Peritoneal metastases from primary appendiceal and colorectal carcinomas demonstrate distinct molecular identities on comprehensive tumor analysis.

BACKGROUND AND OBJECTIVES: Published data comparing peritoneal metastases from appendiceal cancers (pAC) and colorectal cancers (pCRC) remain sparse. We compared pAC and pCRC using comprehensive tumor profiling (CTP). METHODS: CTP was performed, including next-generation sequencing and analysis of copy number variation (CNV), microsatellite instability (MSI) and tumor mutational burden (TMB). RESULTS: One hundred thirty-six pAC and 348 pCRC samples underwent CTP. The cohorts' age and gender were similar. pCRC demonstrated increased pathogenic variants (PATHs) in APC (48% vs. 3%, p < 0.01), ARID1A (12% vs. 2%, p < 0.01), BRAF (12% vs. 2%, p < 0.01), FBXW7 (7% vs. 2%, p < 0.01), KRAS (52% vs. 41%, p < 0.05), PIK3CA (15% vs. 2%, p < 0.01), and TP53 (53% vs. 23%, p < 0.01), and decreased PATHs in GNAS (8% vs. 31%, p < 0.01). There was no difference in CNV, fusion rate, or MSI. Median TMB was higher in pCRC (5.8 vs. 5.0 mutations per megabase, p = 0.0007). Rates of TMB-high tumors were similar (pAC 2.1% vs. pCRC 9.0%, p = 0.1957). pCRC had significantly more TMB-high tumors at lower thresholds. CONCLUSIONS: Despite a reduced overall TMB, pAC demonstrated mutations distinct from those seen in pCRC. These may serve as discrete biomarkers for future study.

Segmental bile duct resection versus pancreatoduodenectomy for middle and distal third bile duct cancer. A systematic review and meta-analysis of comparative studies.

INTRODUCTION: Data regarding oncologic outcomes of segmental bile duct resection (SBDR) versus pancreatoduodenectomy (PD) for bile duct cancers (BDC) are conflicting. We compared SBDR and PD for BDC utilizing pooled data analysis. MATERIALS AND METHODS: A comprehensive PRISMA 2020 systematic review was performed. Studies comparing SBDR with PD for BDC were included. Pooled mean differences (MD), odds ratios (OR), and risk ratios (RR) with 95% confidence intervals (CI) were calculated. Subgroup analyses were performed. Study quality, bias, heterogeneity, and certainty were analyzed. RESULTS: Twelve studies from 2004 to 2021 were included, comprising 533 SBDR and 1,313 PD. SBDR was associated with positive proximal duct margins (OR 1.56; CI 1.11-2.18; P = .01), and distal duct margins (OR 43.25; CI 10.38-180.16; P < .01). SBDR yielded fewer lymph nodes (MD -6.93 nodes; CI -9.72-4.15; P < .01) and detected fewer nodal metastases (OR 0.72; CI 0.55-0.94; P = .01). SBDR portended less perioperative morbidity (OR 0.31; CI 0.21-0.46; P < .01), but not mortality (OR 0.52; CI 0.20-1.32; P = .17). SBDR was associated with locoregional recurrences (OR 1.88; CI 1.01-3.53; P = .02), and lymph node recurrences (OR 2.13; CI 1.42-3.2; P = .04). SBDR yielded decreased 5-year OS (OR 0.75; CI 0.65-0.85; P < .01). CONCLUSIONS: Despite decreased perioperative morbidity, SBDR appears to provide inferior oncologic control for BDC.

Analysis of the Survival Impact of Postoperative Chemotherapy After Preoperative Chemotherapy and Resection for Gastric Cancer.

