the last decade, there has been an unprecedented increase in the number and visibility of transgender and gender diverse (TGD) people seeking support and gender-affirming medical treatment in parallel with a significant rise in the scientific literature in this area. The World Professional Association for Transgender Health (WPATH) is an international, multidisciplinary, professional association whose mission is to promote evidence-based care, education, research, public policy, and respect in transgender health. One of the main functions of WPATH is to promote the highest standards of health care for TGD people through the Standards of Care (SOC). The SOC was initially developed in 1979 and the last version (SOC-7) was published in 2012. In view of the increasing scientific evidence, WPATH commissioned a new version of the Standards of Care, the SOC-8. Aim: The overall goal of SOC-8 is to provide health care professionals (HCPs) with clinical guidance to assist TGD people in accessing safe and effective pathways to achieving lasting personal comfort with their gendered selves with the aim of optimizing their overall physical health, psychological well-being, and self-fulfillment. Methods: The SOC-8 is based on the best available science and expert professional consensus in transgender health. International professionals and stakeholders were selected to serve on the SOC-8 committee. Recommendation statements were developed based on data derived from independent systematic literature reviews, where available, background reviews and expert opinions. Grading of recommendations was based on the available evidence supporting interventions, a discussion of risks and harms, as well as the feasibility and acceptability within different contexts and country settings. Results: A total of 18 chapters were developed as part of the SOC-8. They contain recommendations for health care professionals who provide care and treatment for TGD people. Each of the recommendations is followed by explanatory text with relevant references. General areas related to transgender health are covered in the chapters Terminology, Global Applicability, Population Estimates, and Education. The chapters developed for the diverse population of TGD people include Assessment of Adults, Adolescents, Children, Nonbinary, Eunuchs, and Intersex Individuals, and people living in Institutional Environments. Finally, the chapters related to gender-affirming treatment are Hormone Therapy, Surgery and Postoperative Care, Voice and Communication, Primary Care, Reproductive Health, Sexual Health, and Mental Health. Conclusions: The SOC-8 guidelines are intended to be flexible to meet the diverse health care needs of TGD people globally. While adaptable, they offer standards for promoting optimal health care and guidance for the treatment of people experiencing gender incongruence. As in all previous versions of the SOC, the criteria set forth in this document for gender-affirming medical interventions are clinical guidelines; individual health care professionals and programs may modify these in consultation with the TGD person.

Feasibility of Hyperfunctioning Parathyroid Gland Localization Using [18F]fluciclovine PET/CT.

PURPOSE: To evaluate the ability of anti-1-amino-3-anti-1-amino-3-[18F]fluorocyclobutane-1-carboxylic acid ([18F]fluciclovine) positron emission tomography/X-ray computed tomography (PET/CT) in comparison to Technetium-99m 2-methoxy isobutyl isonitrile ([99mTc]sestamibi) single-photon emission computed tomography/CT (SPECT/CT) for the localization of hyperfunctioning parathyroid glands in patients with hyperparathyroidism. PROCEDURES: Four patients with hyperparathyroidism underwent 60-minutes sequential neck and thorax PET/CT after [18F]fluciclovine (352 ± 28 MBq) injection. Lesion uptake and target-to-background ratios (TBR) were compared with [99mTc]sestamibi (798 ± 27 MBq) SPECT/CT in the same patient. RESULTS: Both techniques detected 4/5 hyperfunctioning parathyroid glands identified at surgery. The highest [18F]fluciclovine uptake and TBRs were at 5-9 min with rapid washout. [99mTc]sestamibi had significantly higher TBRs compared with [18F]fluciclovine (5-9 min) for blood pool (10.9 ± 4.7 vs 1.3 ± 0.6; p < 0.01) and reference muscle backgrounds (5.8 ± 3.0 vs 1.7 ± 0.6; p < 0.01), with non-significant trend for thyroid tissue background (1.3 ± 0.5 vs 1.1 ± 0.5; p = 0.73). CONCLUSION: Hyperfunctioning parathyroid glands can be detected on [18F]fluciclovine PET/CT at early imaging, but conspicuity (TBR) is better with [99mTc]sestamibi. [18F]fluciclovine PET/CT does not seem promising in the detection of hyperfunctioning parathyroid glands.

