Decoupling of respiration rates and abundance in marine prokaryoplankton.

The ocean-atmosphere exchange of CO2 largely depends on the balance between marine microbial photosynthesis and respiration. Despite vast taxonomic and metabolic diversity among marine planktonic bacteria and archaea (prokaryoplankton)1-3, their respiration usually is measured in bulk and treated as a 'black box' in global biogeochemical models4; this limits the mechanistic understanding of the global carbon cycle. Here, using a technology for integrated phenotype analyses and genomic sequencing of individual microbial cells, we show that cell-specific respiration rates differ by more than 1,000× among prokaryoplankton genera. The majority of respiration was found to be performed by minority members of prokaryoplankton (including the Roseobacter cluster), whereas cells of the most prevalent lineages (including Pelagibacter and SAR86) had extremely low respiration rates. The decoupling of respiration rates from abundance among lineages, elevated counts of proteorhodopsin transcripts in Pelagibacter and SAR86 cells and elevated respiration of SAR86 at night indicate that proteorhodopsin-based phototrophy3,5-7 probably constitutes an important source of energy to prokaryoplankton and may increase growth efficiency. These findings suggest that the dependence of prokaryoplankton on respiration and remineralization of phytoplankton-derived organic carbon into CO2 for its energy demands and growth may be lower than commonly assumed and variable among lineages.

Species-resolved, single-cell respiration rates reveal dominance of sulfate reduction in a deep continental subsurface ecosystem.

Rates of microbial processes are fundamental to understanding the significance of microbial impacts on environmental chemical cycling. However, it is often difficult to quantify rates or to link processes to specific taxa or individual cells, especially in environments where there are few cultured representatives with known physiology. Here, we describe the use of the redox-enzyme-sensitive molecular probe RedoxSensor™ Green to measure rates of anaerobic electron transfer physiology (i.e., sulfate reduction and methanogenesis) in individual cells and link those measurements to genomic sequencing of the same single cells. We used this method to investigate microbial activity in hot, anoxic, low-biomass (~103 cells mL-1) groundwater of the Death Valley Regional Flow System, California. Combining this method with electron donor amendment experiments and metatranscriptomics confirmed that the abundant spore formers including Candidatus Desulforudis audaxviator were actively reducing sulfate in this environment, most likely with acetate and hydrogen as electron donors. Using this approach, we measured environmental sulfate reduction rates at 0.14 to 26.9 fmol cell-1 h-1. Scaled to volume, this equates to a bulk environmental rate of ~103 pmol sulfate L-1 d-1, similar to potential rates determined with radiotracer methods. Despite methane in the system, there was no evidence for active microbial methanogenesis at the time of sampling. Overall, this method is a powerful tool for estimating species-resolved, single-cell rates of anaerobic metabolism in low-biomass environments while simultaneously linking genomes to phenomes at the single-cell level. We reveal active elemental cycling conducted by several species, with a large portion attributable to Ca. Desulforudis audaxviator.

Real-world outcomes associated with bevacizumab combined with chemotherapy in platinum-resistant ovarian Cancer.

OBJECTIVES: The addition of bevacizumab to chemotherapy for platinum-resistant (PL-R) ovarian cancer (OC) improved progression-free (PFS) but not overall survival (OS) in clinical trials. We explored real-world outcomes in Ontario, Canada, and compared survival in the pre- and post-bevacizumab era. METHODS: Administrative databases were utilized to identify all patients treated with bevacizumab for PL-R OC. Time on treatment (ToT) was used as surrogate for PFS. Median OS was determined using the Kaplan-Meier method. Factors associated with ToT/OS were identified using a Cox proportional hazard model. A before and after comparative effectiveness analysis was performed to determine mOS for patients treated pre- and post-bevacizumab approval. RESULTS: From 2017 to 2019, 176 patients received bevacizumab. Median ToT was 3 months and OS was 11 months. Sixty-four percent received liposomal doxorubicin and 34% received paclitaxel. ToT (6 vs 3 months; HR 0.44; p < 0.0001) and OS (14 vs 9 months; HR 0.45; p = 0.0089) were longer with bevacizumab/paclitaxel. OS was not significantly different pre- and post-bevacizumab funding (8 vs 9 months; HR 1.01; 0.937). Median OS increased for those receiving paclitaxel (6 vs 11 months), but those in the post group were younger, more likely to have undergone primary surgery and had less co-morbidities. CONCLUSION: Real-world outcomes with bevacizumab in PL-R OC are inferior to those in the pivotal clinical trial. Survival has not significantly improved since funding became publicly available, indicating a substantial efficacy-effectiveness gap between trial and real-world outcomes. Median OS and ToT were significantly better when bevacizumab was given with paclitaxel.

