Biomarker-directed targeted therapy plus durvalumab in advanced non-small-cell lung cancer: a phase 2 umbrella trial.

For patients with non-small-cell lung cancer (NSCLC) tumors without currently targetable molecular alterations, standard-of-care treatment is immunotherapy with anti-PD-(L)1 checkpoint inhibitors, alone or with platinum-doublet therapy. However, not all patients derive durable benefit and resistance to immune checkpoint blockade is common. Understanding mechanisms of resistance-which can include defects in DNA damage response and repair pathways, alterations or functional mutations in STK11/LKB1, alterations in antigen-presentation pathways, and immunosuppressive cellular subsets within the tumor microenvironment-and developing effective therapies to overcome them, remains an unmet need. Here the phase 2 umbrella HUDSON study evaluated rational combination regimens for advanced NSCLC following failure of anti-PD-(L)1-containing immunotherapy and platinum-doublet therapy. A total of 268 patients received durvalumab (anti-PD-L1 monoclonal antibody)-ceralasertib (ATR kinase inhibitor), durvalumab-olaparib (PARP inhibitor), durvalumab-danvatirsen (STAT3 antisense oligonucleotide) or durvalumab-oleclumab (anti-CD73 monoclonal antibody). Greatest clinical benefit was observed with durvalumab-ceralasertib; objective response rate (primary outcome) was 13.9% (11/79) versus 2.6% (5/189) with other regimens, pooled, median progression-free survival (secondary outcome) was 5.8 (80% confidence interval 4.6-7.4) versus 2.7 (1.8-2.8) months, and median overall survival (secondary outcome) was 17.4 (14.1-20.3) versus 9.4 (7.5-10.6) months. Benefit with durvalumab-ceralasertib was consistent across known immunotherapy-refractory subgroups. In ATM-altered patients hypothesized to harbor vulnerability to ATR inhibition, objective response rate was 26.1% (6/23) and median progression-free survival/median overall survival were 8.4/22.8 months. Durvalumab-ceralasertib safety/tolerability profile was manageable. Biomarker analyses suggested that anti-PD-L1/ATR inhibition induced immune changes that reinvigorated antitumor immunity. Durvalumab-ceralasertib is under further investigation in immunotherapy-refractory NSCLC.ClinicalTrials.gov identifier: NCT03334617.

Case Report: Extensive Gangrene: A Rare Presentation of Multisystem Inflammatory Syndrome in Children.

A wide spectrum of cutaneous manifestations are reported in multisystem inflammatory syndrome in children (MIS-C). However, gangrenous changes are less frequently reported. A 3-year old boy, with a known case of unoperated tetralogy of Fallot, presented with a short history of fever, rash, and melena. The rash was black and diffuse, with a rapid progression. The patient was stable hemodynamically at admission, with pallor, grade II clubbing, edema, and oral ulcers. Inflammatory markers were raised. He developed gangrenous changes over the ears and acral areas. He had very high levels of antibodies to severe acute respiratory syndrome coronavirus2 (SARS-CoV-2) infection and was diagnosed as having MIS-C. Skin biopsy revealed near total epidermal necrosis with dermal vascular thrombi and negative immunofluorescence. Skin biopsy was positive for IgG antibodies to SARS-CoV-2. He was treated with antibiotics, immunomodulation with steroids, intravenous immunoglobulin, and plasmapheresis. He had features of both micro- and macroangiopathy. Gradually the child improved, with residual deformity.

Technical Tips in Managing Large Median Lobes During Robot-assisted Radical Prostatectomy.

