Evaluation of association between center colorectal neuroendocrine neoplasm volume and survival among patients with colorectal neuroendocrine carcinoma.

BACKGROUND: Although correlation between center volume and survival has been reported for several complex cancers, it remains unknown if this is true for colorectal neuroendocrine carcinomas (CRNECs). We hypothesized that higher center annual volume of colorectal neuroendocrine neoplasm resections would be associated with overall survival (OS) for patients with CRNECs. METHODS: Patients in the National Cancer Database diagnosed with stages I-III CRNEC between 2006 and 2018 and who underwent surgical resection were identified. The mean annual colorectal neuroendocrine neoplasm resection volume threshold associated with significantly worse mortality hazard was determined using restricted cubic splines. Kaplan-Meier (KM) method was used to compare OS, while Cox proportional hazards model was used for multivariable analysis. RESULTS: There were 694 patients with CRNEC who met inclusion criteria across 1229 centers. Based on the cubic spline, centers treating fewer than one colorectal neuroendocrine neoplasm patient every 3 years on average had worse outcomes. Centers below this threshold were classified as low-volume (LV) centers corresponding with 42% of centers and about 15% of the patient cohort. In unadjusted survival analysis, LV patients had a median OS of 14 months (95% confidence interval [CI]: 10-19) while those treated at HV centers had a median OS of 33 months (95% CI: 25-49). In multivariable analysis, resection at a LV center was associated with increased risk of mortality (1.42 [95% CI: 1.01-2.00], p = 0.04). CONCLUSION: CRNEC patients have a dire prognosis; however, treatment at an HV center may be associated with decreased risk of mortality.

The "Classification Pendulum" of Stage I Colorectal Cancer: A National Level Analysis of the Survival Difference Between T1 and T2 Colorectal Cancer.

BACKGROUND: The eighth edition of the American Joint Committee on Cancer classifies nonmetastatic, node-negative colorectal cancers invading the submucosa (T1) and muscularis propria (T2) as stage I tumors without additional subclassification. OBJECTIVE: The aim of the study was to compare survival of T1N0M0 versus T2N0M0 colorectal cancers and to investigate factors associated with decreased survival. DESIGN: This was an analysis of 2 large population-based data sets. SETTINGS: The study was conducted analyzing data from the Surveillance Epidemiology and End Result program and the National Cancer Database. PATIENTS: Adult patients undergoing major resection without additional therapy for stage I colorectal cancer were included. MAIN OUTCOME MEASURES: Overall and disease-specific survival for T1 versus T2 cancers were measured. Subgroup analyses by tumor location (colon versus rectum) were performed. RESULTS: A total of 30,228 (36.4% T1 and 63.6% T2) and 41,670 (41.1% T1 and 58.9% T2) patients were identified in the Surveillance Epidemiology and End Result database and the National Cancer Database. The 5-year overall survival rates were 87.1% and 86.2% for patients with T1 versus 82.7% and 80.7% for patients with T2 (p < 0.001) in the Surveillance Epidemiology and End Result database and the National Cancer Database. The 10-year overall survival rates were 71.3% and 66.3% for patients with T1 versus 62.2% and 57.2% for patients with T2 tumors (p < 0.001) in the Surveillance Epidemiology and End Result database and the National Cancer Database. The 5- and 10-year disease-specific survival for colorectal cancer in the Surveillance Epidemiology and End Result database was 97.0% (T1) versus 95.2% (T2) and 94.1% (T1) versus 90.3% (T2). Black race (HR = 1.26 and 1.65 for overall survival and disease-specific survival in the Surveillance Epidemiology and End Result database; HR = 1.20 for overall survival in the National Cancer Database) was associated with worse survival. LIMITATIONS: The study was limited by intrinsic biases related to large administrative data sets. CONCLUSIONS: Within stage I colorectal cancer, T2 tumors have decreased overall survival and disease-specific survival as compared with T1 cancers. This survival difference may justify revising the American Joint Committee on Cancer staging system to include the subclassification of stage Ia (T1N0M0) and stage Ib (T2N0M0). See Video Abstract at http://links.lww.com/DCR/B659. LA CLASIFICACIN PNDULO PARA EL CNCER COLORRECTAL EN ESTADIO I UN ANLISIS A NIVEL NACIONAL DE LA DIFERENCIA DE SOBREVIDA ENTRE EL CNCER COLORRECTAL T Y T: ANTECEDENTES:La octava edición del American Joint Committee on Cancer, clasifica los cánceres colorrectales no metastásicos con ganglios negativos, que invaden la submucosa (T1) y la muscularis propia (T2) como tumores en estadio I sin subclasificación adicional.OBJETIVO:El objetivo del estudio fue comparar la sobrevida de los cánceres colorrectales T1N0M0 versus T2N0M0 e investigar los factores asociados con la disminución de la sobrevida.DISEÑO:Análisis de dos grandes conjuntos de datos poblacionales.MARCO:El estudio se realizó analizando datos del Programa de Epidemiología de Vigilancia y Resultados Finales (SEER) y la Base de Datos Nacional del Cáncer.PACIENTES:Pacientes adultos en los cuales se realizó una resección mayor sin terapia adicional por cáncer colorrectal en estadio I.PRINCIPALES VARIABLES ANALIZADAS:Sobrevida global y específica de la enfermedad para los cánceres T1 versus T2. Se realizó un análisis de subgrupos según la ubicación del tumor (colon versus recto).RESULTADOS:Se incluyeron un total de 30.228 (36,4% T1 y 63,6% T2) y 41.670 (41,1% T1 y 58,9% T2) pacientes en las bases de datos SEER y la Base de Datos Nacional del Cáncer, respectivamente. La sobrevida global a 5 años fue del 87,1% y el 86,2% para los pacientes con T1 frente al 82,7% y el 80,7% de los pacientes con T2 (p < 0,001) en el SEER y la Base de Datos Nacional del Cáncer, respectivamente. La sobrevida global a 10 años fue del 71,3% y el 66,3% para los pacientes con T1 frente al 62,2% y el 57,2% de los pacientes con tumores T2 (p < 0,001) en el SEER y la Base de Datos Nacional del Cáncer, respectivamente. La sobrevida específica de la enfermedad a 5 y 10 años para el cáncer colorrectal en el SEER fue del 97,0% (T1) frente al 95,2% (T2) y del 94,1% (T1) frente al 90,3% (T2), respectivamente. La grupo étnico afroamericano se asoció con una sobrevida menor (Hazard Ratio -HR 1,26 y 1,65 para la sobrevida general y sobrevida específica de la enfermedad-SEER; HR 1,20 para la sobrevida general-Base de de Datos Nacional del Cáncer).LIMITACIONES:Sesgos intrínsecos relacionados con el análisis de grandes conjuntos de datos.CONCLUSIONES:Dentro del cáncer colorrectal en estadio I, los tumores T2 han disminuido la sobrevida general y la sobrevida específica de la enfermedad, en comparación con los cánceres T1. Esta diferencia de sobrevida puede justificar la revisión del sistema de estadificación del American Joint Committee on Cancer para incluir la subclasificación del estadio Ia (T1N0M0) y el estadio Ib (T2N0M0). Consulte Video Resumen en http://links.lww.com/DCR/B659.

