Meta-Analysis of Quality of Life in Cancer Patients Treated With Immune Checkpoint Inhibitors.

BACKGROUND: Trials of immune checkpoint inhibitors (ICIs) have published patient-reported quality of life (QOL), but the size and heterogeneity of this literature can make patient education difficult. This meta-analysis aimed to describe change in QOL and symptomatology in patients receiving ICIs for cancer. METHODS: Following Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, databases were searched through November 2019 for articles or abstracts of prospective, original studies reporting longitudinal QOL in adult cancer patients treated with ICIs. The prespecified primary outcomes were change in global QOL among patients treated with ICIs and difference in change since baseline in global QOL between patients treated with ICI vs non-ICI active treatment. Secondary outcomes included physical functioning and symptomatology. All statistical tests were 2-sided. RESULTS: Of 20 323 publications, 26 met inclusion criteria. Global QOL did not change over time in patients treated with ICIs (k = 26, n = 6974; P = .19). Larger improvements in global QOL was observed in patients receiving ICI vs non-ICI regimens (k = 16, ICI: n = 3588; non-ICI: n = 2948; P < .001). Physical functioning did not change in patients treated with ICIs (k = 14, n = 3169; P = .47); there were no differences in mean change between ICI vs non-ICI regimens (k = 11, n = 4630; P = .94). Regarding symptoms, appetite loss, insomnia, and pain severity decreased, but dyspnea severity increased in patients treated with ICIs (k = 14, n = 3243-3499; P < .001). Insomnia severity was higher in patients treated with ICIs than non-ICI regimens (k = 11, n = 4791; P < .001). CONCLUSIONS: This study is among the first to quantitatively summarize QOL in patients treated with ICIs. Findings suggest ICI recipients report no change in global QOL and higher QOL than patients treated with non-ICI regimens.

Outcomes of repeat fineneedle aspiration biopsy for AUS/FLUS thyroid nodules.

OBJECTIVE: To determine the proportion of aspirates reclassified into each Bethesda category and to assess the rates of malignancy in each of them on repeat fine-needle aspiration biopsy (RFNA) following an AUS/FLUS diagnosis. DESIGN: Systematic review and meta-analysis. METHODS: On February 2019, Pubmed/MEDLINE, EMBASE, WoS, and the Cochrane Library were searched for articles published from January 1, 2007. All studies published in English describing RFNA outcomes in AUS/FLUS nodules were included. PRISMA and MOOSE guidelines were followed. Five investigators independently assessed the eligibility of the studies. Two investigators extracted summary data and assessed the risk of bias. Data were pooled using a random-effects model. The rate of malignancy was calculated on resected nodules only (upper limit of true value); and considering all unresected nodules were benign (lower limit of true value). The protocol was registered in PROSPERO (CRD42019123114). RESULTS: Of 2937 retrieved studies, 27 were eligible. The meta-analysis was conducted on summary data of 3932 AUS/FLUS thyroid nodules with RFNA. RFNA cytology would reclassify into categories I through VI of Bethesda: 4% (3%, 5%), 48% (43%, 54%), 26% (20%, 32%), 4% (3%, 6%), 5% (3%, 6%), and 2% (1%, 2%) of AUS/FLUS nodules. Malignancy rates of resected nodules were 24% (9%, 38%), 4% (1%, 7%), 40% (28%, 52%), 37% (27%, 47%), 79% (69%, 90%), and 99% (95%, 100%) for categories I through VI of Bethesda. There was high heterogeneity in these data. CONCLUSIONS: RFNA reclassified two-thirds of the AUS/FLUS specimens into a more definitive cytological category, with a benign call rate of nearly 50% and a negative predictive value greater than 96%.

A systematic review and meta-analysis of selected toxicity endpoints of alpelisib.

