Consequences of a Surveillance Strategy for Side-Branch Intraductal Pancreatic Mucinous Neoplasms: Long-Term Follow-Up of One-Thousand Cysts.

OBJECTIVE: We aim to quantify the rate of progression in surveilled cysts and assess what factors should indicate delayed resection. SUMMARY BACKGROUND DATA: Side-branch intraductal papillary mucinous neoplasms (SB-IPMNs) are increasingly discovered, making it challenging to identify which patients require resection, thus avoiding inappropriate treatment. Most incidental lesions are surveyed, yet the consequences of that decision remain uncertain. METHODS: A prospectively maintained database of pancreatic cystic neoplasms was queried for patients with SB-IPMN. Patients with ≥2 imaging studies >6 months apart were included. Clinically relevant progression (CR-Progression) was defined by symptoms, worrisome/high-risk stigmata, or invasive cancer (IC). Growth ≥5 mm in 2 years is considered CR-Progression; size ≥3 cm alone is not. RESULTS: Between 1997-2023,1,337 patients were diagnosed with SB-IPMN. Thirty-seven (2.7%) underwent up-front surgery; 1,000 (75.0%) had >6 months surveillance.The rate of CR-progression was 15.3% (n=153) based on size increase (n=63, 6.3%), main-duct involvement (n=48, 4.8%), symptoms (n=8, 5.0%), or other criteria (n=34, 3.4%). At a median follow-up of 6.6 years (IQR 3.0-10.26), 17 patients (1.7%) developed IC. Those with CR-progression developed IC in 11.1% (n=17) and high-grade dysplasia (HGD) in 6.5% (n=10). Nearly half of the cancers were not contiguous with the surveyed SB-IPMN.Size ≥3 cm was not associated with HGD/IC (P=0.232). HGD/IC was least common in CR-progression determined by size growth (6.3%) versus main-duct involvement (24%) or other (43%, P<0.001)Patients with CR-progression demonstrated improved survival (OS) with resection on time-to-event (P<0.001) and multivariate cox-regression (HR=0.205, 0.096-0.439, P<0.001) analyses. OS was not improved with resection in all patients (P=0.244). CONCLUSION: Clinically relevant progression for SB-IPMNs is uncommon with development of cancer anywhere in the pancreas being rare. Initial size should not drive resection. Long-term and consistent non-operative surveillance is warranted, with surgery currently reserved for CR-progression knowing that the majority of these still harbor low grade pathology.

Correlation of HER2 Protein Level With mRNA Level Quantified by RNAscope in Breast Cancer.

Trastuzumab deruxtecan (T-DXd) has been approved by the US Food and Drug Administration (FDA) to treat patients with metastatic HER2-positive and HER2-low breast cancer, and clinical trials are examining its efficacy against early-stage breast cancer. Current HER2 immunohistochemical (IHC) assays are suboptimal in evaluating HER2-low breast cancers and identifying which patients would benefit from T-DXd. HER2 expression in 526 breast cancer tissue microarray (TMA) cores was measured using the FDA-approved PATHWAY and HercepTest IHC assays, and the corresponding RNA levels were evaluated by RNAscope. HER2 protein levels by regression analysis using a quantitative immunofluorescence score against cell line arrays with known HER2 protein levels determined by mass spectrometry were available in 48 of the cores. RNAscope was also performed in 32 metastatic biopsies from 23 patients who were subsequently treated with T-DXd, and the results were correlated with response rate. HER2 RNA levels by RNAscope strongly correlated with HER2 protein levels (P < .0001) and with HER2 IHC H-scores from the PATHWAY and HercepTest assays (P < .0001). However, neither protein levels nor RNA levels significantly differed between cases scored 0, ultralow, and 1+ by PATHWAY and HercepTest. The RNA levels were significantly higher (P = .030) in responders (6.4 ± 8.2 dots/cell, n = 12) than those in nonresponders (2.6 ± 2.2, n = 20) to T-DXd. RNAscope is a simple assay that can be objectively quantified and is a promising alternative to current IHC assays in evaluating HER2 expression in breast cancers, especially HER2-low cases, and may identify patients who would benefit from T-DXd.

The Role of Neoadjuvant Immunotherapy in the Management of Merkel Cell Carcinoma with Clinically Detected Regional Lymph Node Metastasis.

BACKGROUND: Immunotherapy is emerging as a promising option for certain locally advanced and metastatic cutaneous malignancies. However, the role of neoadjuvant immunotherapy (NIO) in Merkel cell carcinoma (MCC) with clinically detected regional lymph node metastasis (CDRLNM) has not been fully elucidated. METHODS: For this study, MCC patients with CDRLNM who underwent surgical excision were selected from the National Cancer Database (NCDB). Those who received NIO were propensity-matched with those who did not, and Kaplan-Meier analysis was used to compare overall survival (OS). RESULTS: Of the 1809 selected patients, 356 (19.7%) received NIO followed by wide excision (n = 352, 98.9%) or amputation (n = 4, 1.1%). The rate of complete pathologic response for the primary tumor (ypT0) was 45.2%. Only 223 patents (63.4%) also underwent lymph node dissection (LND). The complete pathologic nodal response (ypN0) rate for these patients was 17.9%. A pathologic complete response of both the primary tumor and the nodal basin (ypT0 ypN0) was seen in 16 of the 223 patients who underwent both primary tumor surgery and LND. Subsequently, 151 pairs were matched between the NIO and no-NIO groups (including only patients with LND). Kaplan-Meier analysis demonstrated a significant OS improvement with NIO (median not reached vs. 35.0 ± 8.0 months; p = 0.025). The 5-year OS was 57% in the NIO group versus 44% in no-NIO group (p = 0.021). CONCLUSION: The study suggests that NIO in MCC with CDRLNM provides improved OS in addition to promising rates of primary complete response, which could change the profile of surgical resection. This supports ongoing clinical trials exploring the use of NIO in MCC.

