Language Proficiency and Survival in Pancreatic Cancer: a Propensity Score-Matched Analysis.

BACKGROUND: Limited English proficiency has been shown to negatively affect health outcomes. However, as of now, little is known about survival rates of patients with limited English proficiency (LEP) and pancreatic ductal adenocarcinoma (PDAC) when compared to patients with English proficiency (EP) in an urban, non-safety net setting. We aimed to compare survival rates between patients with LEP and those with EP who had a diagnosis of PDAC. METHODS: A single-institution retrospective propensity-matched cohort study of patients with biopsy-proven PDAC was undertaken. Demographics, clinical characteristics, and language information were collected for all participants. Patients were classified as having LEP or EP based on their preferred speaking language at the time of admission and matched on baseline characteristics using propensity scores. Survival analysis methods were used to study survival rates in patients with PDAC based on their EP status. RESULTS: Of 739 included patients, 71 (9.48%) had LEP, mean age was 68.4 ± 10.9, and 51.8% were female. Both groups of patients were comparable for age, gender, marital status, and time to treatment. LEP status was associated with higher odds of death in both unmatched (HR 1.65, 95% CI 1.22-2.22) and matched (HR 1.60, 95% CI 1.03-2.47) analyses. Additionally, patients with LEP had significantly decreased odds of receiving cancer-directed treatment and increased odds of advanced stage cancer at presentation. CONCLUSIONS: In this cohort of patients with PDAC, LEP predicted worse survival. The results of this study suggest that, after accounting for interpreter use, other factors contribute to this disparity. Such factors, as yet unmeasured, may include health literacy and cultural expectations, for which further investigation is warranted to better understand and limit this survival disparity.

Differential regulation of human thymosin beta 15 isoforms by transforming growth factor beta 1.

We recently identified an additional isoform of human thymosin beta 15 (also known as NB-thymosin beta, gene name TMSB15A) transcribed from an independent gene, and designated TMSB15B. The purpose of this study was to investigate whether these isoforms were differentially expressed and functional. Our data show that the TMSB15A and TMSB15B isoforms have distinct expression patterns in different tumor cell lines and tissues. TMSB15A was expressed at higher levels in HCT116, DU145, LNCaP, and LNCaP-LN3 cancer cells. In MCF-7, SKOV-3, HT1080, and PC-3MLN4 cells, TMSB15A and TMSB15B showed approximately equivalent levels of expression, while TMSB15B was the predominant isoform expressed in PC-3, MDA-MB-231, NCI-H322, and Caco-2 cancer cells. In normal human prostate and prostate cancer tissues, TMSB15A was the predominant isoform expressed. In contrast, normal colon and colon cancer tissue expressed predominantly TMSB15B. The two gene isoforms are also subject to different transcriptional regulation. Treatment of MCF-7 breast cancer cells with transforming growth factor beta 1 repressed TMSB15A expression but had no effect on TMSB15B. siRNA specific to the TMSB15B isoform suppressed cell migration of prostate cancer cells to epidermal growth factor, suggesting a functional role for this second isoform. In summary, our data reveal different expression patterns and regulation of a new thymosin beta 15 gene paralog. This may have important consequences in both tumor and neuronal cell motility.

The Learning Environment in Surgery Clerkship: What are Faculty Perceptions?

OBJECTIVE: Multiple efforts have sought to improve teaching effectiveness and the learning environment (LE), but prior research has not focused on attending physicians' perceptions of mistreatment or contribution to the LE. The purpose of this study was to assess the perception and role of surgical faculty in the medical student LE. DESIGN: A semistructured interview guide was developed using a comprehensive approach including extensive literature search and focus groups. Data were audio-recorded and transcribed verbatim. Content analysis was used to identify emergent themes. SETTING: Beth Israel Deaconess Medical Center, an academic tertiary care facility located in Boston, Massachusetts. PARTICIPANTS: Fifteen faculty in the Department of Surgery underwent detailed interviews. Participants were selected using purposive-stratified criterion-based sampling. RESULTS: Multiple themes emerged: (1) The competing demands on medical student's time are a negative factor in the LE; (2) Faculty expectations conflict with the existing curriculum; (3) Faculty are concerned with the possibility of being reported for providing negative feedback; (4) Faculty remain unfamiliar with policies regarding the LE/mistreatment; (5) A motivated medical student makes the educational interaction more productive independent of specialty of choice. CONCLUSIONS: Faculty identified that the most important factors contributing to a negative LE were a mismatch between expectations of medical students and faculty, and the conflict between the current curriculum and the faculty member's perceived ideal educational framework. Importantly, faculties were largely unfamiliar with LE/mistreatment policies and standards. These findings suggest a need for targeted curricula for faculty to raise awareness of components of a positive LE and tools to teach effectively within the contemporary medical school curriculum.