An Uncultivated Virus Infecting a Nanoarchaeal Parasite in the Hot Springs of Yellowstone National Park.

The Nanoarchaeota are small cells with reduced genomes that are found attached to and dependent on a second archaeal cell for their growth and replication. Initially found in marine hydrothermal environments and subsequently in terrestrial geothermal hot springs, the Nanoarchaeota species that have been described are obligate ectobionts, each with a different host species. However, no viruses had been described that infect the Nanoarchaeota. Here, we identify a virus infecting Nanoarchaeota by the use of a combination of viral metagenomic and bioinformatic approaches. This virus, tentatively named Nanoarchaeota Virus 1 (NAV1), consists of a 35.6-kb circular DNA genome coding for 52 proteins. We further demonstrate that this virus is broadly distributed among Yellowstone National Park hot springs. NAV1 is one of the first examples of a virus infecting a single-celled organism that is itself an ectobiont of another single-celled organism.IMPORTANCE Here, we present evidence of the first virus found to infect Nanoarchaeota, a symbiotic archaean found in acidic hot springs of Yellowstone National Park, USA. Using culture-independent techniques, we provide the genome sequence and identify the archaeal host species of a novel virus, NAV1. NAV1 is the first example of a virus infecting an archaeal species that is itself an obligate symbiont and dependent on a second host organism for growth and cellular replication. On the basis of annotation of the NAV1 genome, we propose that this virus is the founding member of a new viral family, further demonstrating the remarkable genetic diversity of archaeal viruses.

Discovery and Characterization of Thermoproteus Spherical Piliferous Virus 1: a Spherical Archaeal Virus Decorated with Unusual Filaments.

We describe the discovery of an archaeal virus, one that infects archaea, tentatively named Thermoproteus spherical piliferous virus 1 (TSPV1), which was purified from a Thermoproteales host isolated from a hot spring in Yellowstone National Park (USA). TSPV1 packages an 18.65-kb linear double-stranded DNA (dsDNA) genome with 31 open reading frames (ORFs), whose predicted gene products show little homology to proteins with known functions. A comparison of virus particle morphologies and gene content demonstrates that TSPV1 is a new member of the Globuloviridae family of archaeal viruses. However, unlike other Globuloviridae members, TSPV1 has numerous highly unusual filaments decorating its surface, which can extend hundreds of nanometers from the virion. To our knowledge, similar filaments have not been observed in any other archaeal virus. The filaments are remarkably stable, remaining intact across a broad range of temperature and pH values, and they are resistant to chemical denaturation and proteolysis. A major component of the filaments is a glycosylated 35-kDa TSPV1 protein (TSPV1 GP24). The filament protein lacks detectable homology to structurally or functionally characterized proteins. We propose, given the low host cell densities of hot spring environments, that the TSPV1 filaments serve to increase the probability of virus attachment and entry into host cells.IMPORTANCE High-temperature environments have proven to be an important source for the discovery of new archaeal viruses with unusual particle morphologies and gene content. Our isolation of Thermoproteus spherical piliferous virus 1 (TSPV1), with numerous filaments extending from the virion surface, expands our understanding of viral diversity and provides new insight into viral replication in high-temperature environments.

A Case of Synchronous Malignant and Benign Granular Cell Tumor of the Vulva.