BACKGROUND: Perioperative chemotherapy is a standard-of-care treatment for patients with gastric cancer. However, the impact of the postoperative chemotherapy (postCTX) component on overall survival (OS) is not well defined. METHODS: The National Cancer Database (NCDB) 2006-2014 was queried for patients who received preoperative chemotherapy (preCTX) and resection for gastric cancer. Analysis was performed to identify factors influencing receipt of postCTX. The impact of postCTX on OS was evaluated in propensity-matched groups. RESULTS: Among 3449 patients who received preCTX and resection for gastric cancer, 1091 (31.6%) received postCTX. Independent predictors of receiving postCTX were diagnosis after 2010 (odds ratio [OR] 1.985), distal tumor location (OR 1.348), and 15 or more lymph nodes examined (OR 1.214). Predictors of not receiving postCTX were older age (OR 0.985), comorbidity score higher than 1 (OR 0.592), and black race (OR 0.791). After propensity-matching (1091 per group), the median OS was 56.8 months for those who did receive postCTX versus 52.5 months for those who did not (p = 0.131). Subset analysis according to tumor grade, lymphovascular invasion, number of lymph nodes evaluated, T and N class, and AJCC stage identified an improvement in OS for the patients with N1 disease who received postCTX compared with those who did not (79.6 vs 41.3 months; p = 0.025). However, no other subgroup had a significant survival benefit. CONCLUSIONS: Additional postCTX was administered to a minority of patients who received preCTX and gastrectomy for gastric cancer, and its influence on OS appeared to be limited. Future trials should aim to define patients who will benefit from postCTX.

Implications of Conversion during Attempted Minimally Invasive Adrenalectomy for Adrenocortical Carcinoma.

BACKGROUND: Although advocated by some, minimally invasive adrenalectomy (MIA) for adrenocortical carcinoma (ACC) is controversial. Moreover, the oncologic implications for patients requiring conversion to an open procedure during attempted MIA for ACC are not extensively reported. PATIENTS AND METHODS: The National Cancer Database was queried for patients undergoing resection for ACC. Overall survival (OS) for patients undergoing successful MIA was compared with those requiring conversion, and additionally evaluated with a multivariable Cox regression analysis including other factors associated with OS. After propensity matching, those experiencing conversion were further compared with patients who underwent planned open resection. RESULTS: Among 196 patients undergoing attempted MIA for ACC, 38 (19.4%) required conversion. Independent of 90-day postoperative mortality, conversion was associated with significantly reduced OS compared with successful MIA (median 27.9 months versus not reached, p = 0.002). Even for tumors confined to the adrenal, conversion was associated with worse median OS compared with successful MIA (median 34.2 months versus not reached, p = 0.003). After propensity matching for clinicopathologic covariates to establish well-balanced cohorts (N = 38 per group), patients requiring conversion during MIA had significantly worse OS than those having planned open resection (27.9 months versus 50.5 months, p = 0.020). On multivariable analysis for predictors of OS, conversion during MIA (HR 2.32, p = 0.003) was independently associated with mortality. CONCLUSIONS: ACC is a rare tumor for which adequate oncologic resection is the only chance for cure. Given the relatively high rate of conversion and its associated inferior survival, open resection should be considered standard of care for known or suspected ACC.

Critical analysis of lymph node examination in patients undergoing curative-intent resection for adrenocortical carcinoma.

BACKGROUND: Adrenocortical carcinoma (ACC) is a rare tumor and the role of lymph node dissection remains ill-defined. This study evaluates the effect of nodal examination on prognosis and survival in patients undergoing curative-intent resection of ACC. METHODS: The National Cancer Database (2004-2015) was queried for patients undergoing margin-negative resection for ACC. Patients with distant metastases, neoadjuvant therapy, multivisceral resection and T4 tumors were excluded. RESULTS: Among 897 patients, 147 (16.4%) had lymph nodes examined. Factors associated with lymph node examination included increasing tumor size (P < .001), extra-adrenal extension (P < .001), open operation (P < .001), and resection at an academic facility (P = .003). Lymph node metastasis was significantly associated with extra-adrenal tumor extension (P = .04). Lymph node harvest, regardless of the number of nodes examined, was not associated with a survival benefit. Median overall survival was incrementally worse with increasing number of positive lymph nodes (88.2 months for N0, 34.9 months for 1-3 positive nodes, and 15.6 months for ≥4 positive nodes, P < .001). CONCLUSIONS: Lymph node harvest and lymph node metastasis were associated with more advanced tumors. Although nodal harvest did not offer a survival advantage, stratifying the nodal staging classification may provide important prognostic information.