Natural history and growth prediction model of pancreatic serous cystic neoplasms.

OBJECTIVE: Serous cystic neoplasms (SCN) are benign pancreatic cystic neoplasms that may require resection based on local complications and rate of growth. We aimed to develop a predictive model for the growth curve of SCNs to aid in the clinical decision making of determining need for surgical resection. METHODS: Utilizing a prospectively maintained pancreatic cyst database from a single institution, patients with SCNs were identified. Diagnosis confirmation included imaging, cyst aspiration, pathology, or expert opinion. Cyst size diameter was measured by radiology or surgery. Patients with interval imaging ≥3 months from diagnosis were included. Flexible restricted cubic splines were utilized for modeling of non-linearities in time and previous measurements. Model fitting and analysis were performed using R (V3.50, Vienna, Austria) with the rms package. RESULTS: Among 203 eligible patients from 1998 to 2021, the mean initial cyst size was 31 mm (range 5-160 mm), with a mean follow-up of 72 months (range 3-266 months). The model effectively captured the non-linear relationship between cyst size and time, with both time and previous cyst size (not initial cyst size) significantly predicting current cyst growth (p < 0.01). The root mean square error for overall prediction was 10.74. Validation through bootstrapping demonstrated consistent performance, particularly for shorter follow-up intervals. CONCLUSION: SCNs typically have a similar growth rate regardless of initial size. An accurate predictive model can be used to identify rapidly growing outliers that may warrant surgical intervention, and this free model (https://riskcalc.org/SerousCystadenomaSize/) can be incorporated in the electronic medical record.

Short-term survival analysis of a risk-adjusted model for ovarian cancer care.

OBJECTIVE: To quantify the impact on short-term ovarian cancer survival associated with treatment at high-performing hospitals using the observed-to-expected ratio (O/E) for adherence to ovarian cancer treatment guidelines as a risk-adjusted measure of hospital quality care. METHODS: This was a retrospective population-based study of stage I-IV invasive epithelial ovarian cancer reported to California Cancer Registry 1996-2017. A fit logistic regression model, risk-adjusted for patient and disease characteristics, was used to calculate O/E for each hospital stratified by hospital annual case volume. Cox proportional hazards model was used for survival analyses at 3, 6, 12, 24 months and stratified according to sociodemographic characteristics. RESULTS: The study population included 35,725 subjects treated at 443 hospitals: Low-O/E - 26.4% of cases; Intermediate-O/E - 55.5% of cases; and High-O/E - 18.1% of cases. Overall median survival by hospital category was: High-O/E = 72.5 months (95% CI = 68.6-78.6 months), Intermediate-O/E = 68.6 months (95% CI = 65.9-71.6 months), Low-O/E = 47.0 months (95% CI = 44.2-49.2 months). Initial treatment at a High-O/E hospital (HR = 1.00) was a statistically significant and independent predictor of improved short-term survival compared to Low-O/E hospitals at 3 months (HR = 1.46, 95% CI = 1.29-1.65), 6 months (HR = 1.35, 95% CI = 1.22-1.50), 12 months (HR = 1.27, 95% CI = 1.17-1.38), and 24 months (HR = 1.19, 95% CI = 1.11-1.27). Significant and independent associations between improved sort-term survival and High/O/E care were observed for Whites, Hispanics, Asian/Pacific Islanders (A/PI), across SES strata, and among all payer categories. CONCLUSION: Ovarian cancer care at a High-O/E hospital is an independent predictor of improved outcome and the survival advantage is disproportionately weighted toward the short-term time horizon following diagnosis.

Impact of neoadjuvant therapy on nodal harvest in clinical stage III rectal cancer: Establishing optimum cut-offs by disease response.