Granular cell tumors (GCT) are rare soft tissue neoplasms, which seldom occur in the vulva. They are more commonly benign, but malignant GCT do occur. We report a case of a 50-yr-old postmenopausal woman who presented with a vulvar lesion that was diagnosed as GCT on biopsy. Imaging and clinical examination revealed an enlarged, likely positive lymph node. Pathology of the subsequently resected total deep vulvectomy specimen showed 2 histologically distinct GCTs. The larger lesion met criteria for malignancy and histologically corresponded to metastatic deposits seen in the pelvic lymph nodes. The separate smaller lesion was histologically benign. This case illustrates a malignant GCT with a synchronous, likely benign GCT both occurring in the vulva. Our case demonstrates the application of histologic criteria in the diagnosis of malignant and benign GCT with discussion on the diagnosis and treatment of this rare tumor.

Complication Rates after Endometrial Ablation in Ontario: A Cohort Analysis of 76 446 Patients.

STUDY OBJECTIVES: Endometrial ablation (EA) is an alternative to hysterectomy for the management of heavy menstrual bleeding; however, EA is not without risk. Our objective was to determine complication rates in women undergoing EA in the province of Ontario over a 15-year time period. The primary outcome was a composite of multiple complications within 30 to 180 days of surgery. The secondary outcomes included mortality, length of hospital stay, hospital readmission, and emergency department visit within 30 days of discharge. DESIGN: Retrospective cohort study using Cochran-Armitage test for trend. SETTING: Administrative data from the Canadian province of Ontario, assessing patients undergoing surgery in a publicly funded healthcare system. PATIENTS: Women in Ontario undergoing a primary EA over a 15-year time period. INTERVENTIONS: The intervention was a primary EA. MEASUREMENTS AND MAIN RESULTS: We assessed for genitourinary complication, fistula, gastrointestinal complication, pain, control of bleeding, blood transfusion, infectious complication, venous thromboembolism, fluid overload, thermal injury, and other injuries related to surgery. The secondary outcomes included 1-month and 6-month mortality, length of hospital stay, hospital readmission, and emergency department visit within 30 days of discharge. A total of 76 446 primary EAs were evaluated from 2002 to 2017, with the number of EAs per year increasing over the study period by 47%. Complications were seen in 4.8% of the cohort, with the complication rate being relatively stable over time. Although 6.2% of the cohort re-presented to the emergency department, <1% required readmission, and <0.05% died within 180 days. On multivariable analysis, the risk of complications increased with a preoperative diagnosis of other than bleeding (odds ratio [OR] 2.89; 95% confidence interval [CI], 2.61-3.21; p <.001), previous abdominal surgery (OR 1.42; 95% CI, 1.28-1.56; p <.001), and American Society of Anesthesiologists score 3+ (OR 1.37; 95% CI, 1.27-1.48; p <.001). CONCLUSION: Primary EA is associated with complications in <5% of the patients, with serious complications infrequent.

Genetic and epigenetic profiling of BRCA1/2 in ovarian tumors reveals additive diagnostic yield and evidence of a genomic BRCA1/2 DNA methylation signature.

Poly-ADP-ribose-polymerase inhibitor (PARPi) treatment is indicated for advanced-stage ovarian tumors with BRCA1/2 deficiency. The "BRCAness" status is thought to be attributed to a tumor phenotype associated with a specific epigenomic DNA methylation profile. Here, we examined the diagnostic impact of combined BRCA1/2 sequence, copy number, and promoter DNA methylation analysis, and evaluated whether genomic DNA methylation patterns can predict the BRCAness in ovarian tumors. DNA sequencing of 172 human tissue samples of advanced-stage ovarian adenocarcinoma identified 36 samples with a clinically significant tier 1/2 sequence variants (point mutations and in/dels) and 9 samples with a CNV causing a loss of function in BRCA1/2. DNA methylation analysis of the promoter of BRCA1/2 identified promoter hypermethylation of BRCA1 in two mutation-negative samples. Computational modeling of genome-wide methylation markers, measured using Infinium EPIC arrays, resulted in a total accuracy of 0.75, sensitivity: 0.83, specificity: 0.64, positive predictive value: 0.76, negative predictive value: 0.74, and area under the receiver's operating curve (AUC): 0.77, in classifying tumors harboring a BRCA1/2 defect from the rest. These findings indicate that the assessment of CNV and promoter DNA methylation in BRCA1/2 increases the cumulative diagnostic yield by 10%, compared with the 20% yield achieved by sequence variant analysis alone. Genomic DNA methylation data can partially predict BRCAness in ovarian tumors; however, further investigation in expanded BRCA1/2 cohorts is needed, and the effect of other double strand DNA repair gene defects in these tumors warrants further investigations.