The utilization and impact of adjuvant therapy following neoadjuvant therapy and resection of pancreatic adenocarcinoma: does more really matter?

BACKGROUND: Although neoadjuvant therapy is increasingly administered to patients with pancreatic ductal adenocarcinoma (PDAC), the impact of additional adjuvant therapy (AT) following resection is not well defined. METHODS: The National Cancer Database (NCDB) was queried for patients who received neoadjuvant therapy followed by R0 or R1 resection for PDAC. Factors influencing survival, including the receipt of AT were evaluated. RESULTS: Of patients receiving neoadjuvant therapy and resection 680 (33.8%) received AT and 1331 (66.2%) did not. For R0 resected patients (n = 1800), lymphovascular invasion (HR 1.24, p = 0.034) and increasing N classification (N1: HR 1.27, p = 0.019; N2: HR 1.51, p = 0.004) were associated with increased risk of death while AT was not associated with improved overall survival (OS) (HR 0.88, p = 0.179). Following R1 resection (n = 211), AT was associated with reduced risk of death (HR 0.57, p = 0.038). Within propensity matched cohorts, median OS for patients receiving and not receiving AT was 32.1 and 30.0 months after R0 resection (p = 0.184), and 23.6 and 20.5 months after R1 resection (p = 0.005). CONCLUSION: This analysis demonstrated that AT did not yield OS benefit for patients who had neoadjuvant therapy and R0 resection and a statistically significant, although relatively short, improvement in OS for patients who underwent R1 resection.

Thermodynamics of Conformational Transitions in a Disordered Protein Backbone Model.

Conformational entropy is expected to contribute significantly to the thermodynamics of structural transitions in intrinsically disordered proteins or regions in response to protein/ligand binding, posttranslational modifications, and environmental changes. We calculated the backbone (dihedral) conformational entropy of oligoglycine (GlyN), a protein backbone mimic and model intrinsically disordered region, as a function of chain length (N=3, 4, 5, 10, and 15) from simulations using three different approaches. The backbone conformational entropy scales linearly with chain length with a slope consistent with the entropy of folding of well-structured proteins. The entropic contributions of second-order dihedral correlations are predominantly through intraresidue ϕ-ψ pairs, suggesting that oligoglycine may be thermodynamically modeled as a system of independent glycine residues. We find the backbone conformational entropy to be largely independent of global structural parameters, like the end-to-end distance and radius of gyration. We introduce a framework referred to herein as "ensemble confinement" to estimate the loss (gain) of conformational free energy and its entropic component when individual residues are constrained to (released from) particular regions of the ϕ-ψ map. Quantitatively, we show that our protein backbone model resists ordering/folding with a significant, unfavorable ensemble confinement free energy because of the loss of a substantial portion of the absolute backbone entropy. Proteins can couple this free-energy reservoir to distal binding events as a regulatory mechanism to promote or suppress binding.

Optimal updating magnitude in adaptive flat-distribution sampling.

We present a study on the optimization of the updating magnitude for a class of free energy methods based on flat-distribution sampling, including the Wang-Landau (WL) algorithm and metadynamics. These methods rely on adaptive construction of a bias potential that offsets the potential of mean force by histogram-based updates. The convergence of the bias potential can be improved by decreasing the updating magnitude with an optimal schedule. We show that while the asymptotically optimal schedule for the single-bin updating scheme (commonly used in the WL algorithm) is given by the known inverse-time formula, that for the Gaussian updating scheme (commonly used in metadynamics) is often more complex. We further show that the single-bin updating scheme is optimal for very long simulations, and it can be generalized to a class of bandpass updating schemes that are similarly optimal. These bandpass updating schemes target only a few long-range distribution modes and their optimal schedule is also given by the inverse-time formula. Constructed from orthogonal polynomials, the bandpass updating schemes generalize the WL and Langfeld-Lucini-Rago algorithms as an automatic parameter tuning scheme for umbrella sampling.