INTRODUCTION: A minimum lymph node harvest (LNH) of 12 is the current standard for appropriate nodal staging in resectable rectal cancer. However, the rise of neoadjuvant chemoradiation (NCRT) and total neoadjuvant therapy (TNT) has been associated with decreasing number of LNH. We hypothesize that as tumor response to neoadjuvant therapy increases, the optimum for LNH to achieve appropriate nodal staging should decrease. METHODS: Patients with clinical stage III rectal adenocarcinoma who underwent NCRT/TNT followed by resection were identified from the National Cancer Database. A JoinPoint regression analysis was used to determine the LNH for each tumor regression grade (TRG) category beyond which the rate of positive nodes does not significantly change. RESULTS: Thirteen thousand four hundred and twenty-six patients met inclusion criteria. Of these, 2406 (17.9%) achieved TRG 0 or ypT0 and 8210 (61.2%) achieved ypN0. Collectively, 2043 patients (15.2%) were reported to have a pathologic complete response (ypT0 ypN0). Positive pathologic nodes were found in 15%, 23%, 31%, 54%, and 53% as ypT stage increased from ypT0 to ypT4, respectively. Similarly, ypN+ rates were 15%, 36%, 41%, and 55% in TRG 0-3. No JoinPoint was identified for TRG 0, whereas inflection points were found at 6-10 nodes for TRG1 (p = 0.002) and TRG 2 (p = 0.016), and at 11-15 nodes for TRG 3. CONCLUSION: The benchmark of retrieving 12 nodes in resectable stage III rectal cancer is not consistently achieved after NCRT/TNT. We demonstrate that the LNH requirement to establish accurate pathologic nodal staging can vary depending on the tumor response to neoadjuvant therapies.

Impact of autotransfusion on recurrence of colorectal cancer liver metastasis: Long-term follow-up of patients undergoing curative intent hepatectomy.

INTRODUCTION: Colorectal cancer liver metastasis (CRLM) occurs in upto 50% of cases and drives patient outcomes. Up-front liver resection is the treatment of choice in resectable cases. There is no consensus yet established as to the safety of intraoperative autotransfusion in liver resection for CRLM. METHODS: Patients undergoing curative-intent hepatectomy for CRLM at a single quaternary-care institution from 1999 to 2016 were included. Demographics, surgical variables, Fong Clinical Risk Score (FCRS), use of intraoperative auto and/or allotransfusion, and survival data were analyzed. Propensity score matching (PSM) was performed accounting for allotransfusion, extent of hepatectomy, FCRS, and systemic treatment regimens. RESULTS: Three-hundred sixteen patients were included. The median follow-up was 10.4 years (7.8-14.1 years). The median recurrence-free survival (RFS) and overall survival (OS) in all patients were 1.6 years (interquartile range: 0.63-6.6 years) and 4.4 years (2.1-8.7), respectively.  Before PSM, there was a significantly reduced RFS in the autotransfusion group (0.96 vs. 1.73 years, p = 0.20). There was no difference in OS (4.11 vs. 4.44 years, p = 0.118). Patients in groups of FCRS 0-2 and 3-5 both had reduced RFS when autotransfusion was used (p = 0.005). This reduction in RFS was further found when comparing autotransfusion versus no autotransfusion within the FCRS 0-2 group and within the FCRS 3-5 group (p = 0.027). On Cox-regression analysis, autotransfusion (hazard ratio = 1.423, 1.028-2.182, p = 0.015) remained predictive of RFS. After PSM, there were no differences in FCRS (p = 0.601), preoperative hemoglobin (p = 0.880), allotransfusion (p = 0.130), adjuvant chemotherapy (p = 1.000), immunotherapy (p = 0.172), tumor grade (p = 1.000), use of platinum-based chemotherapy (p = 0.548), or type of hepatic resection (p = 0.967). After matching, there was a higher rate of recurrence with autotransfusion (69.0% vs. 47.6%, p = 0.046). There was also a reduced time to recurrence in the autotransfusion group compared with the group without (p = 0.006). There was no difference in OS after PSM (p = 0.262). CONCLUSION: Autotransfusion may adversely affect recurrence in liver resection for CRLM. Until further studies clarify this risk profile, the use of intraoperative autotransfusion should be critically assessed on a case-by-case basis only when other resuscitation options are not available.

Comparing oncologic and surgical outcomes of robotic and laparoscopic pancreatoduodenectomy in patients with pancreatic cancer: a propensity-matched analysis.

INTRODUCTION: Minimally invasive Pancreatoduodenectomy (MIPD), or the Whipple procedure, is increasingly utilized. No study has compared laparoscopic (LPD) and robotic (RPD) approaches, and the impact of the learning curve on oncologic, technical, and post-operative outcomes remains relatively understudied. METHODS: The National Cancer Database was queried for patients undergoing LPD or RPD from 2010 to 2020 with a diagnosis of pancreatic cancer. Outcomes were compared between approaches using propensity-score matching (PSM); the impact of annual center-level volume of MIPD was also assessed by dividing volume into quartiles. RESULTS: A total of 3,342 patients were included. Most (n = 2,716, 81.3%) underwent LPD versus RPD (n = 626, 18.7%). There was a high rate (20.2%, n = 719) of positive margins. Mean length-of-stay (LOS) was 10.4 ± 8.9 days. Thirty-day mortality was 2.8% (n = 92) and ninety-day mortality was 5.7% (n = 189). PSM matched 625 pairs of patients receiving LPD or RPD. After PSM, there was no differences between groups based on age, sex, race, CCI, T-stage, neoadjuvant chemo/radiotherapy, or type of PD. After PSM, there was a higher rate of conversion to open (HR = 0.68, 95%CI = 0.50-0.92)., but there was no difference in LOS (HR = 1.00, 95%CI = 0.92-1.11), 30-day readmission (HR = 1.08, 95% CI = 0.68-1.71), 30-day (HR = 0.78, 95% CI = 0.39-1.56) or 90-day mortality (HR = 0.70, 95% CI = 0.42-1.16), ability to receive adjuvant therapy (HR = 1.15, 95% CI = 0.92-1.44), nodal harvest (HR = 1.01, 95%CI = 0.94-1.09) or positive margins (HR = 1.19, 95% CI = 0.89-1.59). Centers in lower quartiles of annual volume of MIPD demonstrated reduced nodal harvest (p = 0.005) and a higher rate of conversion to open (p = 0.038). Higher-volume centers had a shorter LOS (p = 0.012), higher rate of initiation of adjuvant therapy (p = 0.042), and, most strikingly, a reduction in 90-day mortality (p = 0.033). CONCLUSION: LPD and RPD have similar surgical and oncologic outcomes, with a lower rate of conversion to open in the robotic cohort. The robotic technique does not appear to eliminate the "learning curve", with higher volume centers demonstrating improved outcomes, especially seen at minimum annual volume of 5 cases.