Impact of minimally invasive gastrectomy on use of and time to adjuvant chemotherapy for gastric adenocarcinoma.

BACKGROUND: Chemotherapy improves outcomes in patients with resectable gastric cancer. Minimally invasive gastrectomy (MIS) rates are increasing, though the impact of MIS on postoperative chemotherapy remains uncertain. This study examines the impact of MIS vs open gastrectomy (OG) on utilization of adjuvant chemotherapy for high-risk gastric cancer. METHODS: Patients in the National Cancer Database who underwent resection for high-risk gastric adenocarcinoma between 2010 and 2015 were included. Patients were stratified by surgical approach (MIS vs OG) and analyzed using multivariable regression modeling. Primary endpoints were utilization of and time to initiation of adjuvant chemotherapy. RESULTS: Overall, 23 071 patients were included; 16 595 (71.9%) underwent OG and 6476 (28.1%) underwent MIS. After adjusting for patient and tumor characteristics, MIS was not associated with increased use of adjuvant chemotherapy (odds ratio [OR]: 1.027, 95% confidence interval [CI]: 0.95 to 1.11, P = .50), and time to initiation of chemotherapy was similar (-2% change, 95% CI: -5% to +1%, P = .27). MIS was associated with shorter hospital stays (-1 day). Thirty-day readmission rates, 90-day mortality, and overall survival were similar between groups. CONCLUSIONS: In this study, while MIS for gastric adenocarcinoma was associated with shorter hospital stays and comparable survival, it was not associated with improved utilization or time to initiation of adjuvant chemotherapy.

Pretransplant Desensitization with Costimulation Blockade and Proteasome Inhibitor Reduces DSA and Delays Antibody-Mediated Rejection in Highly Sensitized Nonhuman Primate Kidney Transplant Recipients.