Resident Trainees Increase Surgical Time: A Comparison of Obstetric and Gynaecologic Procedures in Academic Versus Community Hospitals.

OBJECTIVE: The impact of resident involvement in the operating room for common procedures in obstetrics and gynaecology can shed light on the resource demands of teaching. The objective of this study was to quantify the increased surgical time associated with teaching obstetrics and gynaecology resident trainees across a range of procedures known to require surgical assistance. METHODS: This population-based retrospective cohort study compared surgical duration between academic (teaching) hospitals and community (non-teaching) hospitals. The cohort was made up of adult residents of Ontario between fiscal years 2002 and 2013 who were undergoing commonly performed obstetrics and gynaecologic procedures. The most commonly billed procedures requiring surgical assistance were included: cesarean section, anterior or posterior repair, anterior and posterior repair, salpingo-oophorectomy, myomectomy, ectopic pregnancy, total or subtotal hysterectomy, vaginal hysterectomy, and laparoscopic hysterectomy. Linked administrative databases held at the Institute of Clinical Evaluative Sciences (ICES) were used to define patient-, surgeon-, institution-, and procedure-related variables to limit confounding. Surgical duration, determined by anaesthetic billing records, was analyzed using a negative binomial regression. RESULTS: The total cohort included 337 389 surgical procedures. Of these procedures, 28% (94 203 procedures) were conducted in academic settings. The mean surgical duration of the procedures of interest (excluding vaginal hysterectomy) was significantly longer in academic hospitals compared with community hospitals. With many controls for case variability, this time differential reflects the burden of teaching resident trainees and other learners in the academic environment. The operating time increased between 6% and 20% for cases completed in academic centres versus in the community. As an example, the mean surgical duration of cesarean sections was 20.6 minutes (19%) longer in academic centres. Furthermore, the data highlighted a trend of increased teaching time for laparoscopic procedures compared with open procedures. The time ratio was the greatest for salpingo-oophortectomy and surgical management of ectopic pregnancies. The additional cost of carrying out these nine procedures in academic centres during the study period was $16.3 million. CONCLUSION: The cost of teaching resident trainees is increased operative time. This increased surgical cost in a publicly funded system must be considered as funding models evolve.

Hysterectomy in Ontario: A Population-Based Study of Outcomes and Complications in Minimally Invasive Compared with Abdominal Approaches.

OBJECTIVE: As quality-based procedures (QBPs) are being established across the province of Ontario, it is important to identify reliable quality indicators (QIs) to ensure that compensation coincides with quality. Hysterectomy is the most commonly performed gynaecologic procedure and as such is a care process for which a QBP is being developed. The aim of this study was to evaluate the technicity index (TI) as a QI for hysterectomy by defining it in the context of specific surgical outcomes and complications. METHODS: This population-based, retrospective cohort study included all women who underwent hysterectomy from April 2003 to October 2014 in the province of Ontario. Unadjusted and adjusted generalized linear models were created to assess the effect of a minimally invasive hysterectomy (MIH) approach on the primary outcome measure: all hysterectomy-associated complications (Canadian Task Force Classification II-2). RESULTS: Of the procedures meeting the study's inclusion criteria, 56.8% were performed using an abdominal hysterectomy approach, whereas 43.2% were performed using an MIH approach. Over the study period, TI improved significantly from 33.23% in 2003 to 58.47% in 2014. During this time span, the overall incidence of all hysterectomy-associated complications was 13.1%. CONCLUSION: The composite risk of all hysterectomy-associated complications was reduced by 46% with an MIH approach. The uptake of MIH improved significantly in Ontario from 2003 to 2014 and is adequately assessed by the TI. The TI is an appropriate QI for hysterectomy that can be used to track patients' outcomes and direct hysterectomy funding.