Does reusable mean green? Comparison of the environmental impact of reusable operating room bed covers and lift sheets versus single-use.

INTRODUCTION: As hospitals strive to reduce their environmental footprint, there is an ongoing debate over the environmental implications of reusable versus disposable linens in operating rooms (ORs). This research aimed to compare the environmental impact of reusable versus single-use OR bed covers and lift sheets using life cycle assessment (LCA) methodology. METHODS: LCA is an established tool with rigorous methodology that uses science-based processes to measure environmental impact. This study compared the impacts of three independent system scenarios at a single large academic hospital: reusable bed covers with 50 laundry cycles and subsequent landfill disposal (System 1), single-use bed covers with waste landfill disposal (System 2), and single-use bed covers with waste disposal using incineration (System 3). RESULTS: The total carbon footprint of System 1 for 50 uses was 19.83 â€‹kg carbon dioxide equivalents (CO2-eq). System 2 generated 64.99 â€‹kg CO2-eq. For System 3, the total carbon footprint was 108.98 â€‹kg CO2-eq. The raw material extraction for all the material to produce an equivalent 50 single-use OR bed cover kits was tenfold more carbon-intensive than the reusable bed cover. Laundering one reusable OR bed cover 50 times was more carbon intensive (12.12 â€‹kg CO2-eq) than landfill disposal of 50 single-use OR bed covers (2.52 â€‹kg CO2-eq). DISCUSSION: Our analysis demonstrates that one reusable fabric-based OR bed cover laundered 50 times, despite the carbon and water-intensive laundering process, exhibits a markedly lower carbon footprint than its single-use counterparts. The net difference is 45.16 â€‹kg CO2-eq, equivalent to driving 115 miles in an average gasoline-powered passenger vehicle. This stark contrast underscores the efficacy of adopting reusable solutions to mitigate environmental impact within healthcare facilities.

American Indian Alaska Native (AIAN) adolescents and obesity: the influence of social determinants of health, mental health, and substance use.

OBJECTIVE: To explore the prevalence of obesity among American Indian and Alaska Native (AIAN) adolescents aged 12-19 years in association with social determinants of health (SDOH), and mental health and substance use disorders. METHODS: Guided by the World Health Organization's Social Determinants of Health Framework, we examined data from the Indian Health Service (IHS) Improving Health Care Delivery Data Project from Fiscal Year 2013, supplemented by county-level data from the U.S. Census and USDA. Our sample included 26,226 AIAN adolescents ages 12-19 years. We described obesity prevalence in relationship to SDOH and adolescents' mental health and substance use disorder status. We then fit a multivariable logit generalized linear mixed model to estimate the relationships after adjusting for other individual and county level characteristics. RESULTS: We observed a prevalence of 32.5% for obesity, 13.8% for mental health disorders, and 5.5% for substance use disorders. Females had lower odds of obesity than males (OR = 0.76, p < 0.001), which decreased with age. Having Medicaid coverage (OR = 1.09, p < 0.01), residing in a county with lower education attainment (OR = 1.17, p < 0.05), and residing in a county with higher rates of poverty (OR = 1.51, p < 0.001) were each associated with higher odds of obesity. Residing in a county with high access to a grocery store (OR = 0.73, p < 0.001) and residing in a county with a higher proportion of AIANs (OR = 0.83, p < 0.01) were each associated with lower odds of obesity. Those with mental health disorders had higher odds of obesity (OR = 1.26, p < 0.001); substance use disorders were associated with decreased odds of obesity (OR = 0.73, p < 0.001). CONCLUSIONS: Our findings inform future obesity prevention and treatment programs among AIAN youth; in particular, the need to consider mental health, substance use, and SDOH.

Neoadjuvant Gastric Score: How Response to Neoadjuvant Chemotherapy Affects Overall Survival and Adjuvant Benefit.