PURPOSE: Alpelisib is a first-in-class α-specific phosphatidylinositol 3-kinase inhibitor approved for the treatment of patients with estrogen receptor-positive metastatic breast cancer. High absolute risk (AR) of relevant toxicities has been observed with this treatment. This meta-analysis aimed to improve the precision of the estimated AR of selected adverse events (AEs) associated with this new agent. MATERIALS AND METHODS: A literature search was conducted in August 2019 to identify trials analyzing the anti-tumor efficacy and toxicity profile of alpelisib. Heterogeneity was assessed by using I 2 statistics. Data were analyzed using random effect meta-analyses for AR. Eleven trials and 511 patients were included. RESULTS: There was no evidence of heterogeneity between studies regarding the AR of most AEs except for all-grade weight loss and grade 3-4 stomatitis. The number of serious AEs was clearly reported in only one study, of which the most common was hyperglycemia; the most common all-grade AEs were hyperglycemia (59%), diarrhea (56%), nausea (44%), and rash (38%). Grade 3/4 hyperglycemia and rash occurred in 28% and 10% of patients, respectively. No treatment-associated deaths were observed, and 18% of patients had to stop treatment due to toxicities. CONCLUSIONS: Alpelisib is associated with clinically relevant AEs that can lead to treatment discontinuation. The most common AE was hyperglycemia. No treatment-related deaths were observed.

A brief report of toxicity end points of HER2 vaccines for the treatment of patients with HER2+ breast cancer.

Human epidermal growth factor receptor 2 (HER2)-targeted vaccines are under development, but have so far demonstrated only modest clinical efficacy. Additionally, there has been a lack of adequate safety assessment in large-scale prospective clinical trials. Therefore, we performed a meta-analysis of available clinical trial data to summarize the toxicity profiles of these treatments. Literature search was conducted in February 2018. The trials analyzed had at least one study arm consisting of HER2 vaccine monotherapy. Heterogeneity across studies was analyzed using I 2 statistics. Data were analyzed using random-effects meta-analysis for absolute risk (AR). Eight trials and 248 patients were included. There was no evidence of heterogeneity between studies for grades 3/4 adverse events (AEs) or for death. The AR for treatment-related serious AEs was 5% with no treatment-related deaths. The AR of all-grade fatigue, injection site reaction, and fever/chills/rigors was 33%, 23%, and 31%, respectively. Asymptomatic drop in left ventricle ejection fraction was rare (8%). HER2 vaccines are well tolerated with increased AR of fatigue, injection site reactions, and fever/chills/rigors.

Staging breast cancer by sentinel lymph node biopsy: Do patients with a single negative sentinel node (N=1) experience worse outcomes than those with multiple negative sentinel nodes (N>1)?

BACKGROUND: Though sentinel lymph node biopsy (SLNB) is standard of care for early breast cancer, concern remains for false negative nodes and potential implications for understaging and under-treatment, particularly when only one sentinel node is retrieved. We examined whether patients with a single negative SLN (N = 1) experience worse survival than those with two or more negative SLNs (N > 1). METHODS: This retrospective review examined 730 SLN-negative patients. Clinicopathologic and demographic data, recurrence-free and overall survival were assessed. Statistical analysis included Chi square tests, Kaplan-Meier survival analysis with log-rank tests, and multivariate analysis using the Cox regression model. RESULTS: There were no statistically significant differences in recurrence-free or overall survival between patients in the N = 1 versus the N > 1 group (log rank test, p = 0.75 and p = 0.52, respectively). There were also no differences in local and distant recurrence (1.9% versus 2.1%, p = 0.89 and 2.4% versus 2.3%, p = 0.78) or breast cancer death (2.4% versus 2.7%, p = 0.85). Increased tumor size was associated with finding greater than one negative sentinel node intraoperatively (p = 0.01). CONCLUSIONS: A single negative sentinel node did not portend worse recurrence-free or overall survival. After thorough axillary exploration during SLNB, retrieval of a single negative SLN did not result in worse clinical outcomes.

Cancer Risk Associated with Nuclear Atypia in Cytologically Indeterminate Thyroid Nodules: A Systematic Review and Meta-Analysis.