Financial burden of thyroid cancer in the United States: An estimate of economic and psychological hardship among thyroid cancer survivors.

BACKGROUND: Annual cancer-related healthcare expenditure in the United States is estimated to exceed $150 billion by 2020. As the prevalence of thyroid cancer increases worldwide, thyroid cancer survivorship is associated with increasing personal and cumulative costs. Few studies have examined the psychological and material economic costs experienced by thyroid cancer survivors. We seek to estimate the comparative prevalence of financial and psychological hardship among thyroid cancer and non-thyroid cancer patients in the United States. METHODS: The 2011 Medical Expenditure Panel Survey Experiences with Cancer databank was queried to identify thyroid and non-thyroid (colon, breast, lung, prostate) cancer survivors. This survey includes assessments of financial stress, material hardship, and psychological financial hardship. Cancer incidence-based weighted estimates of responses were compared between thyroid and non-thyroid cancer survivors. Independent predictors of material and psychological financial burden were identified through separate multivariate regression models. RESULTS: Thyroid cancer survivors more frequently reported psychological financial burden compared to non-thyroid cancer (46.1% vs 24.0%, P = .04). Material financial hardship (28.1% vs 19.9%, P = .37) and concurrent material and psychological hardship (25.1% vs 12.5%, P = .09) were noted at similar frequencies between thyroid and non-thyroid cancer survivors. However, on multivariate analysis, only younger age and lack of health insurance coverage were independently associated with psychological financial hardship. CONCLUSION: Thyroid cancer survivors report greater psychological financial hardship than non-thyroid cancer survivors. Because this financial burden may be underrecognized in the medical community, further studies should be conducted to aid physicians in better understanding the impact of a thyroid cancer diagnosis.

Unbiased Phenotype-Based Screen Identifies Therapeutic Agents Selective for Metastatic Prostate Cancer.

In American men, prostate cancer is the second leading cause of cancer-related death. Dissemination of prostate cancer cells to distant organs significantly worsens patients' prognosis, and currently there are no effective treatment options that can cure advanced-stage prostate cancer. In an effort to identify compounds selective for metastatic prostate cancer cells over benign prostate cancer cells or normal prostate epithelial cells, we applied a phenotype-based in vitro drug screening method utilizing multiple prostate cancer cell lines to test 1,120 different compounds from a commercial drug library. Top drug candidates were then examined in multiple mouse xenograft models including subcutaneous tumor growth, experimental lung metastasis, and experimental bone metastasis assays. A subset of compounds including fenbendazole, fluspirilene, clofazimine, niclosamide, and suloctidil showed preferential cytotoxicity and apoptosis towards metastatic prostate cancer cells in vitro and in vivo. The bioavailability of the most discerning agents, especially fenbendazole and albendazole, was improved by formulating as micelles or nanoparticles. The enhanced forms of fenbendazole and albendazole significantly prolonged survival in mice bearing metastases, and albendazole-treated mice displayed significantly longer median survival times than paclitaxel-treated mice. Importantly, these drugs effectively targeted taxane-resistant tumors and bone metastases - two common clinical conditions in patients with aggressive prostate cancer. In summary, we find that metastatic prostate tumor cells differ from benign prostate tumor cells in their sensitivity to certain drug classes. Taken together, our results strongly suggest that albendazole, an anthelmintic medication, may represent a potential adjuvant or neoadjuvant to standard therapy in the treatment of disseminated prostate cancer.

Development and external validation of a prediction model for survival in patients with resected ampullary adenocarcinoma.