Prostate cancer surgeons are commonly faced by a technically challenging situation dealing with prostate cancer having large median lobes. Patients with large median lobes often have larger prostates, which makes it difficult to visualize anatomical planes during robot-assisted radical prostatectomy (RARP). Herein, we described our experience in dealing with large median lobes during RARP. We have focused on technical tips to avoid complications and facilitate a smooth procedure in patients with large median lobes during RARP. A total of 2671 patients who underwent RARP were divided into two groups based on the presence or absence of a protruded median lobe (PML): group A (2411 patients without a PML) and group B (260 patients with a PML). All patients underwent preoperative magnetic resonance imaging and final intraoperative confirmation for the presence of a PML. Pre-, intra-, and postoperative parameters were compared in two groups using the Student t test and two-proportion t test as appropriate. Patients in group B have statistically significantly higher median prostate-specific antigen (PSA; 7.7 vs 5.8 ng/dl), PSA density (0.17 vs 0.09), and International Prostate Symptom Score (19.5 vs 7.2); longer median console time (114 vs 134 min) and surgery time (145 vs 170 min); and higher blood loss (150 vs 175 ml) than those in group A. There were no statistically significant differences in pathological stages (T2, T3; 87%, 13% vs 88%, 12%) and rates of positive surgical margins (7% vs 8.5%) between groups A and B. Single-center and retrospective design was the major limitation of our study. We conclude that understanding the key steps to facilitate bladder neck dissection is vital to avoid serious intraoperative events and to maximize outcomes. Patient summary: In this report, we looked at our robotic radical prostatectomy cohort with large median lobes. We found that surgery in these patients requires more time and blood loss, but similar cancer control. We conclude that following the key steps are important to avoid complications.

Medium-Term Real-World Outcomes of Minimally Invasive Surgical Therapies for Benign Prostatic Hyperplasia: Water Vapor Thermal Therapy (Rezum) vs Prostatic Urethral Lift (UroLift) in a High-Volume Urban Academic Center.

Purpose: Water vapor thermal therapy (WVTT, i.e., Rezum®) and prostatic urethral lift (PUL, i.e., Urolift®) are minimally invasive surgical therapy (MIST) options for benign prostatic hyperplasia (BPH). Few studies have directly compared the two procedures. We examined the clinical characteristics and postoperative outcomes of patients undergoing WVTT and PUL at our high-volume urban academic center. Methods: We reviewed our institutional MIST database to identify patients with prostate sizes ≥30 and ≤80 cc who underwent WVTT or PUL for treatment of BPH between January 2017 and September 2021. Pre- and postoperative outcomes, including retreatment rates, American Urological Association symptom score (AUA-SS), maximum flow (Qmax), postvoid residual (PVR), medication usage, trial of void success rates, catheterization requirements, and postoperative complications within 90 days were extracted and compared between procedures. Results: Three hundred seven patients received WVTT and 110 patients received PUL with average follow-up times of 11.3 and 12.8 months, respectively. WVTT patients showed significant improvements in AUA-SS, Qmax, and PVR, whereas PUL patients showed improvements in only AUA-SS and Qmax. Both WVTT and PUL patients with longitudinal follow-up demonstrated improvements in AUA-SS, Qmax, and PVR. Postoperatively, alpha-blocker utilization was significantly decreased following both WVTT and PUL (WVTT: 73.9%-46.6%, PUL: 76.4%-38.2%, both p < 0.001). Compared to patients receiving PUL, WVTT patients more frequently reported postoperative dysuria (22.8% vs 8.3%, p = 0.001) and nonclot-related retention (18.9% vs 7.3%, p = 0.005); PUL patients more frequently experienced postoperative clot retention (7.3% vs 2.6%, p = 0.027). There were no differences in rates of postoperative bladder spasm, trial of void success, urinary tract infections, or emergency department visits. Postoperative erectile dysfunction and retrograde ejaculation were rare and occurred at similar rates. Conclusion: In the real-world setting, WVTT and PUL have similar medium-term efficacy in improving symptoms and decreasing medication utilization for patients with BPH. Differences in postoperative complication profiles should inform patient counseling.

PARP inhibition is a modulator of anti-tumor immune response in BRCA-deficient tumors.