BACKGROUND: Patients with broad HLA sensitization have poor access to donor organs, high mortality while waiting for kidney transplant, and inferior graft survival. Although desensitization strategies permit transplantation via lowering of donor-specific antibodies, the B cell-response axis from germinal center activation to plasma cell differentiation remains intact. METHODS: To investigate targeting the germinal center response and plasma cells as a desensitization strategy, we sensitized maximally MHC-mismatched rhesus pairs with two sequential skin transplants. We administered a proteasome inhibitor (carfilzomib) and costimulation blockade agent (belatacept) to six animals weekly for 1 month; four controls received no treatment. We analyzed blood, lymph node, bone marrow cells, and serum before desensitization, after desensitization, and after kidney transplantation. RESULTS: The group receiving carfilzomib and belatacept exhibited significantly reduced levels of donor-specific antibodies (P=0.05) and bone marrow plasma cells (P=0.02) compared with controls, with a trend toward reduced lymph node T follicular helper cells (P=0.06). Compared with controls, carfilzomib- and belatacept-treated animals had significantly prolonged graft survival (P=0.02), and renal biopsy at 1 month showed significantly reduced antibody-mediated rejection scores (P=0.02). However, four of five animals with long-term graft survival showed gradual rebound of donor-specific antibodies and antibody-mediated rejection. CONCLUSIONS: Desensitization using proteasome inhibition and costimulation blockade reduces bone marrow plasma cells, disorganizes germinal center responses, reduces donor-specific antibody levels, and prolongs allograft survival in highly sensitized nonhuman primates. Most animals experienced antibody-mediated rejection with humoral-response rebound, suggesting desensitization must be maintained after transplantation using ongoing suppression of the B cell response.

Carotid stenting and endarterectomy and contralateral carotid occlusion.

BACKGROUND: The presence of contralateral carotid occlusion (CCO) has been controversial throughout the history of carotid intervention. Some studies cite a higher stroke risk in the setting of CCO, whereas other studies document no difference in stroke risk. We investigated the risk of stroke after intervention in the setting of CCO in a large, national, validated dataset. METHODS: Data were obtained from the 2011-2014 American College of Surgeons National Surgical Quality Initiative Project files using targeted carotid endarterectomy (CEA), carotid angioplasty, and carotid artery stenting (CAS) data. Patient and procedural characteristics, and 30-day postoperative outcomes were compared using Pearson χ2 tests for categorical variables and Wilcoxon rank-sum tests for continuous variables. Logistic regression was used for multivariable analysis. The primary outcome measure was the stroke rate, with a secondary outcome of major adverse cardiovascular events. RESULTS: During the study period, 11,948 CEA and 422 CAS procedures were available for study, with significantly fewer CEA (4.73% of all CEA) than CAS (9.95%; P < .0001) occurring in the setting of CCO. CAS was associated with more severe degree of stenosis than CEA (P = .045). Multivariable logistic regression showed that stroke after procedures was higher in patients with CCO than without CCO (odds ratio, 1.73; 95% confidence interval, 1.08-2.76; P = .02), but specific procedure (CEA vs CAS) was not associated with stroke while controlling for confounders. However, when evaluating our secondary composite outcome, CCO was not associated with the outcome while controlling for confounders. CONCLUSIONS: There is currently a bias that CCO confers a higher risk on patients undergoing carotid procedures and this notion is manifest in the proportion of CEA and CAS procedures done in the setting of CCO. Our study observes that CCO provides only a minor influence on periprocedural stroke risk and that other factors are more closely tied to outcomes of CEA and CAS.

Underutilization of surgical resection in patients with pancreatic acinar cell carcinoma.

BACKGROUND: Pancreatic acinar cell carcinoma (pACC) is a rare malignancy and surgical utilization has been historically low in these patients. Contemporary outcomes for this patient population remain unknown. METHODS: The 1998-2012 National Cancer Data Base was queried for baseline characteristics in patients with pACC. Patients with potentially operable disease (stage I/II) were grouped by surgical resection. Multivariable logistic regression was used to predict factors associated with resection. Survival was estimated using Kaplan-Meier analysis. A proportional hazards model identified factors associated with overall survival. RESULTS: 980 patients were identified. Mean age at diagnosis was 64 years. Tumors were more common in men (68%), white patients (88%), and within the pancreatic head (57%). Thirty-four percent of patients with localized disease failed to undergo resection. Five-year survival was higher among patients who underwent resection (42% vs. 9%, p < 0.001). In patients with resectable disease, male sex, older age, black race, tumors within the pancreatic head, lower grade tumors and treatment at non-academic centers are associated with failure to undergo surgery. CONCLUSION: Patients with localized pACC have increased survival after resection. However, in this contemporary analysis, resection continues to be underutilized and new efforts to increase resection rates should be undertaken.

Improved survival in simultaneous lung-liver recipients and candidates in the modern era of lung allocation.