Selective modification of fluciclovine (18F) transport in prostate carcinoma xenografts.

We investigated if previously demonstrated inhibition of fluciclovine (18F) in vitro could be replicated in a PC3-Luc xenograft mouse model. Following intratumoral injection of 2-aminobicyclo-(2,2,1)-heptane-2-carboxylic acid (BCH), alpha-(methylamino)isobutyric acid (MeAIB) or saline, fluciclovine PET tumor-to-background activity was 43.6 (± 5.4)% and 25.3 (± 5.2)% lower in BCH (n = 6) and MeAIB (n = 5) injected PC3 Luc xenografts, respectively, compared to saline-injected controls (n = 2). Partial inhibition of fluciclovine uptake by BCH and MeAIB can be demonstrated in vivo similar to previous in vitro modeling.

Syndrome of Inappropriate Anti-Diuretic Hormone Secretion Secondary to Strongyloides stercoralis Infection in an Allogeneic Stem Cell Transplant Patient: A Case Report and Literature Review.

Syndrome of inappropriate anti-diuretic hormone (SIADH) has been reported to be associated with systemic Strongyloides stercoralis. Here, we report a case of a stem cell transplant (SCT) recipient who developed severe SIADH secondary to systemic S Stercoralis. The SIADH resolved quickly after treating the systemic S Stercoralis with ivermectin. A systematic review of the literature was performed by PubMed, Scopus, and Cochrane database search. Only eight cases of S Stercoralis in allogeneic SCT recipients have been previously reported. To our knowledge, ours is the first reported case of SIADH secondary to S Stercoralis infection in an allogeneic SCT recipient. Prior to transplantation, even if asymptomatic, patients from endemic regions should be screened with strongyloides immunoglobulin (Ig)G serology. Pretransplantation eosinophilia should be evaluated by screening multiple stool samples for ova and parasites. Transplant candidates with positive serology or stool tests can be treated pretransplantation to eradicate infection. Patients at risk for S Stercoralis who develop nonspecific gastrointestinal complaints, rash, pulmonary infiltrates, or gram-negative bacteremia or meningitis may have S Stercoralis hyperinfection syndrome. Our case indicates that the development of SIADH may be an additional clue to this diagnosis. Appropriate diagnostic studies, including repeat stool and other body fluid sampling, should be expedited and ivermectin therapy initiated rapidly to prevent significant morbidity and mortality.

Viral infections associated with oral cancers and diseases in the context of HIV: a workshop report.

Human herpesviruses (HHVs) and human papillomavirus (HPV) are common in the general population and, in immunocompetent people, are mostly carried asymptomatically. However, once an individual becomes immunocompromised by age, illness or HIV infection these dormant viruses can manifest and produce disease. In HIV-positive patients, there is an increased risk of disease caused by HHVs and HPV infections and cancers caused by the oncoviruses Epstein-Barr Virus, HHV-8 and HPV. This workshop examined four questions regarding the viruses associated with oral cancers and disease in the HIV-positive and -negative populations, the immune response, and biomarkers useful for accurate diagnostics of these infections and their sequalae. Each presenter identified a number of key areas where further research is required.

Moderators of intervention dose effects on diet quality and physical activity changes in a church-based, multicomponent, lifestyle study: Delta Body and Soul III.