PARP inhibitors are synthetically lethal with BRCA1/2 mutations, and in this setting, accumulation of DNA damage leads to cell death. Because increased DNA damage and subsequent immune activation can prime an anti-tumor immune response, we studied the impact of olaparib ± immune checkpoint blockade (ICB) on anti-tumor activity and the immune microenvironment. Concurrent combination of olaparib, at clinically relevant exposures, with ICB gave durable and deeper anti-tumor activity in the Brca1m BR5 model vs. monotherapies. Olaparib and combination treatment modulated the immune microenvironment, including increases in CD8+ T cells and NK cells, and upregulation of immune pathways, including type I IFN and STING signaling. Olaparib also induced a dose-dependent upregulation of immune pathways, including JAK/STAT, STING and type I IFN, in the tumor cell compartment of a BRCA1m (HBCx-10) but not a BRCA WT (HBCx-9) breast PDX model. In vitro, olaparib induced BRCAm tumor cell-specific dendritic cell transactivation. Relevance to human disease was assessed using patient samples from the MEDIOLA (NCT02734004) trial, which showed increased type I IFN, STING, and JAK/STAT pathway expression following olaparib treatment, in line with preclinical findings. These data together provide evidence for a mechanism and schedule underpinning potential benefit of ICB combination with olaparib.

Robot-assisted vs ultrasonography-guided transversus abdominis plane (TAP) block vs local anaesthesia in urology: results of the UROTAP randomized trial.

OBJECTIVES: To prospectively analyse robotically administered transperitoneal transversus abdominis plane (robot-assisted transversus abdominis plane [RTAP]) compared with both ultrasonography-guided transversus abdominis plane (UTAP) and local anaesthesia (LA) with regard to pain control and narcotic use in patients undergoing robot-assisted prostatectomy (RARP) or robot-assisted partial nephrectomy (RAPN). SUBJECTS/PATIENTS AND METHODS: Patients undergoing RARP or RAPN were randomized in a single-blind 2:2:1 fashion to RTAP:UTAP:LA, with the study powered to evaluate superiority of UTAP to LA and non-inferiority of RTAP to UTAP. We compared time to deliver the block, operating room time, postoperative pain scores using the visual analogue scale, and intra-operative and postoperative analgesia consumption. RESULTS: A total of 143 patients were randomized and received treatment. There was no significant difference in patient baseline characteristics. UTAP did not demonstrate superiority to LA in terms of pain control. RTAP and LA were faster to administer than UTAP (time to perform block 2.5 vs 2.5 vs 6.25 min; P < 0.001). There was no difference in postoperative narcotic, acetaminophen, ketorolac or ondansetron requirements among the three groups (P > 0.05). The study was terminated early due to the unexpected efficacy of LA. CONCLUSION: This study showed that UTAP and RTAP do not provide superior pain control to LA. The efficiency, effectiveness, and ease of administration of LA make it an excellent option for first-line therapy for postoperative analgesia.

A preclinical model of peripheral T-cell lymphoma GATA3 reveals DNA damage response pathway vulnerability.

Peripheral T-cell lymphoma (PTCL) represents a rare group of heterogeneous diseases in urgent need of effective treatments. A scarcity of disease-relevant preclinical models hinders research advances. Here, we isolated a novel mouse (m)PTCL by serially transplanting a lymphoma from a germinal center B-cell hyperplasia model (Cγ1-Cre Blimp1fl/fl ) through immune-competent mice. Lymphoma cells were identified as clonal TCRß+ T-helper cells expressing T-follicular helper markers. We also observed coincident B-cell activation and development of a de novo B-cell lymphoma in the model, reminiscent of B-cell activation/lymphomagenesis found in human PTCL. Molecular profiling linked the mPTCL to the high-risk "GATA3" subtype of PTCL, showing GATA3 and Th2 gene expression, PI3K/mTOR pathway enrichment, hyperactivated MYC, and genome instability. Exome sequencing identified a human-relevant oncogenic ß-catenin mutation possibly involved in T-cell lymphomagenesis. Prolonged treatment responses were achieved in vivo by targeting ATR in the DNA damage response (DDR), a result corroborated in PTCL cell lines. This work provides mechanistic insight into the molecular and immunological drivers of T-cell lymphomagenesis and proposes DDR inhibition as an effective and readily translatable therapy in PTCL.