BACKGROUND: Liver-lung transplantation (LLT) is a rare procedure performed for patients with end-stage liver and lung disease. The lung allocation score (LAS), introduced in 2005, guides lung allocation including those receiving LLT. However, the impact of the LAS on outcomes in LLT is currently unknown. MATERIALS AND METHODS: The OPTN/United Network for Organ Sharing STAR file was queried for LLT candidates and recipients from 1988 to 2016. Demographic characteristics before (historic) and after (modern) the LAS were compared. Survival was analyzed with the Kaplan-Meier method and log-rank test. RESULTS: In total, 167 candidates were listed for LLT, and 62 underwent LLT. The historic cohort had a higher FEV1% (48.22% versus 29.82%, P = 0.014), higher creatinine (1.22 versus 0.72, P < 0.001), and a higher percentage with pulmonary hypertension as the indication for transplantation (40% versus 0%, P = 0.003) compared with the modern cohort. LLT candidates in the historic cohort had a lower rate of transplant per 100 candidates (10.87 versus 33.33, P < 0.0001) and worse waitlist survival (1 y: 69.6% versus 80.9%, 3 y: 39.1% versus 66.8%, P = 0.004). Post-transplant survival was significantly lower in the historic cohort (1 y: 50.0% versus 82.7%, 5 y: 40.0% versus 69.0%, 10 y: 20.0% versus 55.5%, P = 0.0099). CONCLUSIONS: Most analyses of LLT have included patients before and after the introduction of the LAS. Our study shows that LLT candidates and recipients before the modern allocation system had distinct baseline characteristics and worse overall survival. Although many factors contributed to recent improved outcomes, these cohorts are significantly different and should be treated as such in future studies.

Local excision results in comparable survival to radical resection for early-stage rectal carcinoid.

BACKGROUND: Controversy exists regarding current National Comprehensive Cancer Network guidelines, which recommend local excision for rectal carcinoids ≤2 cm and radical resection for tumors >2 cm. Given the limited data examining optimal surgical approach for these lesions, we queried a national database to determine the impact of extent of resection on survival. METHODS: Patients undergoing treatment for clinical stage I and II rectal carcinoid (RC) were identified from the National Cancer Data Base (1998-2012). The association between extent of surgery, tumor size, and the likelihood of pathologic lymph node positivity was examined. Kaplan-Meier analysis was used to compare overall survival. RESULTS: In total, 1900 patients were identified, of whom 1644 (86.5%) were treated with local excision, and 256 (13.5%) were treated with radical resection. A significant majority of patients with tumors ≤2.0 cm (89.0%) and nearly half with tumors 2.1-4.0 cm (44.8%) or >4.0 cm (45.8%) underwent local excision. Nodal positivity was correlated with tumor size (7.1% positivity with ≤2.0 cm tumors, 31.3% with 2.1-4.0 cm tumors, and 50.0% with >4 cm tumors). However, 5-y survival was equivalent between surgical approaches for tumors ≤2 cm (93.0% versus 93.0%) and tumors 2.1-4.0 cm (76.0% versus 76.0%). CONCLUSIONS: We demonstrate in early-stage RC that nearly half of intermediate and large tumors are being treated with local excision outside National Comprehensive Cancer Network guidelines. In addition, radical resection does not appear to be associated with improved overall survival for tumors of any size. These findings suggest that the preferred approach to early-stage RCs without aggressive biological characteristics is local excision due to the decreased morbidity and mortality versus radical resection.

Elevated HbA1c in donor organs from patients without a diagnosis of diabetes portends worse liver allograft survival.

Recipients of liver allografts from diabetic donors have decreased graft survival. However, limited data exist on the effects of donor HbA1c. We hypothesized that allografts from nondiabetic donors with elevated HbA1c would be associated with decreased survival. Liver transplant recipients from the UNOS database from nondiabetic donors were stratified into two groups: euglycemic (HbA1c<6.5) and hyperglycemic (HbA1c≥6.5). Propensity score matching (10:1) was used to adjust for donor and recipient characteristics. Kaplan-Meier analysis was used to assess survival. Donors of hyperglycemic allografts were older (49 vs 36, P<.001), were more likely to be non-white, had a higher BMI (29.8 vs 26.2, P<.001), were more likely to engage in heavy cigarette use (1.5% vs 1.3%, P=.004), had higher serum creatinine levels (1.3 vs 1.0, P=.002), and were more likely to be an expanded-criteria donor (35.8% vs 14.4%, P<.001). After propensity matching to account for these differences, allograft survival was significantly decreased in the recipients of hyperglycemic allografts (P=.049), and patient survival showed a trend toward reduction (P=.082). These findings suggest that HbA1c may be a simple and inexpensive test with potential utility for better organ risk stratification.

Comparative outcomes of treatment modalities in nonagenarians with nonmetastatic pancreatic adenocarcinoma.