Many community-based lifestyle interventions targeting African Americans have reported positive effects on participants' dietary choices and physical activity habits. However, these effects vary and not all participants will have outcome changes. Moderation analysis can help explain differential effects observed, but are not often reported. Hence, the objective of this secondary analysis was to explore potential moderators of intervention dose effects on diet quality and physical activity outcomes in an effective lifestyle intervention. Delta Body and Soul III, conducted from 2011 to 2012, was a 6-month, church-based, multicomponent, educational intervention designed to improve diet quality and increase physical activity in rural Southern African American adults. Generalized linear mixed models were used to determine associations among indicators of intervention dose received by participants, potential moderators and health outcome changes. Results indicated only three baseline characteristics-employment status, food shopping frequency and individual with primary responsibility for meal preparation-moderated the effects of education session attendance on diet quality changes. No evidence for moderation of exercise class attendance effects on physical activity changes was found. Thus, this culturally targeted, multicomponent lifestyle intervention did induce positive health changes in participants with a range of sociodemographic characteristics and food shopping and eating behaviors.

Preferences for return of incidental findings from genome sequencing among women diagnosed with breast cancer at a young age.

While experts have made recommendations, information is needed regarding what genome sequencing results patients would want returned. We investigated what results women diagnosed with breast cancer at a young age would want returned and why. We conducted 60 semi-structured, in-person individual interviews with women diagnosed with breast cancer at age 40 or younger. We examined interest in six types of incidental findings and reasons for interest or disinterest in each type. Two coders independently coded interview transcripts; analysis was conducted using NVivo 10. Most participants were at least somewhat interested in all six result types, but strongest interest was in actionable results (i.e. variants affecting risk of a preventable or treatable disease and treatment response). Reasons for interest varied between different result types. Some participants were not interested or ambivalent about results not seen as currently actionable. Participants wanted to be able to choose what results are returned. Participants distinguished between types of individual genome sequencing results, with different reasons for wanting different types of information. The findings suggest that a focus on actionable results can be a common ground for all stakeholders in developing a policy for returning individual genome sequencing results.

Obesity and survival among women with ovarian cancer: results from the Ovarian Cancer Association Consortium.

BACKGROUND: Observational studies have reported a modest association between obesity and risk of ovarian cancer; however, whether it is also associated with survival and whether this association varies for the different histologic subtypes are not clear. We undertook an international collaborative analysis to assess the association between body mass index (BMI), assessed shortly before diagnosis, progression-free survival (PFS), ovarian cancer-specific survival and overall survival (OS) among women with invasive ovarian cancer. METHODS: We used original data from 21 studies, which included 12 390 women with ovarian carcinoma. We combined study-specific adjusted hazard ratios (HRs) using random-effects models to estimate pooled HRs (pHR). We further explored associations by histologic subtype. RESULTS: Overall, 6715 (54%) deaths occurred during follow-up. A significant OS disadvantage was observed for women who were obese (BMI: 30-34.9, pHR: 1.10 (95% confidence intervals (CIs): 0.99-1.23); BMI: ⩾35, pHR: 1.12 (95% CI: 1.01-1.25)). Results were similar for PFS and ovarian cancer-specific survival. In analyses stratified by histologic subtype, associations were strongest for women with low-grade serous (pHR: 1.12 per 5 kg m(-2)) and endometrioid subtypes (pHR: 1.08 per 5 kg m(-2)), and more modest for the high-grade serous (pHR: 1.04 per 5 kg m(-2)) subtype, but only the association with high-grade serous cancers was significant. CONCLUSIONS: Higher BMI is associated with adverse survival among the majority of women with ovarian cancer.

Infertility and incident endometrial cancer risk: a pooled analysis from the epidemiology of endometrial cancer consortium (E2C2).