INTRODUCTION: The Neoadjuvant Rectal score (NAR) was developed as a short-term surrogate for 5-year overall survival (OS) prediction in locally advanced rectal cancer on the basis of response to neoadjuvant therapy. We aim to assess whether this score can be repurposed for locally advanced gastric adenocarcinoma treated with neoadjuvant chemotherapy followed by surgical resection. METHODS: Patients with gastric adenocarcinoma treated with neoadjuvant systemic therapy followed by surgical resection were extracted from the National Cancer Database. Neoadjuvant Gastric (NAG) scores were calculated, and patients were stratified into low-, intermediate-, and high-score categories, with low scores predicting longer survival. Patients were propensity-matched 1:1:1 between the groups for OS comparison. We also matched patients within each group 1:1 per receipt of adjuvant therapy and compared 5-year OS. RESULTS: There were 2,970 patients identified. NAG classified patients into low- (n = 396, 13.3%), intermediate-(n = 756, 25.5%), and high (n = 1818, 61.2%) groups. After propensity matching, 5-year OS was significantly different between the matched groups (low-NAG 82%, intermediate-NAG 73%, and high-NAG 39%; p < 0.001). NAG score grouping also predicted OS benefit of adjuvant therapy; low- and intermediate-NAG patients had no OS benefit with adjuvant therapy (86% vs. 84%; p = 0.492, and 77% vs. 74%; p = 0.382, respectively), whereas patients with high-NAG score had a 5-year OS benefit with adjuvant therapy (39% vs. 29%; p = 0.024). CONCLUSION: NAR score may be repurposed to generate a prognostic tool in gastric adenocarcinoma to predict 5-year OS and has the potential to guide decision-making regarding allocation of adjuvant therapy. Further studies should prospectively validate these findings to confirm clinical utility.

Differential Effects of Race, Socioeconomic Status, and Insurance on Disease-Specific Survival in Rectal Cancer.

BACKGROUND: National Comprehensive Cancer Network guideline adherence improves cancer outcomes. In rectal cancer, guideline adherence is distributed differently by race/ethnicity, socioeconomic status, and insurance. OBJECTIVE: This study aimed to determine the independent effects of race/ethnicity, socioeconomic status, and insurance status on rectal cancer survival after accounting for differences in guideline adherence. DESIGN: This was a retrospective study. SETTINGS: The study was conducted using the California Cancer Registry. PATIENTS: This study included patients aged 18 to 79 years diagnosed with rectal adenocarcinoma between January 1, 2004, and December 31, 2017, with follow-up through November 30, 2018. Investigators determined whether patients received guideline-adherent care. MAIN OUTCOME MEASURES: ORs and 95% CIs were used for logistic regression to analyze patients receiving guideline-adherent care. Disease-specific survival analysis was calculated using Cox regression models. RESULTS: A total of 30,118 patients were examined. Factors associated with higher odds of guideline adherence included Asian and Hispanic race/ethnicity, managed care insurance, and high socioeconomic status. Asians (HR, 0.80; 95% CI, 0.72-0.88; p < 0.001) and Hispanics (HR, 0.91; 95% CI, 0.83-0.99; p = 0.0279) had better disease-specific survival in the nonadherent group. Race/ethnicity were not factors associated with disease-specific survival in the guideline adherent group. Medicaid disease-specific survival was worse in both the nonadherent group (HR, 1.56; 95% CI, 1.40-1.73; p < 0.0001) and the guideline-adherent group (HR, 1.18; 95% CI, 1.08-1.30; p = 0.0005). Disease-specific survival of the lowest socioeconomic status was worse in both the nonadherent group (HR, 1.42; 95% CI, 1.27-1.59) and the guideline-adherent group (HR, 1.20; 95% CI, 1.08-1.34). LIMITATIONS: Limitations included unmeasured confounders and the retrospective nature of the review. CONCLUSIONS: Race, socioeconomic status, and insurance are associated with guideline adherence in rectal cancer. Race/ethnicity was not associated with differences in disease-specific survival in the guideline-adherent group. Medicaid and lowest socioeconomic status had worse disease-specific survival in both the guideline nonadherent group and the guideline-adherent group. See Video Abstract at http://links.lww.com/DCR/B954 . EFECTOS DIFERENCIALES DE LA RAZA, EL NIVEL SOCIOECONMICO COBERTURA SOBRE LA SUPERVIVENCIA ESPECFICA DE LA ENFERMEDAD EN EL CNCER DE RECTO: ANTECEDENTES: El cumplimiento de las guías de la National Comprehensive Cancer Network mejora los resultados del cáncer. En el cáncer de recto, el cumplimiento de las guías se distribuye de manera diferente según la raza/origen étnico, nivel socioeconómico y el cobertura médica.OBJETIVO: Determinar los efectos independientes de la raza/origen étnico, el nivel socioeconómico y el estado de cobertura médica en la supervivencia del cáncer de recto después de tener en cuenta las diferencias en el cumplimiento de las guías.DISEÑO: Este fue un estudio retrospectivo.ENTORNO CLINICO: El estudio se realizó utilizando el Registro de Cáncer de California.PACIENTES: Pacientes de 18 a 79 años diagnosticados con adenocarcinoma rectal entre el 1 de enero de 2004 y el 31 de diciembre de 2017 con seguimiento hasta el 30 de noviembre de 2018. Los investigadores determinaron si los pacientes recibieron atención siguiendo las guías.PRINCIPALES MEDIDAS DE RESULTADO: Se utilizaron razones de probabilidad e intervalos de confianza del 95 % para la regresión logística para analizar a los pacientes que recibían atención con adherencia a las guías. El análisis de supervivencia específico de la enfermedad se calculó utilizando modelos de regresión de Cox.RESULTADOS: Se analizaron un total de 30.118 pacientes. Los factores asociados con mayores probabilidades de cumplimiento de las guías incluyeron raza/etnicidad asiática e hispana, seguro de atención administrada y nivel socioeconómico alto. Los asiáticos e hispanos tuvieron una mejor supervivencia específica de la enfermedad en el grupo no adherente HR 0,80 (95 % CI 0,72 - 0,88, p < 0,001) y HR 0,91 (95 % CI 0,83 - 0,99, p = 0,0279). La raza o el origen étnico no fueron factores asociados con la supervivencia específica de la enfermedad en el grupo que cumplió con las guías. La supervivencia específica de la enfermedad de Medicaid fue peor tanto en el grupo no adherente HR 1,56 (IC del 95 % 1,40 - 1,73, p < 0,0001) como en el grupo adherente a las guías HR 1,18 (IC del 95 % 1,08 - 1,30, p = 0,0005). La supervivencia específica de la enfermedad del nivel socioeconómico más bajo fue peor tanto en el grupo no adherente HR 1,42 (IC del 95 %: 1,27 a 1,59) como en el grupo adherente a las guías HR 1,20 (IC del 95 %: 1,08 a 1,34).LIMITACIONES: Las limitaciones incluyeron factores de confusión no medidos y la naturaleza retrospectiva de la revisión.CONCLUSIONES: La raza, el nivel socioeconómico y cobertura médica están asociados con la adherencia a las guías en el cáncer de recto. La raza/etnicidad no se asoció con diferencias en la supervivencia específica de la enfermedad en el grupo que cumplió con las guías. Medicaid y el nivel socioeconómico más bajo tuvieron peor supervivencia específica de la enfermedad tanto en el grupo que no cumplió con las guías como en los grupos que cumplieron. Consulte Video Resumen en http://links.lww.com/DCR/B954 . (Traducción- Dr. Francisco M. Abarca-Rendon).