Solvation Thermodynamics of Oligoglycine with Respect to Chain Length and Flexibility.

Oligoglycine is a backbone mimic for all proteins and is prevalent in the sequences of intrinsically disordered proteins. We have computed the absolute chemical potential of glycine oligomers at infinite dilution by simulation with the CHARMM36 and Amber ff12SB force fields. We performed a thermodynamic decomposition of the solvation free energy (ΔG(sol)) of Gly2-5 into enthalpic (ΔH(sol)) and entropic (ΔS(sol)) components as well as their van der Waals and electrostatic contributions. Gly2-5 was either constrained to a rigid/extended conformation or allowed to be completely flexible during simulations to assess the effects of flexibility on these thermodynamic quantities. For both rigid and flexible oligoglycine models, the decrease in ΔG(sol) with chain length is enthalpically driven with only weak entropic compensation. However, the apparent rates of decrease of ΔG(sol), ΔH(sol), ΔS(sol), and their elec and vdw components differ for the rigid and flexible models. Thus, we find solvation entropy does not drive aggregation for this system and may not explain the collapse of long oligoglycines. Additionally, both force fields yield very similar thermodynamic scaling relationships with respect to chain length despite both force fields generating different conformational ensembles of various oligoglycine chains.

Force field-dependent solution properties of glycine oligomers.

Molecular simulations can be used to study disordered polypeptide systems and to generate hypotheses on the underlying structural and thermodynamic mechanisms that govern their function. As the number of disordered protein systems investigated with simulations increase, it is important to understand how particular force fields affect the structural properties of disordered polypeptides in solution. To this end, we performed a comparative structural analysis of Gly(3) and Gly(10) in aqueous solution from all atom, microsecond molecular dynamics (MD) simulations using the CHARMM 27 (C27), CHARMM 36 (C36), and Amber ff12SB force fields. For each force field, Gly(3) and Gly(10) were simulated for at least 300 ns and 1 µs, respectively. Simulating oligoglycines of two different lengths allows us to evaluate how force field effects depend on polypeptide length. Using a variety of structural metrics (e.g., end-to-end distance, radius of gyration, dihedral angle distributions), we characterize the distribution of oligoglycine conformers for each force field and show that each sample conformation space differently, yielding considerably different structural tendencies of the same oligoglycine model in solution. Notably, we find that C36 samples more extended oligoglycine structures than both C27 and ff12SB.

Multibody correlations in the hydrophobic solvation of glycine peptides.

Protein collapse during folding is often assumed to be driven by a hydrophobic solvation energy (ΔGvdw) that scales linearly with solvent-accessible surface area (A). In a previous study, we argued that ΔGvdw, as well as its attractive (ΔGatt) and repulsive (ΔGrep) components, was not simply a linear function of A. We found that the surface tensions, γrep, γatt, and γvdw, gotten from ΔGrep, ΔGatt, and ΔGvdw against A for four configurations of deca-alanine differed from those obtained for a set of alkanes. In the present study, we extend our analysis to fifty decaglycine structures and atomic decompositions. We find that different configurations of decaglycine generate different estimates of γrep. Additionally, we considered the reconstruction of the solvation free energy from scaling the free energy of solvation of each atom type, free in solution. The free energy of the isolated atoms, scaled by the inverse surface area the atom would expose in the molecule does not reproduce the γrep for the intact decaglycines. Finally, γatt for the decaglycine conformations is much larger in magnitude than those for deca-alanine or the alkanes, leading to large negative values of γvdw (-74 and -56 cal/mol/Å(2) for CHARMM27 and AMBER ff12sb force fields, respectively). These findings imply that ΔGvdw favors extended rather than compact structures for decaglycine. We find that ΔGrep and ΔGvdw have complicated dependencies on multibody correlations between solute atoms, on the geometry of the molecular surface, and on the chemical identities of the atoms.