BACKGROUND: Nulliparity is an endometrial cancer risk factor, but whether or not this association is due to infertility is unclear. Although there are many underlying infertility causes, few studies have assessed risk relations by specific causes. METHODS: We conducted a pooled analysis of 8153 cases and 11 713 controls from 2 cohort and 12 case-control studies. All studies provided self-reported infertility and its causes, except for one study that relied on data from national registries. Logistic regression was used to estimate adjusted odds ratios (OR) and 95% confidence intervals (CI). RESULTS: Nulliparous women had an elevated endometrial cancer risk compared with parous women, even after adjusting for infertility (OR=1.76; 95% CI: 1.59-1.94). Women who reported infertility had an increased risk compared with those without infertility concerns, even after adjusting for nulliparity (OR=1.22; 95% CI: 1.13-1.33). Among women who reported infertility, none of the individual infertility causes were substantially related to endometrial cancer. CONCLUSIONS: Based on mainly self-reported infertility data that used study-specific definitions of infertility, nulliparity and infertility appeared to independently contribute to endometrial cancer risk. Understanding residual endometrial cancer risk related to infertility, its causes and its treatments may benefit from large studies involving detailed data on various infertility parameters.

Bone complications among prostate cancer survivors: long-term follow-up from the prostate cancer outcomes study.

BACKGROUND: To assess the relationship between androgen deprivation therapy (ADT) exposure and self-reported bone complications among men in a population-based cohort of prostate cancer survivors followed for 15 years after diagnosis. METHODS: The Prostate Cancer Outcomes Study enrolled 3533 patients diagnosed with prostate cancer between 1994 and 1995. This analysis included participants with non-metastatic disease at the time of diagnosis who completed 15-year follow-up surveys to report development of fracture, and use of bone-related medications. The relationship between ADT duration and bone complications was assessed using multivariable logistic regression models. RESULTS: Among 961 surviving men, 157 (16.3%) received prolonged ADT (>1 year), 120 (12.5%) received short-term ADT (⩽ 1 year) and 684 (71.2%) did not receive ADT. Men receiving prolonged ADT had higher odds of fracture (OR 2.5; 95% confidence interval (CI): 1.1-5.7), bone mineral density testing (OR 5.9; 95% CI: 3.0-12) and bone medication use (OR 4.3; 95% CI: 2.3-8.0) than untreated men. Men receiving short-term ADT reported rates of fracture similar to untreated men. Half of men treated with prolonged ADT reported bone medication use. CONCLUSIONS: In this population-based cohort study with long-term follow-up, prolonged ADT use was associated with substantial risks of fracture, whereas short-term use was not. This information should be considered when weighing the advantages and disadvantages of ADT in men with prostate cancer.

Cancers among US organ donors: a comparison of transplant and cancer registry diagnoses.

Transmission of cancer is a life-threatening complication of transplantation. Monitoring transplantation practice requires complete recording of donor cancers. The US Scientific Registry of Transplant Recipients (SRTR) captures cancers in deceased donors (beginning in 1994) and living donors (2004). We linked the SRTR (52,599 donors, 110,762 transplants) with state cancer registries. Cancer registries identified cancers in 519 donors: 373 deceased donors (0.9%) and 146 living donors (1.2%). Among deceased donors, 50.7% of cancers were brain tumors. Among living donors, 54.0% were diagnosed after donation; most were cancers common in the general population (e.g. breast, prostate). There were 1063 deceased donors with cancer diagnosed in the SRTR or cancer registry, and the SRTR lacked a cancer diagnosis for 107 (10.1%) of these. There were 103 living donors with cancer before or at donation, diagnosed in the SRTR or cancer registry, and the SRTR did not have a cancer diagnosis for 43 (41.7%) of these. The SRTR does not record cancers after donation in living donors and so missed 81 cancers documented in cancer registries. In conclusion, donor cancers are uncommon, but lack of documentation of some cases highlights a need for improved ascertainment and reporting by organ procurement organizations and transplant programs.

Ethnic differences in serum adipokine and C-reactive protein levels: the multiethnic cohort.