Rezum therapy for patients with large prostates (≥ 80 g): initial clinical experience and postoperative outcomes.

PURPOSE: Rezum is a minimally invasive surgery for benign prostatic hyperplasia. Current guidelines recommend Rezum for prostates < 80 cc, but little data exist describing outcomes in patients with prostates ≥ 80 cc. We compare outcomes after Rezum between men with small < 80 cc (SP) and large ≥ 80 cc prostates (LP). METHODS: Patients undergoing Rezum between Jan 2017-Feb 2020 were subdivided by prostate volume (< 80, ≥ 80 cc). Outcomes were documented pre- and postoperatively. Descriptive analyses of urodynamics data (Qmax, PVR), symptom scores (AUA-SS, SHIM), disease management (medications, catheterization, retreatments), and clinical outcomes were conducted. RESULTS: 36 (17.6%) men had prostates ≥ 80 cc (LP mean prostate size 106.8 cc). LP men had improved Qmax and PVR postoperatively; those with longitudinal follow-up exhibited improved Qmax, PVR, and AUA-SS. After one year, alpha-blocker usage decreased significantly (LP 94.44-61.11%, p = 0.001, SP 73.96-46.15%, p = 0.001); other medication usage and self-catheterization rates remained unchanged. Compared to SP patients, differences in passing trial void (LP 94.44%, SP 93.45%), postoperative UTI (LP 19.44%, SP 10.12%), ED visits (LP 22.22%, SP 17.86%), readmissions (LP 8.33%, SP 4.76%), and retreatment (LP 8.33%, SP 4.76%) were insignificant. However, mean days to foley removal (LP 9, SP 5.71, p = 0.003) and urosepsis rates (LP 5.56%, SP 0.00%, p = 0.002) differed. CONCLUSION: In select LP patients, Rezum provided short-term symptomatic relief and improved voiding function comparable to SP patients. Postoperatively, though alpha-blocker usage decreased significantly, use of other medications did not change, and nearly two-thirds of patients still needed alpha-blockade. Further efforts should explore the possibility of expanding Rezum's inclusion criteria.

Robotic-Assisted Partial Nephrectomy and Adrenalectomy: Case of a Pheochromocytoma Invading into Renal Parenchyma.

Although upper pole renal masses and adrenal masses can usually be distinguished on cross-sectional imaging, large masses can obscure the boundaries between the kidney and adrenal gland. We describe a unique case of an adrenal pheochromocytoma in a 42-year-old female who was referred for robotic partial nephrectomy. During the procedure, the patient developed severe hypertension. The case was aborted, and the workup revealed pheochromocytoma. After appropriate pretreatment, the patient underwent a successful robotic adrenalectomy and partial nephrectomy. Therefore, we recommend screening patients with hypertension and large upper pole masses for pheochromocytoma to better direct preoperative management.

Genetic Alterations in the PI3K/AKT Pathway and Baseline AKT Activity Define AKT Inhibitor Sensitivity in Breast Cancer Patient-derived Xenografts.

PURPOSE: AZD5363/capivasertib is a pan-AKT catalytic inhibitor with promising activity in combination with paclitaxel in triple-negative metastatic breast cancer harboring PI3K/AKT-pathway alterations and in estrogen receptor-positive breast cancer in combination with fulvestrant. Here, we aimed to identify response biomarkers and uncover mechanisms of resistance to AZD5363 and its combination with paclitaxel. EXPERIMENTAL DESIGN: Genetic and proteomic markers were analyzed in 28 HER2-negative patient-derived xenografts (PDXs) and in patient samples, and correlated to AZD5363 sensitivity as single agent and in combination with paclitaxel. RESULTS: Four PDX were derived from patients receiving AZD5363 in the clinic which exhibited concordant treatment response. Mutations in PIK3CA/AKT1 and absence of mTOR complex 1 (mTORC1)-activating alterations, for example, in MTOR or TSC1, were associated with sensitivity to AZD5363 monotherapy. Interestingly, excluding PTEN from the composite biomarker increased its accuracy from 64% to 89%. Moreover, resistant PDXs exhibited low baseline pAKT S473 and residual pS6 S235 upon treatment, suggesting that parallel pathways bypass AKT/S6K1 signaling in these models. We identified two mechanisms of acquired resistance to AZD5363: cyclin D1 overexpression and loss of AKT1 p.E17K. CONCLUSIONS: This study provides insight into putative predictive biomarkers of response and acquired resistance to AZD5363 in HER2-negative metastatic breast cancer.