Isolation and Characterization of Metallosphaera Turreted Icosahedral Virus, a Founding Member of a New Family of Archaeal Viruses.

Our understanding of archaeal virus diversity and structure is just beginning to emerge. Here we describe a new archaeal virus, tentatively named Metallosphaera turreted icosahedral virus (MTIV), that was isolated from an acidic hot spring in Yellowstone National Park, USA. Two strains of the virus were identified and were found to replicate in an archaeal host species closely related to Metallosphaera yellowstonensis Each strain encodes a 9.8- to 9.9-kb linear double-stranded DNA (dsDNA) genome with large inverted terminal repeats. Each genome encodes 21 open reading frames (ORFs). The ORFs display high homology between the strains, but they are quite distinct from other known viral genes. The 70-nm-diameter virion is built on a T=28 icosahedral lattice. Both single particle cryo-electron microscopy and cryotomography reconstructions reveal an unusual structure that has 42 turret-like projections: 12 pentameric turrets positioned on the icosahedral 5-fold axes and 30 turrets with apparent hexameric symmetry positioned on the icosahedral 2-fold axes. Both the virion structural properties and the genome content support MTIV as the founding member of a new family of archaeal viruses.IMPORTANCE Many archaeal viruses are quite different from viruses infecting bacteria and eukaryotes. Initial characterization of MTIV reveals a virus distinct from other known bacterial, eukaryotic, and archaeal viruses; this finding suggests that viruses infecting Archaea are still an understudied group. As the first known virus infecting a Metallosphaera sp., MTIV provides a new system for exploring archaeal virology by examining host-virus interactions and the unique features of MTIV structure-function relationships. These studies will likely expand our understanding of virus ecology and evolution.

A Population-Based Assessment of Urologic Procedures and Operations After Surgery or Pelvic Radiation for Cervical Cancer.

OBJECTIVE: The treatment of cervical cancer can result in genitourinary morbidity. We measured selected urologic procedures after the treatment of cervical cancer with either surgery or radiation. METHODS: We used administrative data from the province of Ontario Canada to identify adult women who had nonmetastatic cervical cancer and were treated with surgery or radiation between 1994 and 2014. Study outcomes were surgical or procedure codes representing ureteric repair or fistula repair. Stress incontinence surgery, minimally invasive urologic procedures, open bowel/bladder surgeries, and secondary malignancy were measured to compare between treatment modalities. Multivariable Cox proportional hazards models were used. RESULTS: Our final cohort consisted of 7311 women (median follow-up, 7.0 years [interquartile range, 2.9-13.3 years]), of which 3354 (44.9%) underwent radiation, and 3957 (54.1%) underwent surgery. After treatment of cervical cancer, ureteral repair was less common after surgery (3.4%) compared with radiation (10.3%) (hazard ratio [HR], 0.25; 95% confidence interval [CI], 0.19-0.32). Fistula repair was uncommon (0.9%) and occurred significantly more often in the surgery and radiation group compared with the radiation-alone group (HR, 4.02; 95% CI, 1.80-9.00). Overall, stress incontinence surgery was uncommon (2.2%) but was significantly more likely after surgery versus radiation (HR, 3.73; 95% CI, 2.13-6.53). Minimally invasive urologic procedures were less common after surgery compared with radiation (HR, 0.49; 95% CI, 0.44-0.54). Open bowel/bladder surgeries were similar among treatment modalities, and secondary malignancy was less common after treatment with surgery versus radiation (HR, 0.60; 95% CI, 0.39-0.92; P = 0.02). CONCLUSIONS: Women treated for cervical cancer undergo ureteral stricture interventions at 0.8% per year over the 20 years after their treatment; this risk is higher among women who receive radiation treatment. Fistula repair is rare after cervical cancer.

Examining Survival Outcomes of 852 Women With Advanced Ovarian Cancer: A Multi-institutional Cohort Study.