BACKGROUND: Ethnic disparities in metabolic disease risk may be the result of differences in circulating adipokines and inflammatory markers related to ethnic variations in obesity and body fat distribution. SUBJECTS/METHODS: In a cross-sectional design, we compared serum levels of leptin, adiponectin, C-reactive protein (CRP), interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) in control subjects (321 men and 930 women) from two nested case-control studies conducted within the Multiethnic Cohort Study consisting of whites, Japanese Americans (JA), Latinos, African Americans (AA) and Native Hawaiians (NH). General linear models were applied to evaluate ethnic differences in log-transformed serum biomarker levels before and after adjusting for body mass index (BMI) at cohort entry. RESULTS: In comparison to whites, significant ethnic differences were observed for all biomarkers except TNF-α. JA men and women had significantly lower leptin and CRP levels than whites, and JA women also had lower adiponectin levels. Leptin was significantly higher in AA women (P < 0.01), adiponectin was significantly lower in AA men and women (P = 0.02 and P < 0.001), and CRP and IL-6 were significantly higher in AA men and women. Lower adiponectin (P < 0.0001) and CRP (P = 0.03) levels were the only biomarkers in NH women that differed from whites; no statistically significant differences were seen for NH men and for Latino men and women. When adjusted for BMI at cohort entry, the differences between the lowest and the highest values across ethnic groups decreased for all biomarkers except adiponectin in men indicating that ethnic differences were partially due to weight status. CONCLUSIONS: These findings demonstrate the ethnic variations in circulating adipokine and CRP levels before and after adjustment for BMI. Given the limitation of BMI as a general measure of obesity, further investigation with visceral and subcutaneous adiposity measures are warranted to elucidate ethnicity-related differences in adiposity in relation to disparities in obesity-related disease risk.

Oestradiol alters central 5-HT1A receptor binding potential differences related to psychosocial stress but not differences related to 5-HTTLPR genotype in female rhesus monkeys.

Social subordination in female macaques represents a well-described model of chronic psychosocial stress. Additionally, a length polymorphism (5-HTTLPR) in the regulatory region of the serotonin (5-HT) transporter (5-HTT) gene (SLC6A4) is present in rhesus macaques, which has been linked to adverse outcomes similar to that described in humans with an analogous 5-HTTLPR polymorphism. The present study determined the effects of social status and the 5-HTTLPR genotype on 5-HT1A receptor binding potential (5-HT1A BP(ND)) in brain regions implicated in emotional regulation and stress reactivity in ovariectomised female monkeys, and then assessed how these effects were altered by 17ß-oestradiol (E(2)) treatment. Areas analysed included the prefrontal cortex [anterior cingulate (ACC); medial prefrontal cortex (mPFC); dorsolateral prefrontal cortex; orbitofrontal prefrontal cortex], amygdala, hippocampus, hypothalamus and raphe nucleui. Positron emission tomography using p-[(18) F]MPPF was performed to determine the levels of 5-HT1A BP(ND) under a non-E(2) and a 3-week E(2) treatment condition. The short variant (s-variant) 5-HTTLPR genotype produced a significant reduction in 5-HT1A BP(ND) in the mPFC regardless of social status, and subordinate s-variant females showed a reduction in 5-HT1A BP(ND) within the ACC. Both these effects of 5-HTTLPR were unaffected by E(2). Additionally, E(2) reduced 5-HT1A BP(ND) in the dorsal raphe of all females irrespective of psychosocial stress or 5-HTTLPR genotype. Hippocampal 5-HT1A BP(ND) was attenuated in subordinate females regardless of 5-HTTLPR genotype during the non-E(2) condition, an effect that was normalised with E(2). Similarly, 5-HT1A BP(ND) in the hypothalamus was significantly lower in subordinate females regardless of 5-HTTLPR genotype, an effect reversed with E(2). Taken together, the data indicate that the effect of E(2) on modulation of central 5HT1A BP(ND) may only occur in brain regions that show no 5-HTTLPR genotype-linked control of 5-HT1A binding.

Consensus guidelines from The American Society of Peritoneal Surface Malignancies on standardizing the delivery of hyperthermic intraperitoneal chemotherapy (HIPEC) in colorectal cancer patients in the United States.