BACKGROUND: There has been an increase in the elderly patient population seeking care for pancreatic ductal adenocarcinoma (PDAC). This study aimed to delineate the effectiveness of therapeutic options in nonagenarians (aged 90-99 years) diagnosed with resectable PDAC. METHODS: This study used the National Cancer Database to identify patients with nonmetastatic PDAC (stage I-III) from 2004 to 2021. The study compared median overall survival (mOS) using Kaplan-Meier curves among 5 treatment categories: surgery, surgery along with chemoradiation, chemotherapy alone, radiotherapy alone, and chemoradiation alone. Cox proportional hazards regression was used in multivariate analyses. RESULTS: Of 459,174 patients, 793 aged ≥ 90 years had nonmetastatic PDAC. Of 793 patients, 245 (30.9 %) underwent chemotherapy alone, 296 (37.3 %) underwent radiotherapy alone, 162 (20.4 %) underwent chemoradiation alone, 58 (7.3 %) underwent curative-intent resection, and 32 (4.0 %) underwent surgery combined with chemoradiation. The mOS estimates in different treatment modalities were 9.5 months (95 % CI, 6.7-14.5) for surgery alone, 19.1 months (95 % CI, 2.4-64.3) for surgery combined with chemoradiation, 8.2 months (95 % CI, 7.2-9.2) for chemotherapy alone, 8.4 months (95 % CI, 7.6-9.6) for radiotherapy alone, and 11.2 months (95 % CI, 8.7-12.9) for chemoradiation alone (P < .001). In multivariate analysis, the odds of survival were better for patients who underwent surgery alone than for those who underwent chemotherapy alone, although the odds of survival did not significantly differ between patients who underwent radiotherapy alone and those who underwent chemoradiation alone. Nonetheless, surgery combined with chemoradiation was associated with decreased mortality risk compared with surgery alone (hazard ratio, 0.46; 95 % CI, 0.25-0.87; P = .02). Operative 30-day mortality rate was 8.8 %, and 90-day mortality rate was 17.8 %. CONCLUSION: Surgery combined with chemoradiation improved the survival of nonagenarians with PDAC compared with other therapies. However, only 1 in 25 patients received all 3 treatment components. Moreover, our study highlights a very high operative mortality rate in nonagenarians.

Epidemiology and survival outcomes of colorectal mixed neuroendocrine-non-neuroendocrine neoplasms and neuroendocrine carcinoma.

BACKGROUND: Mixed neuroendocrine-non-neuroendocrine neoplasms are a rare subtype of neuroendocrine neoplasm consisting of ≥30% each of neuroendocrine and non-neuroendocrine differentiation. Neuroendocrine carcinomas are poorly differentiated neuroendocrine tumors. The epidemiology and prognosis of colorectal mixed neuroendocrine-non-neuroendocrine neoplasms and neuroendocrine carcinomas are not clearly defined in the literature. We sought to examine the presentation, patterns of care, and outcomes of patients with mixed neuroendocrine-non-neuroendocrine neoplasms and neuroendocrine carcinomas. METHODS: We identified patients diagnosed with stage I-III colorectal (excluding appendix) mixed neuroendocrine-non-neuroendocrine neoplasms or neuroendocrine carcinomas with only one-lifetime cancer diagnosis who underwent surgical resection between 2010 and 2018 from the National Cancer Database. We performed bidirectional selection to identify variables to include in a multivariable Cox proportional hazards model. RESULTS: We identified 189 patients with a diagnosis of stage I to III colorectal mixed neuroendocrine-non-neuroendocrine neoplasms, 66% of whom had poorly differentiated tumors and 482 with neuroendocrine carcinomas. Among patients with stage III disease, 68% of patients with mixed neuroendocrine-non-neuroendocrine neoplasms and 54% of patients with neuroendocrine carcinomas received adjuvant chemotherapy. The median survival for the overall patients with mixed neuroendocrine-non-neuroendocrine neoplasms and neuroendocrine carcinomas cohorts were 38 and 42 months, respectively (P = .22), and the median survival for patients with mixed neuroendocrine-non-neuroendocrine neoplasms and neuroendocrine carcinomas with stage III disease were 30 and 25 months, respectively (P = .27). In multivariable analysis, fewer number of positive nodes and receipt of adjuvant chemotherapy were independently associated with decreased risk of mortality for patients with mixed neuroendocrine-non-neuroendocrine neoplasms and neuroendocrine carcinomas. CONCLUSION: Adjuvant chemotherapy is associated with improved survival in stage III mixed neuroendocrine-non-neuroendocrine neoplasms and neuroendocrine carcinomas. Future studies are warranted to identify subsets of patients benefiting most from adjuvant therapy.

A Matched Survival Analysis of Lung Transplant Recipients With Coronavirus Disease 2019-Related Respiratory Failure.