BACKGROUND: Indeterminate categories of thyroid cytopathology (categories B-III and B-IV of the Bethesda system) are integrated by a heterogeneous spectrum of cytological scenarios that are generally clustered for analysis and management recommendations. It has been suggested that aspirates exhibiting nuclear atypia have a higher risk of malignancy. This study aimed to assess whether cytologically indeterminate thyroid nodules with nuclear atypia have a significantly higher cancer risk than those without nuclear atypia. METHODS: On June 30, 2016, PubMed and EMBASE were searched for articles in English or Spanish using a search strategy developed by an endocrinologist and a librarian. Case reports were excluded, and no date limits were used. The references of all included studies were also screened for relevant missing studies. Studies were included if the prevalences of malignancy of cytologically indeterminate thyroid nodules with histological confirmation with and without nuclear atypia were reported. Studies were excluded if they had: (i) nodules suspicious for malignancy; (ii) nodules with non-indeterminate (B-III or B-IV) cytology on repeated biopsy, if performed; (iii) nodules not consecutively evaluated; or (iv) cohorts overlapping with another larger series. Two investigators independently assessed the eligibility and risk of bias of the studies. PRISMA and MOOSE guidelines were followed. Summary data were extracted from published reports by one investigator and independently reviewed by another. Data were pooled using a random-effects model. Heterogeneity was explored using subgroup analysis and mixed-effect model meta-regression. The odds ratio for malignancy of cytologically indeterminate thyroid nodules with nuclear atypia over cytologically indeterminate thyroid nodules without nuclear atypia was calculated. RESULTS: Of 2571 retrieved studies, 20 were eligible. The meta-analysis was conducted on summary data of 3532 cytologically indeterminate thyroid nodules: 1162 with and 2370 without nuclear atypia. The odds ratio for malignancy in cytologically indeterminate thyroid nodules with nuclear atypia was 3.63 [confidence interval 3.06-4.35]. There was no evidence of publication bias, and heterogeneity was insignificant (I2 < 0.01%, p = 0.40). CONCLUSIONS: Nuclear atypia is a significant indicator of malignancy in cytologically indeterminate thyroid nodules and needs to be standardized and implemented into clinical practice.

Laparoscopic Distal Pancreatectomy for Cancer Provides Oncologic Outcomes and Overall Survival Identical to Open Distal Pancreatectomy.

BACKGROUND: Laparoscopic distal pancreatectomy (LDP) has been shown to provide short-term clinical outcomes similar to open distal pancreatectomy (ODP) for patients with benign tumors. Our aim was to better define oncologic outcomes and long-term survival profiles following LDP for pancreatic ductal adenocarcinoma (PDAC). METHODS: We queried the National Cancer Database to identify patients with pathologic stage I-III PDAC who underwent distal pancreatectomy between 2010 and 2013. Logistic regression was performed to examine predictors of oncologic outcomes. Cox modeling was used for survival analysis and to estimate median overall survival (OS). RESULTS: One thousand five hundred fifty-four patients were included in the analysis. Patients undergoing LDP and ODP demonstrated identical probabilities of an adequate lymph node sampling and 90-day mortality. Those undergoing LDP demonstrated an increased probability of margin-negative resection (OR 1.78, CI 1.25-2.52) and a decreased probability of a prolonged hospital stay (OR 0.55, CI 0.32-0.95) or readmission (OR 0.56, CI 0.33-0.95) relative to those undergoing ODP. There was no difference in OS between groups (29.6 vs. 23.8 months, p = 0.10). CONCLUSION: LDP is an effective modality for managing resectable cancer in the pancreatic body and tail. LDP provides short-term oncologic outcomes and long-term OS rates identical to those for ODP while affording an accelerated recovery.

Laparoscopic pancreaticoduodenectomy for adenocarcinoma provides short-term oncologic outcomes and long-term overall survival rates similar to those for open pancreaticoduodenectomy.

BACKGROUND: The long-term efficacy of laparoscopic pancreaticoduodenectomy (LPD) relative to open pancreaticoduodenectomy (OPD) for pancreatic adenocarcinoma has not been well studied. METHODS: The National Cancer Data Base was used to compare patients undergoing LPD and OPD for stage I-II pancreatic adenocarcinoma between 2010 and 2013. RESULTS: 828 (10%) patients underwent LPD and 7385 (90%) OPD. There were no differences in tumor or demographic characteristics between groups. On multivariable analysis adjusted for hospital volume, LPD was associated with a lower rate of readmission (p < 0.01) and trends toward shorter initial length of stay (p = 0.14) and time to adjuvant chemotherapy (p = 0.11). There were no differences between patients undergoing LPD and those undergoing OP in rates of margin negative resection, number of lymph nodes examined, perioperative mortality and median overall survival (20.7 vs 20.9 months, p = 0.68). CONCLUSIONS: For patients with localized pancreatic adenocarcinoma, LPD provides short-term oncologic and long-term overall survival outcomes identical to OPD and is associated with decreased rates of readmission and a trend towards accelerated recovery.

Adjuvant Therapy Improves Survival for T2N0 Gastric Cancer Patients with Sub-optimal Lymphadenectomy.