INTRODUCTION: Ampullary adenocarcinoma (AAC) is a rare malignancy with great morphological heterogeneity, which complicates the prediction of survival and, therefore, clinical decision-making. The aim of this study was to develop and externally validate a prediction model for survival after resection of AAC. MATERIALS AND METHODS: An international multicenter cohort study was conducted, including patients who underwent pancreatoduodenectomy for AAC (2006-2017) from 27 centers in 10 countries spanning three continents. A derivation and validation cohort were separately collected. Predictors were selected from the derivation cohort using a LASSO Cox proportional hazards model. A nomogram was created based on shrunk coefficients. Model performance was assessed in the derivation cohort and subsequently in the validation cohort, by calibration plots and Uno's C-statistic. Four risk groups were created based on quartiles of the nomogram score. RESULTS: Overall, 1007 patients were available for development of the model. Predictors in the final Cox model included age, resection margin, tumor differentiation, pathological T stage and N stage (8th AJCC edition). Internal cross-validation demonstrated a C-statistic of 0.75 (95% CI 0.73-0.77). External validation in a cohort of 462 patients demonstrated a C-statistic of 0.77 (95% CI 0.73-0.81). A nomogram for the prediction of 3- and 5-year survival was created. The four risk groups showed significantly different 5-year survival rates (81%, 57%, 22% and 14%, p < 0.001). Only in the very-high risk group was adjuvant chemotherapy associated with an improved overall survival. CONCLUSION: A prediction model for survival after curative resection of AAC was developed and externally validated. The model is easily available online via www.pancreascalculator.com.

Papillary thyroid cancer with extrathyroidal extension of desmoid-type fibromatosis. A case report of an aggressive presentation of an uncommon pathologic entity.

INTRODUCTION: Papillary thyroid cancer with desmoid-type fibromatosis (PTC-DTF) is an uncommon tumor characterized by extensive stromal proliferation of fibroblasts and myofibroblasts with a small component of PTC. We report a case of PTC-DTF with infiltration of the mesenchymal component of tumor into perithyroidal muscle and early recurrence of desmoid after thyroidectomy, an outcome previously not reported. PRESENTATION OF CASE: A 20-year-old man underwent left hemithyroidectomy for a thyroid nodule. Pathology demonstrated a 4.2 cm tumor with PTC-DTF with the PTC comprising <10% of the tumor. The stromal component extended into adjacent skeletal muscle. After completion thyroidectomy, histopathology of the right thyroid lobe revealed no malignancy or fibromatosis. Neck MRI 16 months after the initial operation revealed a 10.5 cm tumor in the left thyroid bed. Core biopsy and open excisional biopsy showed desmoid-type fibromatosis without PTC. The patient is undergoing chemotherapy of his recurrent desmoid-type fibromatosis. DISCUSSION: In patients with PTC-DTF there is a risk of recurrence of the benign component of the tumor. In recent reports, the role of less aggressive surgery, or even non-surgical management, of patients with recurrent DTF has been emphasized, in particular when extensive surgery may be associated with high risk of functional loss. The management of our patient adheres to modern recommendations for the treatment of DTF. CONCLUSION: Patients with PTC-DTF should be carefully monitored after thyroidectomy for both recurrent PTC and local recurrence of the fibrous component of the tumor.

Role of Adjuvant Multimodality Therapy After Curative-Intent Resection of Ampullary Carcinoma.

Importance: Ampullary adenocarcinoma is a rare malignant neoplasm that arises within the duodenal ampullary complex. The role of adjuvant therapy (AT) in the treatment of ampullary adenocarcinoma has not been clearly defined. Objective: To determine if long-term survival after curative-intent resection of ampullary adenocarcinoma may be improved by selection of patients for AT directed by histologic subtype. Design, Setting, and Participants: This multinational, retrospective cohort study was conducted at 12 institutions from April 1, 2000, to July 31, 2017, among 357 patients with resected, nonmetastatic ampullary adenocarcinoma receiving surgery alone or AT. Cox proportional hazards regression was used to identify covariates associated with overall survival. The surgery alone and AT cohorts were matched 1:1 by propensity scores based on the likelihood of receiving AT or by survival hazard from Cox modeling. Overall survival was compared with Kaplan-Meier estimates. Exposures: Adjuvant chemotherapy (fluorouracil- or gemcitabine-based) with or without radiotherapy. Main Outcomes and Measures: Overall survival. Results: A total of 357 patients (156 women and 201 men; median age, 65.8 years [interquartile range, 58-74 years]) underwent curative-intent resection of ampullary adenocarcinoma. Patients with intestinal subtype had a longer median overall survival compared with those with pancreatobiliary subtype (77 vs 54 months; P = .05). Histologic subtype was not associated with AT administration (intestinal, 52.9% [101 of 191]; and pancreatobiliary, 59.5% [78 of 131]; P = .24). Patients with pancreatobiliary histologic subtype most commonly received gemcitabine-based regimens (71.0% [22 of 31]) or combinations of gemcitabine and fluorouracil (12.9% [4 of 31]), whereas treatment of those with intestinal histologic subtype was more varied (fluorouracil, 50.0% [17 of 34]; gemcitabine, 44.1% [15 of 34]; P = .01). In the propensity score-matched cohort, AT was not associated with a survival benefit for either histologic subtype (intestinal: hazard ratio, 1.21; 95% CI, 0.67-2.16; P = .53; pancreatobiliary: hazard ratio, 1.35; 95% CI, 0.66-2.76; P = .41). Conclusions and Relevance: Adjuvant therapy was more frequently used in patients with poor prognostic factors but was not associated with demonstrable improvements in survival, regardless of tumor histologic subtype. The value of a multimodality regimen remains poorly defined.

