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Neuroplastic changes in phrenic motor neurons that underlie recovery from spinal cord injury may be mediated by perineuronal nets. We show that changes in perineuronal nets around phrenic motor neurons occur within 7 days after cervical spinal cord injury, and that the increase in perineuronal nets around larger phrenic motor neurons was more pronounced. These changes are consistent with substantial reorganization of the neural network onto intact phrenic motor neurons following cervical spinal cord injury.

Brain-derived neurotrophic factor (BDNF) signals through its high-affinity full length tropomyosin receptor kinase-B (TrkB.FL). One key downstream target of BDNF/TrkB.FL signaling is phosphorylation of the transcription factor cyclic AMP response element-binding (CREB) protein at serine 133 (pCREBS133). We hypothesized that a positive feedback loop exists in the spinal cord in which BDNF/TrkB.FL induces pCREBS133 which then transcriptionally targets pro-BDNF expression. To test this hypothesis, we employed a loss of function approach using a novel chemogenetic rat model (TrkBF616A) with a knock-in allele sensitive to the selective kinase inhibitor 1NMPP1 to inhibit TrkB.FL kinase activity. In female and male TrkBF616A rats, we then examined the effects of 1NMPP1 (orally through drinking water) induced TrkB.FL kinase inhibition on BDNF levels in the cervical (CSC) and lumbar (LSC) spinal cord. The spinal cord was collected at two time points at 0700 and 010 reflecting the trough and peak timepoints of endogenous BDNF expression. BDNF levels were quantified using ELISA. We found in the CSC, BDNF levels did not vary across timepoints in either 1NMPP1 or vehicle treated groups. However, 1NMPP1-induced TrkB.FL inhibition significantly reduced BDNF levels at both timepoints (P=0.004). This reduction suggests that cervical circuits rely on continuous CREB-dependent support of BDNF expression and that inhibiting TrkB.FL disrupts this loop throughout the day. In the LSC, control rats displayed time of day-dependent variations in BDNF with lower levels at 0700 compared to 0100 (P=0.02). In contrast, 1NMPP1-induced inhibition of TrkB.FL reduced BDNF levels at 0100—when BDNF normally peaks in the LSC (P=0.01). This nighttime specific deficit supports the idea that activity-driven pCREBS133 activation is necessary to elevate BDNF during the active phase and that blocking TrkB.FL signaling disrupts this pCREBS133-mediated positive feedback. Overall, these results support a positive feedback that is region- and time-specific and involves BDNF/TrkB.FL signaling inducing pCREBS133 phosphorylation which then targets pro-BDNF expression in the spinal cord. Supported by NIH grants HL146114 and AG44615. This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.

ABSTRACT Background and Objectives NCCN guidelines recommend right hemicolectomy (RHC) for appendiceal neuroendocrine tumors (aNETs) > 2 cm and observation for < 1 cm. However, optimal surgical management of 1–2 cm tumors remains controversial. This study compared long‐term survival and recurrence between patients undergoing RHC versus appendectomy (APY) for 1–2 cm aNETs. Methods Patients with pathologically confirmed 1–2 cm aNETs treated at three Mayo Clinic sites (1972–2024) were included. Primary outcomes were recurrence and all‐cause mortality after resection. Associations with lymph node (LN) metastasis were assessed in patients with lymphadenectomy. Results Sixty‐five patients were identified: 29 (45%) underwent APY, 35 (54%) RHC, and one ileocecectomy. Median age at diagnosis was 39 years; 71% were female and 94% white. LN positivity was 15.2% for tumors with nodes examined. Tumor size > 1.5 cm, stage T3/T4, and lymphovascular invasion were not associated with nodal metastasis. No survival differences were observed between APY and RHC. LN positivity did not impact survival. No recurrences occurred during a median follow‐up of 6.25 years (IQR 2.44–12.63). Conclusions Among patients with 1–2 cm aNETs, RHC conferred no survival benefit over APY. Absence of recurrence and the limited prognostic value of nodal disease suggest APY alone may suffice for this population.