A cross-sectional study for prevalence and risk factors of peri-implant marginal bone loss.

STATEMENT OF PROBLEM: Progressive peri-implant marginal bone loss and peri-implantitis have become a growing problem, but cross-sectional studies on their prevalence and risk factors are sparse. PURPOSE: The purpose of this cross-sectional clinical study was to investigate the prevalence of peri-implant marginal bone loss (MBL) and to identify systemic and local risk factors. MATERIAL AND METHODS: All adult patients who had received dental implants at the National Taiwan University Hospital (NTUH) during 2009 or 2010 were included. Their medical records were collected from the NTUH-integrative Medical Database. Consecutive follow-up radiographs were accessed for severity of MBL. The influence of each factor on MBL was estimated by using generalized estimating equations (GEEs). RESULTS: A total of 732 participants with 1873 implants were analyzed (mean follow-up: 5.30 years). The prevalence of MBL was 59.15% at the individual level and 49.55% at the implant level. The risk indicators identified for the presence of MBL were follow-up period of more than 2 years, diagnosis of diabetes within 12 months, radiation therapy (2 years after implant placement), implant location at maxillary canine (compared with mandibular molar), and implants from the Nobel Biocare brands (Brånemark System and NobelActive). A second multivariate GEE model confirmed the association of progressive MBL with implant location at the maxillary canine and mandibular incisor and implant brand or design. CONCLUSIONS: The identified risk indicators for MBL were longer follow-up period, diagnosis of diabetes, radiation therapy, implant location at maxillary canine, and implant brand or design.

The role of minimally invasive surgery in resectable distal pancreatic adenocarcinoma.

BACKGROUND: In distal pancreatectomy (DP) for pancreatic ductal adenocarcinoma (PDAC), we hypothesize that minimally invasive DP (MIDP) carries short-term benefits over ODP (ODP) in the absence of postoperative pancreatic fistula (POPF). METHODS: NSQIP database was queried to select patients who underwent DP for PDAC with available report on POPF. The population was divided into No-POPF vs. POPF groups. In each group, propensity-score matching was applied to compare 30-day outcomes of ODP vs. MIDP. RESULTS: There were 2,824 patients; 2,332 (82%) had No-POPF and 492 (21%) had POPF. In No-POPF patients, 921 pairs were matched between ODP and MIDP. MIDP patients had slightly longer operations (227 vs. 205 minutes; p < 0.001), but lower rates of surgical site complications (1% vs. 2.9%; p = 0.002), postoperative transfusion (7.1% vs. 11.0%; p = 0.003), overall morbidity (21.1% vs. 26.3%; p = 0.009), and one-day shorter median length of stay (LOS) (5 vs. 6 days; p = 0.001). In the POPF group, 172 pairs were matched. There was no difference in morbidity, mortality, reoperation, LOS, and home discharge. Similar conclusions were drawn in the intention-to-treat and per-protocol analyses. CONCLUSION: POPF is common following DP for PDAC. In the absence of POPF, MIDP is associated with fewer postoperative morbidities and shorter LOS.