BACKGROUND: Lung transplantation is an acceptable and potentially life-saving treatment option for coronavirus disease 2019 (COVID-19)-induced acute respiratory distress syndrome and pulmonary fibrosis. This study was conducted to determine whether recipients of lung transplantation (LT) for COVID-19-related lung disease have comparable outcomes to other recipients with a similar level of lung dysfunction. METHODS: The Organ Procurement and Transplant Network database was queried for adult LT candidates between 2006 and 2021. Recipients with COVID-19-related respiratory failure were matched 1:2 using a nearest-neighbor algorithm. Kaplan-Meier methods with log-rank tests were used to compare long-term survival. A proportional hazards model was used to calculate risk of death. RESULTS: A total of 37,333 LT candidates from all causes were compared with 334 candidates from COVID-19-related respiratory failure. COVID-19 recipients were more likely to be younger (50 vs 57 years, P < .001), male (79% vs 60%, P < .001), require extracorporeal membrane oxygenation (56.3% vs 4.0%, P < .001), and have worse lung function (lung allocation score, 82.4 vs 47.8; P < .001) at transplantation. Subsequently, 227 COVID-19 recipients were matched with 454 controls. Patients who received a transplant for COVID-19 had similar rates of mechanical ventilation, extracorporeal membrane oxygenation, postoperative complications, and functional status at discharge compared with controls. There was no difference in overall survival or risk of death from COVID-19 (hazard ratio, 0.82; 95% CI, 0.45-1.53; P = .54). CONCLUSIONS: Six-month survival for recipients of LT for COVID-19-related respiratory failure was comparable to that of other LT recipients.

Krt14 and Krt15 differentially regulate regenerative properties and differentiation potential of airway basal cells.

Keratin expression dynamically changes in airway basal cells (BCs) after acute and chronic injury, yet the functional consequences of these changes on BC behavior remain unknown. In bronchiolitis obliterans (BO) after lung transplantation, BC clonogenicity declines, which is associated with a switch from keratin15 (Krt15) to keratin14 (Krt14). We investigated these keratins' roles using Crispr-KO in vitro and in vivo and found that Krt14-KO and Krt15-KO produce contrasting phenotypes in terms of differentiation and clonogenicity. Primary mouse Krt14-KO BCs did not differentiate into club and ciliated cells but had enhanced clonogenicity. By contrast, Krt15-KO did not alter BC differentiation but impaired clonogenicity in vitro and reduced the number of label-retaining BCs in vivo after injury. Krt14, but not Krt15, bound the tumor suppressor stratifin (Sfn). Disruption of Krt14, but not of Krt15, reduced Sfn protein abundance and increased expression of the oncogene dNp63a during BC differentiation, whereas dNp63a levels were reduced in Krt15-KO BCs. Overall, the phenotype of Krt15-KO BCs contrasts with Krt14-KO phenotype and resembles the phenotype in BO with decreased clonogenicity, increased Krt14, and decreased dNp63a expression. This work demonstrates that Krt14 and Krt15 functionally regulate BC behavior, which is relevant in chronic disease states like BO.

Development and characterization of ferret ex vivo tracheal injury and cell engraftment model.

The field of airway biology research relies primarily on in vitro and in vivo models of disease and injury. The use of ex vivo models to study airway injury and cell-based therapies remains largely unexplored although such models have the potential to overcome certain limitations of working with live animals and may more closely replicate in vivo processes than in vitro models can. Here, we characterized a ferret ex vivo tracheal injury and cell engraftment model. We describe a protocol for whole-mount staining of cleared tracheal explants, and showed that it provides a more comprehensive structural overview of the surface airway epithelium (SAE) and submucosal glands (SMGs) than 2D sections, revealing previously underappreciated structural anatomy of tracheal innervation and vascularization. Using an ex vivo model of tracheal injury, we evaluated the injury responses in the SAE and SMGs that turned out to be consistent with published in vivo work. We used this model to assess factors that influence engraftment of transgenic cells, providing a system for optimizing cell-based therapies. Finally, we developed a novel 3D-printed reusable culture chamber that enables live imaging of tracheal explants and differentiation of engrafted cells at an air-liquid interface. These approaches promise to be useful for modeling pulmonary diseases and testing therapies. Graphical abstract1,2. We describe here a method for differential mechanical injury of ferret tracheal explants that can be used to evaluate airway injury responses ex vivo. 3. Injured explants can be cultured at ALI (using the novel tissue-transwell device on the right) and submerged long-term to evaluate tissue-autonomous regeneration responses. 4. Tracheal explants can also be used for low throughput screens of compounds to improve cell engraftment efficiency or can be seeded with particular cells to model a disease phenotype. 5. Lastly, we demonstrate that ex vivo-cultured tracheal explants can be evaluated by various molecular assays and by immunofluorescent imaging that can be performed live using our custom-designed tissue-transwell.