BACKGROUND: Subtotal cholecystectomy is increasingly recommended as a bailout strategy for the difficult gallbladder, yet its long-term durability and the risk profile of subsequent completion cholecystectomy remain incompletely defined. STUDY DESIGN: We performed a population-based retrospective cohort study of adults undergoing laparoscopic or open subtotal cholecystectomy for acute cholecystitis from 2012 to 2021 using Healthcare Cost and Utilization Project state databases from New York and Florida. The primary endpoint was remnant cholecystitis, defined as a postoperative emergency, inpatient, or outpatient diagnosis of cholecystitis or need for subsequent cholecystectomy. Kaplan–Meier analysis estimated cumulative incidence. Secondary outcomes included completion cholecystectomy and bile duct injury requiring surgical repair. RESULTS: Among 2,682 patients (98.7% laparoscopic), the cumulative incidence of remnant cholecystitis was 13.3% during a median follow-up of 2 years (interquartile range [IQR] 0.7 to 4.1). The median time to developing remnant cholecystitis was 28 days (IQR 13 to 91), with 79.7% occurring within 6 months. Only 70 patients (2.6%) underwent completion cholecystectomy at a median of 103 days (IQR 43 to 202). Completion cholecystectomy was performed via open surgery in 47.1% of patients and was associated with a 7.1% bile duct injury rate and median length of stay of 3 days (IQR 1 to 7), compared with a 0.9% bile duct injury rate for subtotal cholecystectomy overall. CONCLUSIONS: Although remnant cholecystitis occurred in 13.3% of patients after subtotal cholecystectomy, few required completion cholecystectomy. When necessary, completion cholecystectomy was frequently open and associated with a substantially higher bile duct injury rate, supporting referral to experienced hepatobiliary centers for reoperation.

Abstract Background Robotic left pancreatectomy (RLP) is increasingly adopted worldwide. Current guidelines suggest a learning curve of 21 cases, yet its impact on major morbidity and oncological quality remains uncertain. Methods A retrospective multicentre international study was undertaken across 10 centres in the UK, Spain, Germany, the USA, and Australia (2014–2025). Consecutive patients undergoing RLP were categorised into competency (first 21 cases per centre) or proficiency phase (&gt;21). The primary outcome was major morbidity (Clavien–Dindo grade ≥ IIIa), and secondary outcome was the R1-margin rate. Mixed-effects logistic regression and risk-adjusted cumulative sum (RA-CUSUM) analyses were performed. Results 521 patients underwent RLP, including 200 (38.4%) in the competency phase and 321 (61.6%) in the proficiency phase. Median age was 63 years (IQR 54–73), and 56.4% were female. Rates of major morbidity were similar between phases (14.5% versus 14.0%, P = 0.981), as were R1 margin rates (21.6% versus 19.7%, P = 0.092). Independent predictors of major morbidity included male sex (OR 1.76, P = 0.037), preoperative pancreatitis (OR 2.23, P = 0.031), and multivisceral resection (OR 2.29, P = 0.034). Among patients with adenocarcinoma (n = 110), prolonged operative time (OR 1.39 per hour, P = 0.004) and nodal positivity (OR 2.62, P = 0.047) predicted R1 resection, while learning phase was not associated with margin status. RA-CUSUM demonstrated no excess morbidity over time in any centre. Conclusions In this first multicentre international analysis, the learning phase of RLP did not increase the risk of major morbidity or compromise oncological quality. These findings support the safe global adoption of RLP with appropriate training and case selection.