Totally minimally invasive laparoscopic robot-assisted Ivor Lewis esophagectomy: improved technique and outcomes over 200 cases.

Background: Surgical resection of esophageal and gastroesophageal junction cancers is a very complex procedure with step learning curve. New technologies have made minimally invasive surgery possible, but challenges still remain for wide spread adoption of these techniques. This article aims to describe the outcomes and salient technical points of a totally minimally invasive, laparoscopic, robot-assisted Ivor Lewis esophagectomy (LRAMIE). Methods: Retrospective observational cohort study performed at a specialty cancer center using a prospectively maintained institutional database. Patients undergoing LRAMIE (laparoscopic abdomen, robotic chest) from 2014-2023 were included. Patients undergoing transhiatal and three-field esophagectomy were excluded. Operative and postoperative outcomes were compared over the study period to identify potential associations between outcomes over time. Results: Two-hundred patients were identified who underwent LRAMIE. Median age was 65 years and most were male (87.5%). The open conversion rate was 1% (n=2), which occurred within the first 30 cases. Operative time and blood loss were improved at the 60-case mark (P<0.001). Anastomotic stricture rate improved after 50 cases, and leak rate improved after 80 cases. Postoperative length of stay improved at both 50 and 100 cases with a median LOS of 6 days after 100 cases. Rate of postoperative pneumonia, 30- and 90-day mortality were reduced after 100 cases, although not statistically significant for mortality due to too few events. Conclusions: Totally minimally invasive Ivor Lewis esophagectomy at a high-volume center is a safe procedure. Operative outcomes improved significantly after 50-80 cases, followed by improvement in anastomotic results and postoperative outcomes, with corresponding excellent oncologic outcomes.

Perioperative cyclooxygenase inhibition and postoperative pancreatic fistula after pancreatoduodenectomy: A systematic review and meta-analysis of comparative studies.

BACKGROUND: Nonsteroidal anti-inflammatory drug (NSAID) use has been investigated as a modifiable risk factor for postoperative pancreatic fistula (POPF) after pancreatoduodenectomy (PD). This study comprises a systematic review and meta-analysis examining the impact of perioperative NSAID use on rates of POPF after PD. METHODS: A Preferred Reporting Items for Systematic Reviews and Meta-Analyses 2020-compliant systematic review was performed. Pooled mean differences (MD), odds ratios (OR), and risk ratios with 95% CIs were calculated. RESULTS: Seven studies published from 2015 to 2021 were included, reporting 2851 PDs (1372 receiving NSAIDs and 1479 not receiving NSAIDs). There were no differences regarding blood loss (MD -99.40 mL; 95% CI, -201.71 to 2.91; P = .06), overall morbidity (OR 1.05; 95% CI, 0.68-1.61; P = .83), hemorrhage (OR 2.35; 95% CI, 0.48-11.59; P = .29), delayed gastric emptying (OR 0.98; 95% CI, 0.60-1.60; P = .93), bile leak (OR 0.68; 95% CI, 0.12-3.89; P = .66), surgical site infection (OR 1.02; 95% CI, 0.33-3.22; P = .97), abscess (OR 0.99; 95% CI, 0.51-1.91; P = .97), clinically relevant POPF (OR 1.18; 95% CI, 0.84-1.64; P = .33), readmission (OR 0.94; 95% CI, 0.61-1.46; P = .78), or reoperation (OR 0.82; 95% CI, 0.33-2.06; P = .68). NSAID use was associated with a shorter hospital stay (MD -1.05 days; 95% CI, -1.39 to 0.71; P < .00001). CONCLUSION: The use of NSAIDs in the perioperative period for patients undergoing PD was not associated with increased rates of POPF.