INTRODUCTION: This study examines patterns of clinical practice in the management of women with advanced high-grade serous ovarian carcinoma (HGSC). METHODS: A total of 852 patients with advanced HGSC were included in this retrospective cohort analysis. Patients underwent primary cytoreductive surgery (PCS) or neoadjuvant chemotherapy (NACT). Wilcoxon rank-sum test and χ test were applied. Univariate- and multivariate-analyses were performed, and survival outcomes were measured using Kaplan-Meier curves. RESULTS: A total of 449 (53%) of 852 patients underwent PCS, and 403(47%) of 852 patients underwent NACT. The median 5-year overall survival (OS) was 3.89 in PCS and 2.48 in NACT. Patients with 0 mm residual had OS of 4.66, compared with 1- to 9-mm residual (OS = 2.80) and 10-mm residual or longer (OS = 2.50). The survival advantage harbored by the extent of surgical cytoreduction was more pronounced in PCS compared with NACT (P < 0.001). Patients who had PCS with 1- to 9-mm residual had similar OS to NACT patients with 0-mm residual (P = 0.17) and superior OS to NACT with 1- to 9-mm residual (P < 0.001). CONCLUSIONS: In this multicenter study, 53% of women with advanced HGSC seen by a gynecologic oncologist were selected for PCS. Survival was longer in patients who underwent PCS than patients who underwent NACT. Within each group, survival was highest in those who had complete cytoreduction to 0-mm residual disease. We believe all patients with advanced HGSC should be assessed by a gynecologic oncologist for the feasibility of surgical resection. Primary cytoreductive surgery should be the favorable treatment modality with the goal of complete resection to 0 mm residual disease. Importantly, if 0 mm residual is not feasible, PCS to a residual of 1 to 9 mm should be attempted given the survival advantage in this group over patients who were treated with NACT.

Treatment Tolerance and Side Effects of Intraperitoneal Carboplatin and Dose-Dense Intravenous Paclitaxel in Ovarian Cancer.

OBJECTIVE: To describe the frequency of clinically significant side effects associated with adjuvant intraperitoneal (IP) carboplatin and intravenous (IV) dose-dense paclitaxel chemotherapy for epithelial ovarian cancer (EOC). METHODS: Patients with stage II to IV EOC who underwent upfront cytoreductive surgery followed by adjuvant IP carboplatin (AUC 6) every 3 weeks with IV paclitaxel weekly at 80 mg/m2 were included. Side effects and the resulting changes in treatment are presented using univariate analysis and compared to major phase III RCTs. RESULTS: Between March 2013 and October 2015, 49 patients comprising 289 cycles of chemotherapy were included in the analysis; 43 patients (87.8%) completed six cycles of chemotherapy and 38 (77.6%) completed six cycles of IP carboplatin. Treatment was discontinued early due to neuropathy (5/49) and disease progression (1/49). Carboplatin IV was substituted due to port access (3/49) and poor postoperative performance status (3/49). Neutropenia occurred in 16 patients (32.7%). Fourteen patients (28.6%) required red blood cell transfusion. Thrombocytopenia affected nine patients (18.4%). Infection delaying treatment occurred in five patients (10.4%). Gastrointestinal and renal toxicity occurred in four (8.1%) and one patient (2.0%), respectively. Four patients experienced a taxane reaction. No patients experienced ototoxicity, fistula formation, chemotherapy leakage, or severe abdominal pain. CONCLUSION: Carboplatin IP and weekly IV paclitaxel was well-tolerated with a side-effect profile similar to or better than previously published traditional treatment regimens.

Acidianus Tailed Spindle Virus: a New Archaeal Large Tailed Spindle Virus Discovered by Culture-Independent Methods.