Abstract Background Minimally invasive left-sided pancreatectomy (MIS-LP) is increasingly adopted for pancreatic neuroendocrine tumours (PNETs), yet its oncological safety compared with open surgery (O-LP) remains debated. Robust population-level evidence is required to guide practice. Methods Patients ≥65 years with grade 1–2 PNETs undergoing left pancreatectomy were identified from the SEER-Medicare database (2010–2019). Overall and cancer-specific survival outcomes were analysed using multilevel Cox regression after propensity-score matching (PSM). Landmark analysis from 6 months excluded early postoperative deaths. Results 772 patients were included: 257 (33%) MIS-LP and 515 (67%) O-LP. Median age was 71 years; 87% had grade 1 and 13% grade 2 tumours. Before matching, MIS-LP patients had lower comorbidity (median Charlson Index 2 versus 3, P = 0.011) and fewer with metastatic disease (2.0% versus 5.7%, P = 0.019). After PSM (MIS-LP n = 248; O-LP n = 441), 5-year overall survival was higher with MIS-LP (88.1% versus 84.5%, P = 0.03), while 5-year cancer-specific survival was similar (95.2% versus 93.5%, P = 0.11). O-LP was associated with increased risk of death (HR 1.75, 95% c.i. 1.05–2.91, P = 0.030), though not cancer-specific death (HR 1.97, 95% c.i. 0.86–4.54, P = 0.110). Notably, all 90-day mortalities (n = 15, 1.9%) occurred in the O-LP group. In landmark analysis beyond 6 months, surgical approach was no longer predictive of OS or CSS. Conclusions MIS-LP confers an early survival advantage, driven by reduced perioperative mortality, without compromising long-term oncological outcomes. As the largest population-based analysis in this setting, these findings support MIS-LP as the standard surgical approach for older patients with low- to intermediate-grade PNETs.

Importance Adjuvant chemotherapy regimens may be administered after pancreatic resection for adenocarcinoma arising from intraductal papillary mucinous neoplasms (A-IPMNs), although the evidence supporting their use is limited. Objective To evaluate the survival benefit associated with contemporary adjuvant chemotherapy regimens after resection in A-IPMNs between 2017 and 2023. Design, Setting, and Participants This retrospective cohort study was an international, multicenter study with 69 participating centers across Europe, North America, South America, and the Asia-Pacific region. Patients undergoing resection for A-IPMNs were included. Data were analyzed from May to August 2025. Intervention Contemporary adjuvant chemotherapy regimens, such as gemcitabine-capecitabine (GemCap); 5-fluorouracil, leucovorin, oxaliplatin, and irinotecan (FOLFIRINOX), modified FOLFIRINOX (mFOLFIRINOX), and S-1. Main Outcome and Measure Overall survival (months). Results Among 1321 patients (median [IQR] age 70 [63 to 76] years; 713 males [54.0%] and 608 females [46.0%]), 781 patients (59.1%) received adjuvant chemotherapy, while in 181 patients (13.7%) it was omitted due to poor patient fitness. Of patients who received adjuvant chemotherapy, 568 patients (72.6%) received contemporary regimens, including GemCap (232 patients [29.7%]), FOLFIRINOX (176 patients [22.5%]), mFOLFIRINOX (71 patients [9.1%]), and S-1 (70 patients [9.0%]). The median (IQR) follow-up for the cohort was 64.2 (40.4 to 85.0) months, and the median overall survival was 73.8 months (95% CI, 66.4 to 81.9 months). After 90-day landmark analysis and exclusion of patients ineligible for chemotherapy, adjuvant chemotherapy vs no adjuvant chemotherapy (propensity score–matched populations, 243:243 patients) was not associated with improved overall survival (median, 82.3 months; 95% CI, 78.2 months to not applicable [NA] vs not reached; 95% CI, 75.3 months to NA; P = .58). Contemporary regimens vs no adjuvant chemotherapy (propensity score–matched populations, 309:309 patients) was not associated with longer survival, and a mean survival benefit greater than 4.2 months over 5 years was excluded (difference in restricted mean survival, 1.26 months; 95%, −1.72 to 4.24 months). Treatment outcomes did not vary by chemotherapy regimen or disease characteristic (eg, N stage or carbohydrate antigen 19-9 level). Conclusions and Relevance In this study, contemporary adjuvant chemotherapy was not associated with improved overall survival in A-IPMNs, and a randomized clinical trial is indicated.