BACKGROUND: The benefit of adjuvant therapy following resection of early stage, node-negative gastric adenocarcinoma following a margin negative (R0) resection is unclear. METHODS: The National Cancer Data Base was used to identify patients with a T2N0 gastric adenocarcinoma (tumor invasion into the muscularis propria) who underwent R0 resection. Patients treated with neoadjuvant therapy and those for whom lymph node count was unavailable were excluded from the analysis. Kaplan-Meier and Cox regression were used to evaluate differences in and predictors of overall survival. RESULTS: A total of 1687 patients underwent R0 resection for T2N0 gastric adenocarcinoma between 2003-2011. Adjuvant chemotherapy treatment was administered to 7.1 and 14.1 % received adjuvant chemoradiation; 65.4 % had <15 lymph nodes examined. Multivariate Cox regression identified higher Charlson score, <15 lymph nodes examined, higher tumor grade, and tumor location in the cardia as factors associated with significantly decreased overall survival. With a median follow-up of 36 months, the 5-year overall survival was 71 % for patients with ≥15 lymph nodes examined and 53 % for those with <15 lymph nodes (p < 0.001). In patients who had <15 lymph nodes examined, there was an overall survival benefit for adjuvant chemoradiation (hazard ratio 0.71, p = 0.043). In patients with ≥15 lymph nodes examined, no survival benefit for adjuvant therapy was identified (p > 0.74). CONCLUSIONS: Adequate lymph node dissection and pathologic staging is critical in directing optimal treatment of patients with early gastric cancer. Understaging as a result of suboptimal lymphadenectomy may explain the perceived benefit of adjuvant chemoradiation after an R0 resection for T2N0 gastric cancer.

Early National Experience with Laparoscopic Pancreaticoduodenectomy for Ductal Adenocarcinoma: A Comparison of Laparoscopic Pancreaticoduodenectomy and Open Pancreaticoduodenectomy from the National Cancer Data Base.

BACKGROUND: There is considerable debate about the safety and clinical equivalence of laparoscopic pancreaticoduodenectomy (LPD) and open pancreaticoduodenectomy (OPD) for pancreatic ductal adenocarcinoma (PDCA). STUDY DESIGN: We queried the National Cancer Data Base to identify patients undergoing LPD and OPD for PDCA between 2010 and 2011. Chi-square and Student's t-tests were used to evaluate differences between the 2 approaches. Multivariable logistic regression modeling was performed to identify patient, tumor, or facility factors associated with perioperative mortality. RESULTS: Four thousand and thirty-seven (91%) patients underwent OPD. Three hundred and eighty-four (9%) patients underwent LPD. There were no statistical differences between the 2 surgical cohorts with regard to age, race, Charlson score, tumor size, grade, stage, or treatment with neoadjuvant chemoradiotherapy. Laparoscopic pancreaticoduodenectomy demonstrated a shorter length of stay (10 ± 8 days vs 12 ± 9.7 days; p < 0.0001) and lower rates of unplanned readmission (5% vs 9%; p = 0.027) than OPD. In an unadjusted comparison, there was no difference in 30-day mortality between the LPD and OPD cohorts (5.2% vs 3.7%; p = 0.163). Multivariable logistic regression modeling predicting perioperative mortality controlling for age, Charlson score, tumor size, nodal positivity, stage, facility type, and pancreaticoduodenectomy volume identified age (odds ratio [OR] = 1.05; p < 0.0001), positive margins (OR = 1.45; p = 0.030), and LPD (OR = 1.89; p = 0.009) as associated with an increased probability of 30-day mortality; higher hospital volume was associated with a lower risk of 30-day mortality (OR = 0.98; p < 0.0001). In institutions that performed ≥10 LPDs, the 30-day mortality rate of the laparoscopic approach was equal to that for the open approach (0.0% vs 0.7%; p = 1.00). CONCLUSIONS: Laparoscopic pancreaticoduodenectomy is equivalent to OPD in length of stay, margin-positive resection, lymph node count, and readmission rate. There is a higher 30-day mortality rate with LPD, but this appears driven by a surmountable learning curve for the procedure.

The laparoscopic approach to distal pancreatectomy for ductal adenocarcinoma results in shorter lengths of stay without compromising oncologic outcomes.