UNLABELLED: The field of viral metagenomics has expanded our understanding of viral diversity from all three domains of life (Archaea, Bacteria, and Eukarya). Traditionally, viral metagenomic studies provide information about viral gene content but rarely provide knowledge about virion morphology and/or cellular host identity. Here we describe a new virus, Acidianus tailed spindle virus (ATSV), initially identified by bioinformatic analysis of viral metagenomic data sets from a high-temperature (80°C) acidic (pH 2) hot spring located in Yellowstone National Park, followed by more detailed characterization using only environmental samples without dependency on culturing. Characterization included the identification of the large tailed spindle virion morphology, determination of the complete 70.8-kb circular double-stranded DNA (dsDNA) viral genome content, and identification of its cellular host. Annotation of the ATSV genome revealed a potential three-domain gene product containing an N-terminal leucine-rich repeat domain, followed by a likely posttranslation regulatory region consisting of high serine and threonine content, and a C-terminal ESCRT-III domain, suggesting interplay with the host ESCRT system. The host of ATSV, which is most closely related to Acidianus hospitalis, was determined by a combination of analysis of cellular clustered regularly interspaced short palindromic repeat (CRISPR)/Cas loci and dual viral and cellular fluorescence in situ hybridization (viral FISH) analysis of environmental samples and confirmed by culture-based infection studies. This work provides an expanded pathway for the discovery, isolation, and characterization of new viruses using culture-independent approaches and provides a platform for predicting and confirming virus hosts. IMPORTANCE: Virus discovery and characterization have been traditionally accomplished by using culture-based methods. While a valuable approach, it is limited by the availability of culturable hosts. In this research, we report a virus-centered approach to virus discovery and characterization, linking viral metagenomic sequences to a virus particle, its sequenced genome, and its host directly in environmental samples, without using culture-dependent methods. This approach provides a pathway for the discovery, isolation, and characterization of new viruses. While this study used an acidic hot spring environment to characterize a new archaeal virus, Acidianus tailed spindle virus (ATSV), the approach can be generally applied to any environment to expand knowledge of virus diversity in all three domains of life.

Neoadjuvant chemotherapy and chemotherapy cycle number: A national multicentre study.

OBJECTIVES: Six cycles of consolidation chemotherapy have become the standard for ovarian cancer treatment regimen following primary cytoreduction, yet with neoadjuvant chemotherapy (NAC), only 3 consolidation cycles are used. This study examines the effects of number of chemotherapy cycles in women with ovarian cancer that are being treated with neoadjuvant chemotherapy. In addition, we examined the effect of number of cycles on survival on consolidation and total chemotherapy. METHODS: All patients with stage IIIC and IV high grade serous carcinoma (HGSC) were identified at 4 major Canadian cancer centers treated with NAC. A retrospective chart review was conducted using the medical charts and registry databases. RESULTS: 403 NAC patients were identified. 47% had zero residual disease. Chemotherapy cycles were divided into <3cycles or ≥4cycles for NAC and consolidation treatments and analyzed with multivariate analysis. 139/403 (34.5%) received ≥4cycles of NAC and had a worse prognosis than <3cycles (p=0.011). 70/403 (17.4%) received ≥4cycles of consolidation treatment and there was no difference in survival (p=0.33) CONCLUSION: Women with advanced HGSC are managed with a combination of surgery and chemotherapy. This is a study of a homogenous cohort of patients with stage IIIC or IV high grade serous cancers who received NAC. ≥4cycles of NAC had a worse outcome than <3cycles likely due to poor prognostic factors or poor response. The number of consolidation cycles did not appear to make a difference in overall survival.

Risk of breast cancer after a diagnosis of ovarian cancer in BRCA mutation carriers: Is preventive mastectomy warranted?