Evaluating approaches to diagnosis and management of idiopathic acute pancreatitis.

INTRODUCTION: Idiopathic acute pancreatitis (IAP) is a diagnosis of exclusion; systematic work-up is challenging but essential. Recent advances suggest IAP results from micro-choledocholithiasis, and that laparoscopic cholecystectomy (LC) or endoscopic sphincterotomy (ES) may prevent recurrence. METHODS: Patients diagnosed with IAP from 2015-21 were identified from discharge billing records. Acute pancreatitis was defined by the 2012 Atlanta classification. Complete workup was defined per Dutch and Japanese guidelines. RESULTS: A total of 1499 patients were diagnosed with IAP; 455 screened positive for pancreatitis. Most (N = 256, 56.2%) were screened for hypertriglyceridemia, 182 (40.0%) for IgG-4, and 18 (4.0%) MRCP or EUS, leaving 434 (29.0%) patients with potentially idiopathic pancreatitis. Only 61 (14.0%) received LC and 16 (3.7%) ES. Overall, 40% (N = 172) had recurrent pancreatitis versus 46% (N = 28/61) following LC and 19% (N = 3/16) following ES. Forty-three percent had stones on pathology after LC; none developed recurrence. CONCLUSION: Complete workup for IAP is necessary but was performed in <5% of cases. Patients who potentially had IAP and received LC were definitively treated 60% of the time. The high rate of stones on pathology further supports empiric LC in this population. A systematic approach to IAP is lacking. Interventions aimed at biliary-lithiasis to prevent recurrent IAP have merit.

Arp2/3 nucleates F-actin coating of fusing insulin granules in pancreatic ß cells to control insulin secretion.

F-actin dynamics are known to control insulin secretion, but the point of intersection with the stimulus-secretion cascade is unknown. Here, using multiphoton imaging of ß cells isolated from Lifeact-GFP transgenic mice, we show that glucose stimulation does not cause global changes in subcortical F-actin. Instead, we observe spatially discrete and transient F-actin changes around each fusing granule. This F-actin remodelling is dependent on actin nucleation and is observed for granule fusion induced by either glucose or high potassium stimulation. Using GFP-labelled proteins, we identify local enrichment of Arp3, dynamin 2 and clathrin, all occurring after granule fusion, suggesting early recruitment of an endocytic complex to the fusing granules. Block of Arp2/3 activity with drugs or shRNA inhibits F-actin coating, traps granules at the cell membrane and reduces insulin secretion. Block of formin-mediated actin nucleation also blocks F-actin coating, but has no effect on insulin secretion. We conclude that local Arp2/3-dependent actin nucleation at the sites of granule fusion plays an important role in post-fusion granule dynamics and in the regulation of insulin secretion.

Clinical factors and association with treatment modalities in patients with breast cancer and brain metastases who develop leptomeningeal metastases.

PURPOSE: Leptomeningeal metastases (LM) are an aggressive complication of metastatic breast cancer (MBC) with brain metastases (BM), with a short survival of weeks to months. Studies suggest that surgical resection of BM may increase the risk of LM, especially in infratentorial metastases. In this retrospective study, we examine this and other factors which may be associated with increased risk of LM. METHODS: A database search at a single institution identified 178 patients with MBC and treated BM between 2007 and 2020. We collected demographic, clinical, radiographic, and other treatment data. LM was diagnosed by cerebrospinal fluid (CSF) cytology, neuroimaging, or both. Cox proportional hazards model was used. RESULTS: After a median follow-up of 8.5 months, 41 out of 178 patients (23%) with BM developed LM. Median time to develop LM was 130 days. Mean age was 51.3 years. The number and size of the BM, hemorrhagic/cystic lesions, progressive/stable systemic disease, and extracranial metastases sites other than liver did not pose a higher risk of LM. Infratentorial lesions (HR = 5.41) and liver metastases (HR = 2.28) had a higher risk of LM. Patients who had any surgery did not have a higher risk for LM (HR 1.13). The LM group had a worse overall survival as compared to the non-LM group. CONCLUSION: Among MBC patients with BM, infratentorial BM and visceral liver lesions increase the risk of LM, whereas local treatment modalities such as surgery and radiation do not. These data imply that local treatment strategy should not differ based on potential risk for LM.

Impact of Lifetime Obesity on Urinary Incontinence in the Women's Health Initiative.