Sugarbaker Versus Keyhole Repair for Parastomal Hernia: a Systematic Review and Meta-analysis of Comparative Studies.

INTRODUCTION: Parastomal hernia is a debilitating complication of stoma creation. Parastomal hernia repair with mesh reduces recurrence rates in open and laparoscopic settings. Recent comparative studies conflict with previously pooled data on optimal mesh repair technique. The objective of this study is to examine parastomal hernia recurrence rates after Sugarbaker and keyhole repairs by performing an updated systematic review and meta-analysis of comparative studies. METHODS: A systematic review of PubMed, MEDLINE, EMBASE, the Cochrane database, SCOPUS, and the PROSPERO registry was performed according to PRISMA 2020 guidelines (PROSPERO ID: CRD42021290483). Studies comparing parastomal hernia recurrences after Sugarbaker and keyhole repairs were included. Studies with overlapping patient cohorts (duplicate data), non-comparative studies, studies that did not report the primary outcome of interest, and studies not in the English language were excluded. Study bias was assessed using the Newcastle-Ottawa scale. Pooled mean differences (MD), odds ratios (OR), and risk ratios (RR) with 95% confidence intervals (CI) were calculated. Heterogeneity was assessed using the I2 statistic. Forest plots and funnel plots were generated. Study quality was analyzed using MINORS. Additional subgroup analysis of modern studies was performed. RESULTS: Ten comparative studies published between 2005 and 2021 from 5 countries were included for analysis comprising 347 Sugarbaker repairs and 246 keyhole repairs. There were no differences in patient age, sex, or BMI between the groups. There was no difference between the groups regarding surgical site infection (OR 0.78; CI 0.31-1.98; P = 0.61) or post-operative bowel obstruction (OR 0.76; CI 0.23-2.56; P = 0.66). Sugarbaker repairs were significantly less often associated with parastomal hernia recurrence when compared to keyhole repairs (OR 0.38; CI 0.18-0.78; P = 0.008). There was no significant heterogeneity among the studies comparing parastomal hernia recurrence (I2 = 32%; P = 0.15). Quality analysis revealed a median MINORS score of 11 (range 6-16). Subgroup analysis of studies performed after the previously published pooled analysis (2015-2021) revealed no significant difference in parastomal hernia recurrence between the two groups (OR 0.58; CI 0.24-1.38; P = 0.22) with a significant subgroup effect (P = 0.05). CONCLUSIONS: Though there were lower rates of parastomal hernia recurrence with Sugarbaker repairs on overall analysis, this phenomenon disappeared on subgroup analysis of modern studies. Randomized controlled trials with contemporary cohorts would help further evaluate these repairs and minimize potential bias.

Tumor Location in the Pancreatic Tail Is Associated with Decreased Likelihood of Receiving Chemotherapy for Pancreatic Adenocarcinoma.

BACKGROUND: Chemotherapy (CTX) is associated with improved survival for patients undergoing resection for pancreatic ductal adenocarcinoma (PDAC). The current study evaluated the influence of tumor location on receipt of CTX. METHODS: The NCDB (2006-2017) was queried to identify patients with clinical stage I-III PDAC. Predictors of receipt of CTX, sequencing of CTX, and overall survival (OS) were analyzed. RESULTS: Among 14,557 patients who underwent resection for PDAC 3,453 (24%) did not receive CTX. On multivariable analysis, patients with tail tumors were 15% less likely to receive CTX (OR 0.85, 95% CI 0.747-0.968) and 58% less likely to receive neoadjuvant CTX (OR 0.42, 95% CI 0.351-0.509) relative to patients with head/neck tumors. For patients with body tumors, there was no difference in rates of administration or sequence of CTX. For patients with resected tail tumors, median OS was 29.9 vs 18.9 months (p < 0.001) between those who did and did not receive CTX. For patients with tail tumors, independent predictors of not receiving CTX, regardless of sequence, were increasing age (OR 0.95, 95% CI 0.935-0.965), increasing post-op length of stay (OR 0.95, 95% CI 0.932-0.968), and 30-day post-op readmission (OR 0.46, 95% CI 0.315-0.670). CONCLUSIONS: In patients with clinical stage I-III PDAC, tumor location within the tail was independently associated with not receiving CTX. Given the marked improvement in OS when CTX is administered, strategies aimed at increasing the number of these patients who receive CTX are necessary.