BACKGROUND: The oncologic equivalence of laparoscopic distal pancreatectomy (LDP) to open pancreatectomy (ODP) for ductal adenocarcinoma (DAC) is not established. METHODS: The National Cancer Data Base was used to compare perioperative outcomes following LDP and ODP for DAC between 2010 and 2011. RESULTS: One hundred forty-five patients underwent LDP; 625 underwent ODP. Compared with ODP, patients undergoing LDP were older (68 ± 10.1 vs 66 ± 10.5 years, P = .027), more likely treated in academic centers (70% vs 59%, P = .01), and had shorter hospital stays (6.8 ± 4.6 vs 8.9 ± 7.5 days, P < .001). Demographic data, lymph node count, 30-day unplanned readmission, and 30-day mortality were identical between groups. Multivariable regression identified a lower probability of prolonged length of stay with LDP (odds ratio .51, 95% confidence interval .327 to .785, P = .0023). There was no association between surgical approach and node count, readmission, or mortality. CONCLUSION: LDP for DAC provides shorter postoperative lengths of stay and rates of readmission and 30-day mortality similar to OPD without compromising perioperative oncologic outcomes.

Surgical resection provides an overall survival benefit for patients with small pancreatic neuroendocrine tumors.

BACKGROUND: The optimal management of small (≤2 cm) pancreatic neuroendocrine tumors (PNETs) remains controversial. We evaluated these tumors in the National Cancer Data Base (NCDB) to determine if resection provides a survival advantage over observation. METHODS: The NCDB was queried to identify patients with nonmetastatic PNETs ≤2 cm treated between 1998 and 2006. Kaplan-Meier survival estimates, stratified by grade and treatment type, evaluated the difference in 5-year overall survival (OS) between patients who underwent resection and observation. Multivariable Cox regression was used to determine the importance of resection in OS. RESULTS: Three hundred eighty patients met inclusion criteria. Eighty-one percent underwent resection; 19% were observed. Five-year OS was 82.2% for patients who underwent surgery and 34.3% for those who were observed (p < 0.0001). When controlling for age, comorbidities, income, facility type, tumor size and location, grade, margin status, nodal status, surgical management, and nonsurgical therapy in the Cox model, observation [hazard ratio (HR) 2.80], poorly differentiated histology (HR 3.79), lymph node positivity (HR 2.01), and nonsurgical therapies (HR 2.23) were independently associated with an increase in risk of mortality (p < 0.01). CONCLUSION: Patients with localized PNETs ≤2 cm had an overall survival advantage with resection compared to observation, independent of age, comorbidities, tumor grade, and treatment with nonsurgical therapies.

Wait times for breast surgical operations, 2003-2011: a report from the National Cancer Data Base.

BACKGROUND: Few large-scale multicenter studies have examined wait times for breast surgery and no benchmarks exist. METHODS: Using the National Cancer Data Base, we analyzed time from diagnosis to first surgery for 819,175 non-neoadjuvant AJCC stage 0-III breast cancer patients treated from 2003 to 2011. Chi-square tests and logistic regression models were used to examine factors associated with delays to surgery and adjuvant chemotherapy. RESULTS: Seventy percent of patients underwent an initial lumpectomy (LP), 22% a mastectomy (MA), and 8% a mastectomy with reconstruction (MR). The median time from diagnosis to first surgery significantly increased by approximately 1 week for all three procedures over the study period. In a multivariate analysis, the following variables were independent predictors of a longer wait time to first surgery: increasing age, black or Hispanic race, Medicaid or no insurance, low-education communities and metropolitan areas, increasing comorbidities, stage 0 and grade 1 disease, academic/research facilities, high-volume facilities, and facilities located in the New England, Mid-Atlantic, and Pacific regions. In 2010-2011, patients who waited >30 days for surgery were 1.36 times more likely (OR = 1.36, 95% CI 1.30-1.43) to experience a delay to adjuvant chemotherapy >60 days compared with patients who were surgically treated within 30 days of diagnosis. CONCLUSIONS: Facility and socioeconomic factors are most strongly associated with longer wait times for breast operations, and delays to surgery are associated with delays to adjuvant chemotherapy initiation.

Defining the Benefit of Adjuvant Therapy Following Resection for Intrahepatic Cholangiocarcinoma.