Occurrence, antimicrobial susceptibility patterns and genotypic relatedness of Salmonella spp. isolates from captive wildlife, their caretakers, feed and water in India.

Occurrence of Salmonella spp. in captive wild animal species in India is largely unknown. The purpose of this study was to determine the occurrence of different Salmonella serotypes, antimicrobial resistance patterns and genotypic relatedness of recovered isolates. A total of 370 samples including faecal (n = 314), feed and water (n = 26) and caretakers stool swabs (n = 30) were collected from 40 different wild animal species in captivity, their caretakers, feed and water in four zoological gardens and wildlife enclosures in India. Salmonellae were isolated using conventional culture methods and tested for antimicrobial susceptibility with the Kirby-Bauer disc diffusion method. Salmonella isolates were serotyped and genotyping was performed using enterobacterial repetitive intergenic consensus (ERIC) PCR and 16S rRNA sequencing. Animal faecal samples were also subjected to direct PCR assay. Salmonella was detected in 10 of 314 (3.1%) faecal samples by isolation and 18 of 314 (5.7%) samples by direct PCR assay; one of 26 (3.8%) feed and water samples and five of 30 (16.7%) caretakers stool swabs by isolation. Salmonella was more commonly isolated in faecal samples from golden pheasants (25%; 2/8) and leopard (10%; 2/20). Salmonella enterica serotypes of known public health significance including S. Typhimurium (37.5%; 6/14), S. Kentucky (28.5%; 4/14) and S. Enteritidis (14.3%; 2/14) were identified. While the majority of the Salmonella isolates were pan-susceptible to the commonly used antibiotics. Seven (43.7%; 7/16) of the isolates were resistant to at least one antibiotic and one isolate each among them exhibited penta and tetra multidrug-resistant types. Three S. Kentucky serotype were identified in a same golden pheasants cage, two from the birds and one from the feed. This serotype was also isolated from its caretaker. Similarly, one isolate each of S. Typhimurium were recovered from ostrich and its caretaker. These isolates were found to be clonally related suggesting that wildlife may serve as reservoir for infections to humans and vice versa. These results emphasise the transmission of Salmonella among hosts via environmental contamination of feces to workers, visitors and other wildlife.

Role of Preablative Stimulated Thyroglobulin in Prediction of Nodal and Distant Metastasis on Iodine Whole-Body Scan.

BACKGROUND: Preablative stimulated thyroglobulin (ps-Tg) is an important investigation in the follow-up of patients with Differentiated thyroid cancer(DTC) after surgery. Levels of ps-Tg >2-10 ng/ml have been suggested to predict metastasis to cervical and extracervical sites. There is still debate on the need for routine iodine whole-body scan (131I WBS) in the management of low-to-intermediate-risk DTC patients. OBJECTIVE: We analyzed our data of patients with DTC who underwent total thyroidectomy to discuss the predictability of ps-Tg on metastatic disease on the 131I WBS. MATERIALS AND METHODS: Retrospective analysis of patient records. RESULTS: One hundred and seventeen patients with DTC (95 papillary thyroid cancer [71 had classic histology, 8 had tall cell variant, 16 had follicular variant] and 22 follicular thyroid cancer [18 minimally invasive, 2 hurtle cell, and 2 widely invasive cancers]) had undergone total thyroidectomy. All these patients underwent ps-Tg assessment and an 131I WBS. About 65% of them went on to have radioiodine ablation along with a posttherapy 131I WBS. We divided the cohort into four groups based on their ps-Tg levels: Group 1 (ps-Tg <1), Group 2 (ps-Tg 1-1.9), Group 3 (ps-Tg 2-5), and Group 4 (ps-Tg >5). None of the patients in Group 1, 7% of those combined in Groups 2 and 3 (2 out of 28 patients), and 26% (12 out of 47) of those in Group 4 had either cervical or extracervical metastasis. Those with extracervical metastatic disease to lungs and bones had a mean (standard deviation) ps-Tg value of 436 (130) and median of 500 ng/ml and those with cervical metastatic disease had a mean Tg value of 31 (64) and median 6.6 ng/ml. CONCLUSIONS: A ps-Tg value in the absence of anti-Tg antibodies <1 ng/ml reliably excludes metastatic disease in DTC, while a value >5 ng/ml has a 26% risk of having either cervical or extracervical metastasis.