Does Fragmentation of Care in Locally Advanced Rectal Cancer Increase Patient Mortality?

OBJECTIVE: To evaluate health care fragmentation in patients with stage II and III rectal cancers. BACKGROUND: Fragmentation of care among multiple hospitals may worsen outcomes for cancer patients. METHODS: National Cancer Database was queried for adult patients who underwent radiation and surgery for locally advanced (stage II-III) rectal adenocarcinoma from 2006 to 2015. Fragmented care was defined as receiving radiation at a different hospital from surgery. Descriptive statistics characterized patients, and survival probability was plotted using the Kaplan-Meier method and a Cox proportional hazards model. RESULTS: A total of 37,081 patients underwent surgery and radiation for stage II-III rectal cancer from 2006 to 2015 (24,102 integrated care vs. 12,979 fragmented care). Patients who received fragmented care (hazard ratio [HR] 1.105; 95% CI 1.045-1.169) had a higher risk of mortality. Patients who received at least surgery (HR 0.84; 95% CI 0.77-0.92) at academic hospitals had a lower risk of mortality. Academic hospitals had a higher proportion of patients with fragmented care (38.0 vs. comprehensive community 32.8% vs. community 33.8%, p < 0.001). Within academic hospitals, fragmented care portended worse survival (integrated academic 80.0% vs. fragmented academic 76.7%, p = 0.0002). Fragmented care at academic hospitals had increased survival over integrated care at community hospitals (fragmented academic 76.7 vs. integrated community 72.2%, p = 0.00039). CONCLUSIONS: In patients with stage II-III rectal cancer, patients who have integrated care at academic hospitals or at least surgery at academic centers had better survival. All efforts should be made to reduce care fragmentation and surgery at academic centers should be prioritized.

Emerging New Approaches in Desensitization: Targeted Therapies for HLA Sensitization.

There is an urgent need for therapeutic interventions for desensitization and antibody-mediated rejection (AMR) in sensitized patients with preformed or de novo donor-specific HLA antibodies (DSA). The risk of AMR and allograft loss in sensitized patients is increased due to preformed DSA detected at time of transplant or the reactivation of HLA memory after transplantation, causing acute and chronic AMR. Alternatively, de novo DSA that develops post-transplant due to inadequate immunosuppression and again may lead to acute and chronic AMR or even allograft loss. Circulating antibody, the final product of the humoral immune response, has been the primary target of desensitization and AMR treatment. However, in many cases these protocols fail to achieve efficient removal of all DSA and long-term outcomes of patients with persistent DSA are far worse when compared to non-sensitized patients. We believe that targeting multiple components of humoral immunity will lead to improved outcomes for such patients. In this review, we will briefly discuss conventional desensitization methods targeting antibody or B cell removal and then present a mechanistically designed desensitization regimen targeting plasma cells and the humoral response.

Targeting Calcium Release-activated Calcium Channel Is Not Sufficient to Prevent Rejection in Nonhuman Primate Kidney Transplantation.

BACKGROUND: Calcineurin inhibitors successfully control rejection of transplanted organs but also cause nephrotoxicity. This study, using a rhesus monkey renal transplantation model, sought to determine the applicability of a new immunomodulatory drug inhibiting the store-operated calcium release-activated calcium channel of lymphocytes to control transplant rejection without nephrotoxicity. METHODS: Animals underwent kidney transplantation and were treated with tacrolimus alone (n = 3), a CRACM1 inhibitor (PRCL-02) (n = 6) alone, or with initial tacrolimus monotherapy followed by gradual conversion at 3 weeks to PRCL-02 alone (n = 3). PRCL-02 was administered via a surgically inserted gastrostomy tube BID. RESULTS: Dose-related drug exposure in monkeys was established and renal transplants were then performed using PRCL-02 monotherapy. Oral dosing of PRCL-02 was well tolerated and resulted in suppressed T-cell proliferation in in vitro MLR comparable to animals in the tacrolimus control arm. Animals receiving tacrolimus monotherapy were e on day 100 without rejection. PRCL-02 monotherapy only marginally prolonged graft survival (MST = 13.16 d; group 2) compared with untreated controls. Animals treated initially with tacrolimus and converted to PRCL-02 monotherapy had a mean graft survival of 35.3 days which was prolonged compared with PRCL-02 monotherapy but not compared with the tacrolimus-treated group. Pharmacokinetic studies showed inconsistent drug exposures despite attempts to adjust dose and exposure which may have contributed to the rejections. CONCLUSIONS: We conclude that, in this nonhuman primate model of kidney transplantation, PRCL-02 demonstrated evidence of in vivo immunosuppressive activity but was inferior to tacrolimus treatment with respect to suppressing immune transplant rejection.