BACKGROUND: The American Society of Peritoneal Surface Malignancies (ASPSM) is a consortium of cancer centers performing cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (HIPEC). This is a position paper from the ASPSM on the standardization of the delivery of HIPEC. METHODS: A survey was conducted of all cancer centers performing HIPEC in the United States. We attempted to obtain consensus by the modified method of Delphi on seven key HIPEC parameters: (1) method, (2) inflow temperature, (3) perfusate volume, (4) drug, (5) dosage, (6) timing of drug delivery, and (7) total perfusion time. Statistical analysis was performed using nonparametric tests. RESULTS: Response rates for ASPSM members (n = 45) and non-ASPSM members (n = 24) were 89 and 33 %, respectively. Of the responders from ASPSM members, 95 % agreed with implementing the proposal. Majority of the surgical oncologists favored the closed method of delivery with a standardized dual dose of mitomycin for a 90-min chemoperfusion for patients undergoing cytoreductive surgery for peritoneal carcinomatosis of colorectal origin. CONCLUSIONS: This recommendation on a standardized delivery of HIPEC in patients with colorectal cancer represents an important first step in enhancing research in this field. Studies directed at maximizing the efficacy of each of the seven key elements will need to follow.

HPV-related cancers after solid organ transplantation in the United States.

Transplant recipients have elevated cancer risk including risk of human papillomavirus (HPV)-associated cancers of the cervix, anus, penis, vagina, vulva and oropharynx. We examined the incidence of HPV-related cancers in 187 649 US recipients in the Transplant Cancer Match Study. Standardized incidence ratios (SIRs) compared incidence rates to the general population, and incidence rate ratios (IRRs) compared rates across transplant subgroups. We observed elevated incidence of HPV-related cancers (SIRs: in situ 3.3-20.3, invasive 2.2-7.3), except for invasive cervical cancer (SIR 1.0). Incidence increased with time since transplant for vulvar, anal and penile cancers (IRRs 2.1-4.6 for 5+ vs. <2 years). Immunophenotype, characterized by decreased incidence with HLA DRB1:13 and increased incidence with B:44, contributed to susceptibility at several sites. Use of specific immunosuppressive medications was variably associated with incidence; for example, tacrolimus, was associated with reduced incidence for some anogenital cancers (IRRs 0.4-0.7) but increased incidence of oropharyngeal cancer (IRR 2.1). Thus, specific features associated with recipient characteristics, transplanted organs and medications are associated with incidence of HPV-related cancers after transplant. The absence of increased incidence of invasive cervical cancer highlights the success of cervical screening in this population and suggests a need for screening for other HPV-related cancers.

CRH receptor antagonism reverses the effect of social subordination upon central GABAA receptor binding in estradiol-treated ovariectomized female rhesus monkeys.

Persistent exposure to environmental stressors causes dysregulation of the limbic-hypothalamic-pituitary-adrenal (LHPA) axis and alters GABAA receptor (GABAAR) levels throughout the brain. Social subordination in socially housed female rhesus results in distinctive stress-related physiological and behavioral phenotypes that are dependent on the ovarian hormone estradiol (E2). In the present study, we utilized ovariectomized adult female rhesus monkeys undergoing hormone replacement with E2 to test the hypothesis that the chronic psychosocial stress of subordination alters GABAAR binding potential (GABAAR BPND) in limbic regions implicated in emotional processing including the prefrontal cortex, temporal lobe (amygdala and hippocampus), and hypothalamus. Furthermore, we tested the hypothesis that peripheral administration of a corticotropin-releasing hormone (CRH) receptor antagonist (astressin B) would reverse the alterations in GABAAR binding within these regions in subordinate females. After subjects received astressin B or saline for three consecutive days, GABAAR BPND was determined by positron emission tomography (PET) using (18)F-flumazenil as a radioligand. T1-weighted structural magnetic resonance imaging scans were also acquired for PET scan co-registration, in order to perform a region of interest analysis using the pons as a reference region. Compared to socially dominant females, subordinate females exhibited increased GABAAR BPND in the prefrontal cortex but not in the temporal lobe or the hypothalamus. Administration of astressin B eliminated the status difference in GABAAR BPND in the prefrontal cortex, suggesting that the chronic stressor of social subordination modulates GABAergic tone via effects on CRH and the LHPA axis, at least in prefrontal regions.