BACKGROUND: Intrahepatic cholangiocarcinoma (ICC) is rare but is increasing in incidence. While hepatectomy can be curative, the benefit of adjuvant therapy (AT) remains unclear. We utilized the National Cancer Data Base (NCDB) to isolate predictors of overall survival, describe the national pattern of AT administration, and identify characteristics of patients who experience a survival benefit from AT following resection for ICC. METHODS: Patients who were diagnosed with ICC between 1998 and 2006 and underwent surgical resection were identified through the NCDB. Kaplan-Meier and Cox regression analyses evaluated differences in overall survival between patients who received AT and those who did not. RESULTS: Overall, 638 patients who underwent surgery for ICC were identified. Multivariate Cox regression analysis identified positive lymph nodes, unexamined lymph nodes, positive margins, and lack of AT as predictors of decreased overall survival; 28.1 % of patients had positive margins while 20.1 % had positive nodes. These patients, as well as those who were younger and had fewer co-morbid conditions, were most likely to receive AT. After adjusting for other prognostic variables, patients were found to significantly benefit from AT if they had positive lymph nodes [chemotherapy: hazard ratio (HR) 0.54, p = 0.0365; chemoradiation: HR 0.50, p = 0.005] or positive margins (chemotherapy: HR 0.44, p = 0.0016; chemoradiation: HR 0.57, p = 0.0039). CONCLUSIONS: Positive lymph nodes and positive margins were associated with poor survival after resection for ICC. After controlling for other prognostic factors, AT was associated with significant survival benefits among patients with positive nodes or positive margins.

On the age of eukaryotes: evaluating evidence from fossils and molecular clocks.

Our understanding of the phylogenetic relationships among eukaryotic lineages has improved dramatically over the few past decades thanks to the development of sophisticated phylogenetic methods and models of evolution, in combination with the increasing availability of sequence data for a variety of eukaryotic lineages. Concurrently, efforts have been made to infer the age of major evolutionary events along the tree of eukaryotes using fossil-calibrated molecular clock-based methods. Here, we review the progress and pitfalls in estimating the age of the last eukaryotic common ancestor (LECA) and major lineages. After reviewing previous attempts to date deep eukaryote divergences, we present the results of a Bayesian relaxed-molecular clock analysis of a large dataset (159 proteins, 85 taxa) using 19 fossil calibrations. We show that for major eukaryote groups estimated dates of divergence, as well as their credible intervals, are heavily influenced by the relaxed molecular clock models and methods used, and by the nature and treatment of fossil calibrations. Whereas the estimated age of LECA varied widely, ranging from 1007 (943-1102) Ma to 1898 (1655-2094) Ma, all analyses suggested that the eukaryotic supergroups subsequently diverged rapidly (i.e., within 300 Ma of LECA). The extreme variability of these and previously published analyses preclude definitive conclusions regarding the age of major eukaryote clades at this time. As more reliable fossil data on eukaryotes from the Proterozoic become available and improvements are made in relaxed molecular clock modeling, we may be able to date the age of extant eukaryotes more precisely.

Impact of bilateral versus unilateral mastectomy on short term outcomes and adjuvant therapy, 2003-2010: a report from the National Cancer Data Base.

BACKGROUND: Rates of bilateral mastectomy (BM) have increased, but the impact on length of stay (LOS), readmission rate, 30-day mortality, and time to adjuvant therapy is unknown. METHODS: Using the National Cancer Data Base, we selected 390,712 non-neoadjuvant AJCC stage 0-III breast cancer patients who underwent either unilateral mastectomy (UM) or BM from 2003 to 2010 with and without reconstruction. We used chi-square and logistic regression models for the analysis. RESULTS: A total of 315,278 patients (81 %) had UM, and 75,437 (19 %) had BM; 97,031 (25 %) underwent reconstruction. The number of median days from diagnosis to UM increased from 19 days in 2003 to 28 days in 2010, and for BM, increased from 21 to 31 days (p < 0.001). BM was independently associated with a longer time to surgery when adjusting for patient, facility, and tumor factors and reconstruction (OR 1.11; 95 % CI 1.07-1.15; p < 0.001). Reconstructed patients were twice as likely to have a longer time to surgery (OR 2.07; 95 % CI 2.01-2.14; p < 0.001). The median LOS was 1 day (range 0-184 days) for UM versus 2 (range 0-182) for BM (p < 0.001); 30-day mortality and readmission rates were not different between BM and UM. The median number of days from diagnosis to definitive chemotherapy, hormonal therapy, and radiation therapy was significantly greater in the BM group. CONCLUSIONS: Delays to surgical and adjuvant treatment are significantly longer for BM irrespective of reconstruction, and these delays have increased over the study period. These findings can be used by clinicians to counsel patients on BM.

Phylogenomics demonstrates that breviate flagellates are related to opisthokonts and apusomonads.