Video-assisted thoracoscopic surgery pleurectomy: a suitable alternative for treating malignant pleural effusions.

BACKGROUND: Malignant pleural effusions (MPEs) are common manifestations of metastatic cancers and are associated with a dismal prognosis. Talc pleurodesis has been proven to be effective in the management of MPEs, however, class-action lawsuits linking talc to ovarian adenocarcinoma have rendered it unavailable at many institutions. As a result, surgeons have resorted to less effective chemical pleurodesis as an alternative to indwelling pleural drainage catheters. Given the absence of talc, we explored the effectiveness of video-assisted thoracoscopic surgery (VATS) partial pleurectomy (VPP) for treating MPEs. METHODS: We performed a retrospective review of patients with MPEs managed after talc became unavailable at our institution. Between 2016 and 2018, we identified five patients who refused pleural drainage catheters and underwent VPP. Symptoms at presentation included fatigue, dyspnea, and pleuritic chest pain. All had unilateral MPEs (left n=3, right n=2). VPP included removal of parietal surfaces of the pleura other than the pleura overlying the subclavian vessels, the mediastinum, and the lung viscera. RESULTS: There were no significant perioperative adverse events and post-operative pain was well controlled. Chest tubes were removed between post-operative day (POD) 3 and 7. Follow-up time ranged from four to 36 weeks. All patients had symptomatic relief and radiographic evidence of improved MPEs. No patients required re-interventions. One patient expired six months after surgery while the remaining four were alive at last follow-up. CONCLUSIONS: VPP offers an effective alternative to chemical pleurodesis for managing MPEs in patients who prefer to avoid pleural drainage catheters.

Characteristics of Matriculants to Thoracic Surgery Residency Training Programs.

BACKGROUND: Thoracic surgery (TS) residency positions are in high demand. There is no study describing the nationwide attributes of successful matriculants in this specialty. We examined the characteristics of TS resident applicants and identified factors associated with acceptance. METHODS: Applicant data from 2014 to 2017 application cycles was extracted from the Electronic Residency Application System and stratified by matriculation status. Medical education, type of general surgery residency, and research achievements were analyzed. The number of peer-reviewed publications and the corresponding impact factor for the journals where they were published were quantified. RESULTS: There were 492 applicants and 358 matriculants. The overall population was primarily male (79.5%), white (55.1%), educated at United States allopathic medical schools (66.5%), and trained at university-based general surgery residencies (59.6%). Education at United States allopathic schools (odds ratio [OR], 2.54; P < .0001), being a member of the American Osteopathic Association (OR, 3.27; P = .021), general surgery residency affiliation with a TS residency (OR, 2.41; P = .0003) or National Cancer Institute designated Comprehensive Cancer Center (OR, 1.76; P = .0172), and being a first-time applicant (OR, 4.71, P < .0001) were independently associated with matriculation. Matriculants published a higher number of manuscripts than nonmatriculants (median of 3 vs 2, P < .0001) and more frequently published in higher impact journals (P < .0001). CONCLUSIONS: Our study includes objective and quantifiable data from recent application cycles and represents an in-depth examination of applicants to TS residency. The type of medical school and residency, as well as academic productivity, correlate with successful matriculation.