Diversity of toxin-genotypes among Clostridium perfringens isolated from healthy and diarrheic neonatal cattle and buffalo calves.

The diversity of toxin-genotypes of C. perfringens in neonatal calves was determined in this study. A total of 682 fresh faecal samples comprising 559 healthy and 123 diarrheic neonatal calves (cattle and buffalo) were collected from various farms in Northern India. The samples were processed for isolation of C. perfringens and toxin-genotyping by multiplex PCR. The overall prevalence of C. perfringens was 37.2%. The most predominant toxin-genotype was type A (59.7%) and the least prevalent was type C. There was no association between toxin genotypes and diarrhea of cattle and buffalo neonatal calves (P > .05). Also, 38 (14.6%) and 16 (6.1%) isolates out of the 259 carried enterotoxin (cpe) and beta 2 toxin (cpb2) genes, respectively. Ten different toxin-genotypes were identified, and iota toxin gene was not detected in any of the sample.

Prevalence and molecular typing of Clostridium perfringens in captive wildlife in India.

The prevalence of Clostridium perfringens in captive wildlife in India has not been reported. The objective of the study was to determine the fecal prevalence of C. perfringens in captive wildlife in India. The prevalence in captive wild ruminants, non-ruminants, birds and caretakers were 34.1%, 36%, 22.5% and 6.7%, respectively. Toxinotyping of C. perfringens indicated that the predominant type was type A with a prevalence rate of 69.7%, followed by type A with cpb2 gene (28.3%) and type B (2.%).

Prostate biopsies: Available technique, approaches and diagnostic accuracy / Biopsias prostáticas: técnica disponible, abordajes y precisión diagnostica

Despite advances in the diagnosis of prostate cancer over the past century, it remains a leading cause of cancer related death. A recent recommendation against screening has further complicated the diagnosis and management of this condition. It remains to be demonstrated if newer diagnostic modalities will have an impact on mortality rates. Most certainly, not all prostate cancers need to be diagnosed, and methods of accurately diagnosing those cancers that lead to death needs more work. In this review article, we describe the different techniques, approaches and diagnostic accuracies of the currently used biopsy methods

A pesar de los avances en el diagnóstico del cáncer de próstata durante el siglo pasado, éste sigue siendo una causa principal de muerte relacionada con cáncer. Una recomendación reciente contra el screening ha complicado más aún el diagnóstico y tratamiento de esta enfermedad. Sigue por demostrarse si las modalidades diagnósticas más nuevas tendrán un impacto sobre las tasas de mortalidad. Con toda certeza, no es necesario diagnosticar todos los cánceres de próstata, y es necesario seguir trabajando con los métodos que permiten diagnosticar con precisión los cánceres mortales. En este artículo de revisión describimos las diferentes técnicas, abordajes y precisión diagnóstica de los métodos de biopsia utilizados actualmente

Epithelial ovarian cancer: An overview.