Radiologic evaluation of patients undergoing the modified Appleby procedure for locally advanced pancreatic neoplasms: a case series.

PURPOSE: Despite advances in medical and surgical care, pancreatic ductal adenocarcinoma remains one of the most locally aggressive neoplastic processes in the abdomen. Unfortunately, most pancreatic adenocarcinomas present late and are unresectable at time of diagnosis. The modified Appleby procedure is a surgical option in patients with locally advanced pancreatic neoplasms of the body and tail with vascular invasion of the celiac trunk. To our knowledge, no radiologic journal has previously reported on the pre-operative evaluation or postoperative imaging findings of such patients. METHODS: We report herein three patients who underwent the modified Appleby procedure, each with a unique complication, in an attempt to illustrate common pitfalls of interpretation in these advanced cases. RESULTS: Our case series emphasizes the importance of pre-operative radiologic assessment of variant arterial anatomy, knowledge of pre- and intraoperative procedures and appearances, and familiarity with potential postoperative complications. CONCLUSIONS: Thorough understanding of the important aspects of the pre-surgical anatomy, as well as possible post-surgical complications, is the key to the radiologist being a useful participant in the clinical care of these patients.

Using Individual Clinical Evaluations to Assess Residents' Clinical Judgment; Feasibility and Residents' Perception.

OBJECTIVE: In surgical training, most assessment tools focus on advanced clinical decision-making or operative skill. Available tools often require significant investment of resources and time. A high stakes oral examination is also required to become board-certified in surgery. We developed Individual Clinical Evaluation (ICE) to evaluate intern-level clinical decision-making in a time- and cost-efficient manner, and to introduce the face-to-face evaluation setting. DESIGN: Intern-level ICE consists of 3 clinical scenarios commonly encountered by surgical trainees. Each scenario was developed to be presented in a step-by-step manner to an intern by an attending physician or chief resident. The interns had 17 minutes to complete the face-to-face evaluation and 3 minutes to receive feedback on their performance. The feedback was transcribed and sent to the interns along with incorrect answers. Eighty percent correct was set as a minimum to pass each scenario and continue with the next one. Interns who failed were retested until they passed. Frequency of incorrect response was tracked by question/content area. After passing the 3 scenarios, interns completed a survey about their experience with ICE. SETTING: Beth Israel Deaconess Medical Center, an academic tertiary care facility located in Boston, Massachusetts. PARTICIPANTS: All first-year surgery residents in our institution (n = 17) were invited to complete a survey. RESULTS: All 2016-2017 surgical interns (17) completed the ICEs. A total of $171 (US) was spent conducting the ICEs, and an average of 17 minutes was used to complete each evaluation. In total, 5 different residents failed 1 scenario, with the most common mistake being: failing to stabilize respiration before starting management. After completing the 3 clinical scenarios, more than 90% of respondents agreed or strongly agreed that the evaluations were appropriately challenging for training level, and that the evaluations helped to identify personal strengths and weaknesses in skill and knowledge. The majority believed their knowledge improved as a result of the ICE and felt better prepared to manage these scenarios (88% and 76%, respectively). CONCLUSIONS: The ICE is an inexpensive and time efficient way to introduce interns to board type examinations and assess their preparedness for perioperative patient care issues. Common errors were identified which were able to inform educational efforts. ICEs were well accepted by residents. Next steps include extension of the ICE to PGY2 and PGY3 residents.

Value-based assessment of robotic pancreas and liver surgery.