Patient Comorbidities Drive High Mortality Rates Associated with Major Liver Resections Irrespective of Hospital Volume.

INTRODUCTION: Major hepatectomies are utilized to manage primary hepatic malignancies. Reports from high-volume centers (HVCs) with minimal perioperative mortality focus on multiple aspects of perioperative care, although patient-specific factors remain unelucidated. We identified patient factors associated with outcomes and examined whether these contribute to survival differences. METHODS: We queried the National Cancer Database (2006-2015) for patients with primary liver malignancies managed with major hepatectomy. Facilities were dichotomized by volume (high volume: >15 hepatectomies/year). Perioperative outcomes were compared based on patient demographic and clinical characteristics as well as center volume. RESULTS: 4263 patients were included with 78.5% receiving care in low-volume centers (LVCs). 90-day postoperative mortality was higher in LVCs vs. HVCs (12% vs. 7.5%; P < .001). Factors associated with undergoing surgery in LVCs included: living in areas with lower income (P = .006) and education (P < .001), having nonprivate insurance (P < .001), residing near the care center (P < .001), and having a comorbidity score (CDS) >1 (P = .014). Patients with CDS ≤ 1 had higher 90-day mortality in LVCs (11.3% vs. 6.6%; P < .001) and had similar outcomes in LVCs and HVCs (15.6% vs. 13.7% P = .6). Patients with CDS > 1 were more likely to receive care in LVCs (16.3% vs. 12.7%; P < .001). CONCLUSION: Reduced perioperative mortality following major hepatectomy in HVCs is driven by optimal management of patients with low CDS. However, nearly 1 in 5 patients who undergo major hepatectomies have a high CDS and approximately 15% of them succumb in the perioperative period irrespective of the treating centers' experience.

Physical Chemistry of the Protein Backbone: Enabling the Mechanisms of Intrinsic Protein Disorder.

Over the last two decades it has become clear that well-defined structure is not a requisite for proteins to properly function. Rather, spectra of functionally competent, structurally disordered states have been uncovered requiring canonical paradigms in molecular biology to be revisited or reimagined. It is enticing and oftentimes practical to divide the proteome into structured and unstructured, or disordered, proteins. While function, composition, and structural properties largely differ, these two classes of protein are built upon the same scaffold, namely, the protein backbone. The versatile physicochemical properties of the protein backbone must accommodate structural disorder, order, and transitions between these states. In this review, we survey these properties through the conceptual lenses of solubility and conformational populations and in the context of protein-disorder mediated phenomena (e.g., phase separation, order-disorder transitions, allostery). Particular attention is paid to the results of computational studies, which, through thermodynamic decomposition and dissection of molecular interactions, can provide valuable mechanistic insight and testable hypotheses to guide further solution experiments. Lastly, we discuss changes in the dynamics of side chains and order-disorder transitions of the protein backbone as two modes or realizations of "entropic reservoirs" capable of tuning coupled thermodynamic processes.

Bidirectional chemotherapy in patients with gastric cancer and peritoneal metastasis.

Gastric cancer is a lethal malignancy due to the combination of late-stage presentation, propensity for early metastasis, and lack of effective systemic therapies. Given the high rates of gastric peritoneal metastasis, both macro- and microscopic, regional therapy represents both an attractive and rational treatment option for patients given its success in other peritoneal surface malignancies. Bidirectional chemotherapy (intraperitoneal and intravenous) for treatment of metastatic gastric cancer has not been evaluated prospectively in a contemporary North American cohort. Here we present the rationale and design of a phase II clinical trial of intraperitoneal paclitaxel in combination with intravenous paclitaxel and oral capecitabine. We hypothesize that the combination of systemic and regional chemotherapy may result in improved progression free survival (PFS) for patients with gastric adenocarcinoma and peritoneal-only metastasis. In addition to studying clinical outcomes associated with this treatment regimen, both basic and translational science efforts are planned to better understand this complex malignancy.