PURPOSE: We assessed the impact of lifetime obesity on the development of urinary incontinence (UI). MATERIALS AND METHODS: Using data from the Women's Health Initiative, we evaluated the cumulative impact of obesity over a postmenopausal woman's lifetime on the development of UI. Analyses using logistic models assessed the relationship between overweight/obesity duration and the development of UI during the Women's Health Initiative study at year 3. RESULTS: Of the 15,420 women aged 50-79 years, 4,568 (30.0%) developed UI by year 3. When controlling for covariates, the duration of overweight years (OWY) and obese years (OBY) was significantly associated with overall UI. The number of OWY was associated with an increased risk of developing UI postmenopausally (OR 1.17, 95% CI 1.13-1.22) compared to those with 0 OWY. The number of OBY was associated with a higher risk of developing UI postmenopausally (OR 1.28, 95% CI 1.18-1.39). Severity of UI was also associated with higher OWY/OBY. Compared to participants who maintained normal weight, those who gained weight from age 18 to 50 years were more likely to report increased UI (OR 1.26, 95% CI 1.16-1.37), as did those who remained overweight/obese (OR 1.27, 95% CI 1.04-1.55). Those who lost weight reported no difference in rates of any UI. CONCLUSIONS: Chronic, increased body mass index status is associated with an elevated risk of UI later in life. Symptom severity also appears to be worsened with duration of increased body mass index status. Weight management should be supported throughout one's lifetime, as it may impact UI in later stages of life.

Better late than never: Brachytherapy is more important than timing in treatment of locally advanced cervical cancer.

PURPOSE: To evaluate the utilization of brachytherapy and duration of treatment on overall survival for locally advanced cervical cancer. METHODS: The National Cancer Database (NCDB) was queried to identify stage II-IVA cervical cancer patients diagnosed in the United States between 2004 and 2015 who were treated with definitive chemoradiation therapy. We defined standard of care (SOC) treatment as receiving external beam radiation therapy (EBRT) and concurrent chemotherapy, brachytherapy (BT), and completing treatment within 8 weeks, and compared SOC treatment to non-SOC. The primary outcome was overall survival (OS). We also evaluated the effect of sociodemographic and clinical variables on receiving SOC. RESULTS: We identified 10,172 women with locally advanced cervical cancer primarily treated with chemotherapy and concurrent EBRT of which 6047 (59.4%) patients received brachytherapy, and only 2978 (29.3%) completed treatment within 8 weeks (SOC). Receipt of SOC was associated with significantly improved overall survival (median OS 131.0 mos vs 95.5 mos, 78.1 mos, 49.2 mos; p < 0.0001). Furthemore, in patients whose treatment extended beyond 8 weeks, brachytherapy was still associated with an improved survival (median OS 95.5 vs 49.2 mos, p < 0.0001). More advanced stage, Non-Hispanic Black race, lower income, lack of insurance or government insurance, less education, and rural residence were associated with decreased likelihood of receiving SOC. CONCLUSIONS: Completing standard of care concurrent chemoradiation therapy and brachytherapy in the recommended 8 weeks was associated with a superior overall survival. Patients who received brachytherapy boost show superior survival to patients receiving EBRT alone, regardless of treatment duration. Disparities in care for vulnerable populations highlight the challenges and importance of care coordination for patients with cervical cancer.

Targeting renal cell carcinoma with a HIF-2 antagonist.

Clear cell renal cell carcinoma (ccRCC) is characterized by inactivation of the von Hippel-Lindau tumour suppressor gene (VHL). Because no other gene is mutated as frequently in ccRCC and VHL mutations are truncal, VHL inactivation is regarded as the governing event. VHL loss activates the HIF-2 transcription factor, and constitutive HIF-2 activity restores tumorigenesis in VHL-reconstituted ccRCC cells. HIF-2 has been implicated in angiogenesis and multiple other processes, but angiogenesis is the main target of drugs such as the tyrosine kinase inhibitor sunitinib. HIF-2 has been regarded as undruggable. Here we use a tumourgraft/patient-derived xenograft platform to evaluate PT2399, a selective HIF-2 antagonist that was identified using a structure-based design approach. PT2399 dissociated HIF-2 (an obligatory heterodimer of HIF-2α-HIF-1ß) in human ccRCC cells and suppressed tumorigenesis in 56% (10 out of 18) of such lines. PT2399 had greater activity than sunitinib, was active in sunitinib-progressing tumours, and was better tolerated. Unexpectedly, some VHL-mutant ccRCCs were resistant to PT2399. Resistance occurred despite HIF-2 dissociation in tumours and evidence of Hif-2 inhibition in the mouse, as determined by suppression of circulating erythropoietin, a HIF-2 target and possible pharmacodynamic marker. We identified a HIF-2-dependent gene signature in sensitive tumours. Gene expression was largely unaffected by PT2399 in resistant tumours, illustrating the specificity of the drug. Sensitive tumours exhibited a distinguishing gene expression signature and generally higher levels of HIF-2α. Prolonged PT2399 treatment led to resistance. We identified binding site and second site suppressor mutations in HIF-2α and HIF-1ß, respectively. Both mutations preserved HIF-2 dimers despite treatment with PT2399. Finally, an extensively pretreated patient whose tumour had given rise to a sensitive tumourgraft showed disease control for more than 11 months when treated with a close analogue of PT2399, PT2385. We validate HIF-2 as a target in ccRCC, show that some ccRCCs are HIF-2 independent, and set the stage for biomarker-driven clinical trials.