Surgical interventions for drug-resistant tuberculosis: a systematic review and meta-analysis.

BACKGROUND: With the emergence of multidrug-resistant (MDR-) and extensively drug-resistant tuberculosis (XDR-TB), surgery, which had been replaced by short-course chemotherapy, is again being considered a viable treatment option. OBJECTIVE: To assess the literature on the effectiveness of surgical interventions in the treatment of drug-resistant TB. METHODS: Medline, EMBASE, and PubMed were searched from 1975 to April 2012 in addition to hand searching reference lists, and the International Journal of Tuberculosis and Lung Disease. Potentially relevant studies were assessed according to pre-defined eligibility criteria: MDR- and XDR-TB patients undergoing surgical and non-surgical treatment. Treatment outcomes were extracted according to internationally accepted definitions and included in meta-analyses using random effects models. RESULTS: Summary meta-analysis of 24 comparison studies revealed a significant association between surgery and successful treatment compared to non-surgical interventions (OR 2.24, 95%CI 1.68-2.97). A meta-analysis from 23 single-arm studies demonstrated that respectively 92% (95%CI 88.1-95) and 87% (95%CI 83-91) of surgical patients achieved successful short- and long-term outcomes. Subgroup analyses showed that favorable surgical outcomes were associated with increased drug resistance in studies reporting surgical and non-surgical treatment outcomes. CONCLUSIONS: While the results suggest that surgical intervention is associated with successful treatment outcomes in patients with drug-resistant TB, there is insufficient evidence to recommend surgery plus chemotherapy over chemotherapy alone, to evaluate the potential harm from surgery and to determine the optimal conditions for surgery. Controlled studies are needed to better assess the effectiveness of surgery and to investigate other contextual issues.

A comprehensive review of incidence and survival in patients with rare histological variants of prostate cancer in the United States from 1973 to 2008.

BACKGROUND: The American Joint Commission on Cancer (AJCC) identifies five rare variants of prostate adenocarcinoma: mucinous, ductal, signet ring cell, adenosquamous and neuroendocrine including small cell. No prior study has comprehensively detailed incidence and outcomes for all AJCC variants of prostate cancer. METHODS: We used the Surveillance, Epidemiology and End Results (SEER) program to analyze prostate cancers diagnosed from 1973 to 2008. Cases of mucinous, ductal, signet ring cell, adenosquamous and neuroendocrine carcinoma were identified, along with cases of non-variant adenocarcinoma for comparison. Age-adjusted incidence rates (IRs) and overall survival (OS) were evaluated and stratified by race, age, stage and PSA. All IRs represent the number of cases per million people per year. RESULTS: Each variant is rare, with IRs between 0.03 (adenosquamous) and 0.61 (mucinous). There was a significant difference in incidence between Caucasian and African American patients with mucinous adenocarcinoma. Median OS varied ranged from 10.0 months in neuroendocrine carcinoma to 125.0 months in mucinous adenocarcinoma. In all, 5-year OS ranged from 12.6% in neuroendocrine carcinoma to 75.1% in mucinous adenocarcinoma. There was a significant difference in survival between Caucasian and African American patients for mucinous adenocarcinoma (median survival 144.0 vs 99.0 months, P<0.01). African American patients with mucinous adenocarcinoma also presented with more advanced stage disease compared with Caucasian patients. Multivariate analysis demonstrated that African American race was not associated with worse survival when corrected for stage. CONCLUSIONS: There are differences in IRs and OS among rare variants of prostate cancer. For mucinous adenocarcinoma, there are significant differences in incidence and survival between Caucasian and African American patients. These differences should be considered in clinical decision making for patients with these malignancies.