OBJECTIVE: Preventive breast surgery and MRI screening are offered to unaffected BRCA mutation carriers. The clinical benefit of these two modalities has not been evaluated among mutation carriers with a history of ovarian cancer. Thus, we sought to determine whether or not BRCA mutation carriers with ovarian cancer would benefit from preventive mastectomy or from MRI screening. METHODS: First, the annual mortality rate for ovarian cancer patients was estimated for a cohort of 178 BRCA mutation carriers from Ontario, Canada. Next, the actuarial risk of developing breast cancer was estimated using an international registry of 509 BRCA mutation carriers with ovarian cancer. A series of simulations was conducted to evaluate the reduction in the probability of death (from all causes) associated with mastectomy and with MRI-based breast surveillance. Cox proportional hazards models were used to evaluate the impacts of mastectomy and MRI screening on breast cancer incidence as well as on all-cause mortality. RESULTS: Twenty (3.9%) of the 509 patients developed breast cancer within ten years following ovarian cancer diagnosis. The actuarial risk of developing breast cancer at ten years post-diagnosis, conditional on survival from ovarian cancer and other causes of mortality was 7.8%. Based on our simulation results, among all BRCA mutation-carrying patients diagnosed with stage III/IV ovarian cancer at age 50, the chance of dying before age 80 was reduced by less than 1% with MRI and by less than 2% with mastectomy. Greater improvements in survival with MRI or mastectomy were observed for women who had already survived 10years after ovarian cancer, and for women with stage I or II ovarian cancer. CONCLUSIONS: Among BRCA mutation-carrying ovarian cancer patients without a personal history of breast cancer, neither preventive mastectomy nor MRI screening is warranted, except for those who have survived ovarian cancer without recurrence for ten years and for those with early stage ovarian cancer.

Genetics Consultation Rates Following a Diagnosis of High-Grade Serous Ovarian Carcinoma in the Canadian Province of Ontario.

OBJECTIVE: In 2001, the province of Ontario expanded cancer genetic testing eligibility to include all women with high-grade serous ovarian carcinoma (HGSC) of the ovary, fallopian tube, and peritoneum. The aim of this study was to determine the proportion of women who attended genetics counseling for consideration of BRCA1/2 gene analysis. We also sought to examine if regional differences in consultation rate exist across administrative health regions in the province of Ontario. METHODS: We identified all women with a pathological diagnosis of HGSC in the province of Ontario between 1997 until 2011. Our primary outcome was the 2-year rate of genetics consultation following a diagnosis of HGSC. We compared consultation rates over time and geographical regions and applied multiple logistic regression to identify predictors of genetics consultation. RESULTS: Of the 5412 women with a diagnosis of HGSC over the study period, 6.6% were seen for genetics consultation within 2 years of diagnosis. Factors predictive of genetics consultation included history of breast cancer (odds ratio [OR], 3.56; 95% confidence interval [CI], 1.87-6.78), era of diagnosis (2009-2011 vs 1997-2000; OR, 10.59; 95% CI, 5.02-22.33), and younger age at diagnosis (OR, 0.95; 95% CI, 0.94-0.97 for each additional year). No regional differences in consultation rate were seen. CONCLUSIONS: Despite an increasing rate across eras, a small proportion of women with HGSC undergo genetics consultation. Efforts are required to increase cancer genetics consultation in patients with HGSC in the province of Ontario.

Role of Adjuvant Therapy for Stage IA Serous and Clear Cell Uterine Cancer: Is Observation a Valid Strategy?

OBJECTIVES: The adjuvant treatment of early stage IA serous and clear cell carcinomas of the uterus is controversial. The aims of the study were to report on a single institution experience treating these high-risk early uterine cancers and to identify women who may be suitable for observation alone. METHODS AND MATERIALS: A retrospective review of patients presenting from 2003 to 2013 with pathologic stage IA (International Federation of Gynecology and Obstetrics 2009) serous or clear cell uterine carcinoma was performed. Patient and disease characteristics, surgical staging, treatment details, and recurrence data were collected. Recurrence rates and 5-year actuarial estimates of recurrence free survival (RFS) were the primary outcomes of interest. RESULTS: A total of 77 patients with stage IA were identified. Median (range) follow-up was 34 (1-108) months. Staging lymphadenectomy was performed in 83%. Adjuvant treatment was given to 27 patients, whereas 50 underwent observation. There were 12 recurrences total, with the 5-year RFS 79% for the cohort, with no statistically significant difference between observation and adjuvant treatment. Only 4 patients received adjuvant chemotherapy and none recurred. In the observation cohort, the presence versus absence of myometrial invasion showed a trend to poorer 5-year RFS (75% vs 93%, P = 0.06). CONCLUSIONS: Observation seems to be a valid strategy in those patients with stage IA serous and clear cell carcinoma without myometrial invasion. The presence of any myometrial invasion may confer a higher risk of recurrence, although further studies are needed to determine the optimal adjuvant treatment regimen.