Current healthcare economic evaluations are based only on the perspective of a single stakeholder to the healthcare delivery process. A true value-based decision incorporates all of the outcomes that could be impacted by a single episode of surgical care. We define the value proposition for robotic surgery using a stakeholder model incorporating the interests of all groups participating in the provision of healthcare services: patients, surgeons, hospitals and payers. One of the developing and expanding fields that could benefit the most from a complete value-based analysis is robotic hepatopancreaticobiliary (HPB) surgery. While initial robot purchasing costs are high, the benefits over laparoscopic surgery are considerable. Performing a literature search we found a total of 18 economic evaluations for robotic HPB surgery. We found a lack of evaluations that were carried out from a perspective that incorporates all of the impacts of a single episode of surgical care and that included a comprehensive hospital cost assessment. For distal pancreatectomies, the two most thorough examinations came to conflicting results regarding total cost savings compared to laparoscopic approaches. The most thorough pancreaticoduodenectomy evaluation found non-significant savings for total hospital costs. Robotic hepatectomies showed no cost savings over laparoscopic and only modest savings over open techniques. Lastly, robotic cholecystectomies were found to be more expensive than the gold-standard laparoscopic approach. Existing cost accounting data associated with robotic HPB surgery is incomplete and unlikely to reflect the state of this field in the future. Current data combines the learning curves for new surgical procedures being undertaken by HPB surgeons with costs derived from a market dominated by a single supplier of robotic instruments. As a result, the value proposition for stakeholders in this process cannot be defined. In order to solve this problem, future studies must incorporate (I) quality of life, survival, and return to independent function alongside data such as (II) intent-to-treat analysis of minimally-invasive surgery accounting for conversions to open, (III) surgeon and institution experience and operative time as surrogates for the learning curve; and (IV) amortization and maintenance costs as well as direct costs of disposables and instruments.

Robotic enucleation of benign pancreatic tumors.

Robot-assisted enucleation provides the dual benefits of a minimally-invasive technique and pancreatic parenchymal conservation to selected patients with functional pancreatic neuroendocrine tumors (F-pNETs) and serous cystadenomas. Insulinomas, the most common F-pNETs, are ideal candidates for enucleation when <2 cm given the 80% probability of being benign. Current evidence suggests enucleation for the following: benign, isolated lesions with a distance between tumor and main pancreatic duct ≥3 mm (no focal stricture or dilation), insulinomas, gastrinomas <2 cm, and nonfunctional pancreatic neuroendocrine tumors (NF-pNETs) <1-2 cm and low Ki67 mitotic index. Minimally-invasive enucleation is an imaging-dependent procedure that requires recognizable anatomic landmarks for successful completion, including tumor proximity to the pancreatic duct as well as localization relative to major structures such as the gastroduodenal artery, bile duct, and portal vein. Tumor localization often mandates intraoperative ultrasound aided by duplex studies of intratumoral blood flow and frozen section confirmation. Five patients have undergone robot-assisted enucleation at Beth Israel Deaconess Medical Center between January 2014 and January 2017 with median tumor diameter of 1.3 cm (0.9-1.7 cm) located in the pancreatic head [2] and tail [3]. Surgical indications included insulinoma [2] and NF-pNETs [3]. Median operative time was 204 min (range, 137-347 min) and estimated blood loss of 50 mL. There were no conversions to open or transfusions. Robotic enucleation is a safe and feasible technique that allows parenchymal conservation in a minimally-invasive setting, reducing operative time and length of stay with equivalent pathological outcomes compared to open surgery.

Modifications of H3 and H4 during chromatin replication, nucleosome assembly, and histone exchange.

Histone posttranslational modifications that accompany DNA replication, nucleosome assembly, and H2A/H2B exchange were examined in human tissue culture cells. Through microsequencing analysis and chromatin immunoprecipitation, it was found that a subset of newly synthesized H3.2/H3.3 is modified by acetylation and methylation at sites that correlate with transcriptional competence. Immunoprecipitation experiments suggest that cytosolic predeposition complexes purified from cells expressing FLAG-H4 contain H3/H4 dimers, not tetramers. Studies of the deposition of newly synthesized H2A/H2B onto replicating and nonreplicating chromatin demonstrated that H2A/H2B exchange takes place in chromatin regions that contain acetylated H4; however, there is no single pattern of H4 acetylation that accompanies exchange. H2A/H2B exchange is also largely independent of the deposition of replacement histone variant, H3.3. Finally, immunoprecipitation of nucleosomes replicated in the absence of de novo nucleosome assembly showed that histone modifications do not prevent the transfer of parental histones to newly replicated DNA and thus have the potential to serve as means of epigenetic inheritance. Our experiments provide an in-depth analysis of the "histone code" associated with chromatin replication and dynamic histone exchange in human cells.