Most eukaryotic lineages belong to one of a few major groups. However, several protistan lineages have not yet been robustly placed in any of these groups. Both the breviates and apusomonads are two such lineages that appear to be related to the Amoebozoa and Opisthokonta (i.e. the 'unikonts' or Amorphea); however, their precise phylogenetic positions remain unclear. Here, we describe a novel microaerophilic breviate, Pygsuia biforma gen. nov. sp. nov., isolated from a hypoxic estuarine sediment. Ultrastructurally, this species resembles the breviate genera Breviata and Subulatomonas but has two cell morphologies, adherent and swimming. Phylogenetic analyses of the small sub-unit rRNA gene show that Pygsuia is the sister to the other breviates. We constructed a 159-protein supermatrix, including orthologues identified in RNA-seq data from Pygsuia. Phylogenomic analyses of this dataset show that breviates, apusomonads and Opisthokonta form a strongly supported major eukaryotic grouping we name the Obazoa. Although some phylogenetic methods disagree, the balance of evidence suggests that the breviate lineage forms the deepest branch within Obazoa. We also found transcripts encoding a nearly complete integrin adhesome from Pygsuia, indicating that this protein complex involved in metazoan multicellularity may have evolved earlier in eukaryote evolution than previously thought.

Role of lipase-generated free fatty acids in converting mesenteric lymph from a noncytotoxic to a cytotoxic fluid.

Recent studies have shown that mesenteric lymph plays a very important role in the development of multiple-organ dysfunction syndrome under critical conditions. Great efforts have been made to identify the biologically active molecules in the lymph. We used a trauma-hemorrhagic shock (T/HS) model and the superior mesenteric artery occlusion (SMAO) model, representing a global and a localized intestinal ischemia-reperfusion insult, respectively, to investigate the role of free fatty acids (FFAs) in the cytotoxicity of mesenteric lymph in rats. Lymph was collected before, during, and after (post) shock or SMAO. The post-T/HS and SMAO lymph, but not the sham lymph, manifested cytotoxicity for human umbilical vein endothelial cells (HUVECs). HUVEC cytotoxicity was associated with increased FFAs, especially the FFA-to-protein ratio. Addition of albumin, especially delipidated albumin, reduced this cytotoxicity. Lipase treatment of trauma-sham shock (T/SS) lymph converted it from a noncytotoxic to a cytotoxic fluid, and its toxicity correlated with the FFA-to-protein ratio in a fashion similar to that of the T/HS lymph, further suggesting that FFAs were the key components leading to HUVEC cytotoxicity. Analysis of lymph by gas chromatography revealed that the main FFAs in the post-T/HS or lipase-treated T/SS lymph were palmitic, stearic, oleic, and linoleic acids. When added to the cell culture at levels comparable to those in T/HS lymph, all these FFAs were cytotoxic, with linoleic acid being the most potent. In conclusion, this study suggests that lipase-generated FFAs are the key components resulting in the cytotoxicity of T/HS and SMAO mesenteric lymph.

Influence of cell size and DNA content on growth rate and photosystem II function in cryptic species of Ditylum brightwellii.

DNA content and cell volume have both been hypothesized as controls on metabolic rate and other physiological traits. We use cultures of two cryptic species of Ditylum brightwellii (West) Grunow with an approximately two-fold difference in genome size and a small and large culture of each clone obtained by isolating small and large cells to compare the physiological consequences of size changes due to differences in DNA content and reduction in cell size following many generations of asexual reproduction. We quantified the growth rate, the functional absorption cross-section of photosystem II (PSII), susceptibility of PSII to photoinactivation, PSII repair capacity, and PSII reaction center proteins D1 (PsbA) and D2 (PsbD) for each culture at a range of irradiances. The species with the smaller genome has a higher growth rate and, when acclimated to growth-limiting irradiance, has higher PSII repair rate capacity, PSII functional optical absorption cross-section, and PsbA per unit protein, relative to the species with the larger genome. By contrast, cell division rates vary little within clonal cultures of the same species despite significant differences in average cell volume. Given the similarity in cell division rates within species, larger cells within species have a higher demand for biosynthetic reductant. As a consequence, larger cells within species have higher numbers of PSII per unit protein (PsbA), since PSII photochemically generates the reductant to support biosynthesis. These results suggest that DNA content, as opposed to cell volume, has a key role in setting the differences in maximum growth rate across diatom species of different size while PSII content and related photophysiological traits are influenced by both growth rate and cell size.