Ovarian cancer is the second most common gynecological cancer and the leading cause of death in the United States. In this article we review the diagnosis and current management of epithelial ovarian cancer which accounts for over 95 percent of the ovarian malignancies. We will present various theories about the potential origin of ovarian malignancies. We will discuss the genetic anomalies and syndromes that may cause ovarian cancers with emphasis on Breast cancer type 1/2 mutations. The pathology and pathogenesis of ovarian carcinoma will also be presented. Lastly, we provide a comprehensive overview of treatment strategies and staging of ovarian cancer, conclusions and future directions.

BRCA1 proteins regulate growth of ovarian cancer cells by tethering Ubc9.

Mutation in the BRCA1 gene is associated with increased risk for hereditary breast and ovarian cancers. In sporadic ovarian tumors, BRCA1 dysfunction is thought to be common. BRCA1 is a nuclear-cytoplasm shuttling protein. Our group has previously reported that BRCA1 proteins, unlike K109R and cancer-predisposing mutant C61G BRCA1 proteins, bind the sole SUMO E2-conjugating enzyme Ubc9. In this study, we examined the result of altered Ubc9 binding and knockdown on the sub-cellular localization and growth inhibitory function of BRCA1 proteins in ovarian cancer cells. Using live imaging of YFP, RFP-tagged BRCA1 and BRCA1a proteins, our results show enhanced cytoplasmic localization of K109R and C61G mutant BRCA1 proteins in ES-2, NIHOVCAR3 and UWB 1.289 ovarian cancer cells. Down-regulation of Ubc9 in ovarian cancer cells using Ubc9 siRNA resulted in cytoplasmic localization of BRCA1 and BRCA1a proteins. These mutant BRCA1a proteins were impaired in their capacity to inhibit growth of ES-2 ovarian cancer cells. Several ovarian cancer cells, including a BRCA1-null ovarian cancer cell line, showed higher levels of expression of Ubc9. This is the first study demonstrating the physiological link between loss of Ubc9 binding and loss of growth suppression of disease-associated mutant BRCA1a proteins in ovarian cancer cells. BRCA1, by turning off or on Ubc9 binding, regulates growth of ovarian cancers.

How best to manage dysfunctional uterine bleeding.

Irregular or unusually heavy periods are a common complaint. Most often, the condition is benign and can by managed conservatively. Assess postmenopausal women for cancer by endometrial biopsy, transvaginal ultrasound, or saline infusion sonohysterogram. Treat mild dysfunctional uterine bleeding (DUB) with nonsteroidal anti-inflammatory drugs, levonorgestrel intrauterine device (IUD), or danazol. Treat moderate DUB with oral contraceptive pills, levonorgestrel IUD, danazol, or tranexamic acid.

Diagnosis and management of adnexal masses.

Adnexal masses represent a spectrum of conditions from gynecologic and nongynecologic sources. They may be benign or malignant. The initial detection and evaluation of an adnexal mass requires a high index of suspicion, a thorough history and physical examination, and careful attention to subtle historical clues. Timely, appropriate laboratory and radiographic studies are required. The most common symptoms reported by women with ovarian cancer are pelvic or abdominal pain; increased abdominal size; bloating; urinary urgency, frequency, or incontinence; early satiety; difficulty eating; and weight loss. These vague symptoms are present for months in up to 93 percent of patients with ovarian cancer. Any of these symptoms occurring daily for more than two weeks, or with failure to respond to appropriate therapy warrant further evaluation. Transvaginal ultrasonography remains the standard for evaluation of adnexal masses. Findings suggestive of malignancy in an adnexal mass include a solid component, thick septations (greater than 2 to 3 mm), bilaterality, Doppler flow to the solid component of the mass, and presence of ascites. Family physicians can manage many nonmalignant adnexal masses; however, prepubescent girls and postmenopausal women with an adnexal mass should be referred to a gynecologist or gynecologic oncologist for further treatment. All women, regardless of menopausal status, should be referred if they have evidence of metastatic disease, ascites, a complex mass, an adnexal mass greater than 10 cm, or any mass that persists longer than 12 weeks.