Medical Student Involvement and Learning Objectives in Morbidity and Mortality Conferences: A National Survey of the Association for Surgical Education's Committee of Clerkship Directors.

BACKGROUND: Despite implementation of Morbidity and Mortality (M&M) Conference across surgical graduate medical education, sparse literature exists regarding the attendance and involvement of medical students. We sought to examine student involvement and learning objectives for M&M on a national level. METHODS: A survey was distributed through the Association for Surgical Education Committee of Clerkship Directors. Questions examined demographics, teaching practices regarding M&M, and student learning objectives. RESULTS: Forty-eight responses were collected reflecting practices of weekly M&M (96%) and required student attendance (93%). Students are observers in 61% of M&Ms, observer with questions in 37%, and presenter at 2%. Learning objectives for M&M highlighted exposing students to conference style (76%), reflective learning (63%), and highlighting medical error (78%). CONCLUSIONS: It is the national standard for medical students to attend weekly M&M. Student learning objectives reflect desires to improve exposure to this style of teaching conference and understanding the gravity of medical error.

A Propensity-matched Survival Analysis: Do Simultaneous Liver-lung Transplant Recipients Need a Liver?

BACKGROUND: There is debate whether simultaneous lung-liver transplant (LLT) long-term outcomes warrant allocation of 2 organs to a single recipient. We hypothesized that LLT recipients would have improved posttransplant survival compared with matched single-organ lung recipients with an equivalent degree of liver dysfunction. METHODS: The Organ Procurement and Transplant Network/United Network for Organ Sharing STAR file was queried for adult candidates for LLT and isolated lung transplantation from 2006 to 2016. Waitlist mortality and transplant odds were calculated for all candidates. Donor and recipient demographic characteristics were compiled and compared. The LLT recipients were matched 1:2 with a nearest neighbor method to single-organ lung recipients. Kaplan-Meier methods with log-rank test compared long-term survival between groups. Univariate regression was used to calculate the association of LLT and mortality within 6 months of transplant. A proportional hazards model was used to calculate risk-adjusted mortality after 6 months posttransplantation. RESULTS: Thirty-eight LLT patients were matched to 75 single-organ lung recipients. After matching, no differences in baseline demographics or liver function were observed between cohorts. Length of stay was significantly longer in LLT recipients compared to isolated lung recipients (45.89 days vs 22.44 days, P < 0.001). There was no significant difference in survival probability between LLT and isolated lung transplant (1 y, 89.5% vs 86.7%; 5 y, 67.0% vs 64.6%; P = 0.20). CONCLUSIONS: After matching for patient characteristics and level of liver dysfunction, survival in simultaneous LLT was comparable to isolated lung transplantation. Although this population is unique, the clinical picture prompting liver transplant is not clear. National guidelines to better elucidate patient selection are needed.

Psychosocial Assessment of Candidates for Transplantation (PACT) Score Identifies High Risk Patients in Pediatric Renal Transplantation.

Background: Currently, there is no standardized approach for determining psychosocial readiness in pediatric transplantation. We examined the utility of the Psychosocial Assessment of Candidates for Transplantation (PACT) to identify pediatric kidney transplant recipients at risk for adverse clinical outcomes. Methods: Kidney transplant patients <21-years-old transplanted at Duke University Medical Center between 2005 and 2015 underwent psychosocial assessment by a social worker with either PACT or unstructured interview, which were used to determine transplant candidacy. PACT assessed candidates on a scale of 0 (poor candidate) to 4 (excellent candidate) in areas of social support, psychological health, lifestyle factors, and understanding. Demographics and clinical outcomes were analyzed by presence or absence of PACT and further characterized by high (≥3) and low (≤2) scores. Results: Of 54 pediatric patients, 25 (46.3%) patients underwent pre-transplant evaluation utilizing PACT, while 29 (53.7%) were not evaluated with PACT. Patients assessed with PACT had a significantly lower percentage of acute rejection (16.0 vs. 55.2%, p = 0.007). After adjusting for HLA mismatch, a pre-transplant PACT score was persistently associated with lower odds of acute rejection (Odds Ratio 0.119, 95% Confidence Interval 0.027-0.52, p = 0.005). In PACT subsection analysis, the lack of family availability (OR 0.08, 95% CI 0.01-0.97, p = 0.047) and risk for psychopathology (OR 0.34, 95% CI 0.13-0.87, p = 0.025) were associated with a low PACT score and post-transplant non-adherence. Conclusions: Our study highlights the importance of standardized psychosocial assessments and the potential use of PACT in risk stratifying pre-transplant candidates.