ABSTRACT Soluble tumor necrosis factor receptor 2 (sTNFR2) is a member of the TNF superfamily whose normal bodily distribution is largely limited to low level expression on lymphoid cells. It has emerged as an important inducible receptor that activates a signaling pathway for cancer growth. We evaluated sTNFR2 as a prognostic biomarker for overall survival (OS) in newly diagnosed lymphoma using a prospective cohort study with banked pretreatment serum samples. sTNFR2 was higher in 1513 lymphoma patients compared to 499 age and sex matched controls ( p < 0.0001). Using Kaplan–Meier curves and Cox proportional hazards models to estimate hazard ratios [HR] (high vs. low tertile), higher levels of sTNFR2 at diagnosis were associated with inferior OS across all seven major lymphoma subtypes: Hodgkin lymphoma ( p < 0.0001; HR = 12.6), diffuse large B‐cell lymphoma ( p < 0.0001; HR = 2.6), follicular lymphoma ( p = 0.00017; HR = 2.5), mantle cell lymphoma ( p < 0.0001; HR = 4.2), small lymphocytic lymphoma ( p = 0.012; HR = 2.4), marginal zone lymphoma ( p = 0.0012; HR = 3.1), and T‐cell lymphoma ( p < 0.0001; HR = 3.1). Using CITE‐seq profiling of tumor microenvironment tissue, we sought to identify cellular source(s) of circulating sTNFR2. In tumor tissue from follicular lymphoma, high TNFR2‐expressing cells were found to be T‐regulatory (Treg) cells, suggestive of a Treg‐driven cancer. In tissue from a case of marginal zone lymphoma, high TNFR2 expression was found on CD4+ and CD8+ T cells, B cells, and monocytes but also directly on tumor cells. We conclude sTNRF2 is a strong prognostic biomarker of OS across major lymphoma subtypes and may be useful to guide therapeutic choices, including targeted therapies against immunosuppressive TNFR2‐expressing Tregs.

ABSTRACT Background Postoperative venous thromboembolism (VTE) is a major source of morbidity and mortality. Real‐time risk stratification for VTE is important to guide measures for thromboprophylaxis. We sought to compare the discrimination of three VTE predictive systems in classifying 90‐day postoperative VTE among cancer patients undergoing pancreas and liver surgery using administrative data. Methods We conducted a retrospective analysis of the 2001–2015 SEER‐Medicare data for patients with newly diagnosed primary pancreatic or liver malignancies who underwent surgery. The primary outcome was 90‐day postoperative VTE (including deep venous thrombosis and pulmonary embolism [PE]). We used the 2001–2010 dataset to create a new VTE predictive model using multivariable logistic regression. We then compared the discrimination of the Caprini score (adapted for claims data), the Elixhauser comorbidity score, and the new predictive model using the 2011–2015 dataset. Results Our sample included 15 479 patients (12 005 pancreas and 3474 liver surgery). Median age was 74 years (interquartile range: 69–78) and 7619 were female (49%). The overall incidence of 90‐day VTE was 10.0% (90‐day PE: 4.5%). The new VTE model included age, race, history of VTE, cancer stage, preoperative chemotherapy, and Elixhauser score. The discrimination of all predictive models was modest for both VTE ( c ‐statistic 63.0%, 59.4%, and 67.8%) and PE (61.5%, 59.7%, 65.6% for Caprini, Elixhauser, and new score respectively). Conclusions The existing tools for predicting postoperative VTE show poor performance using claims data. Future research should supplement administrative data with additional data sources to better predict patients at high risk for postoperative VTE.

Background: ASCO recommends extended venous thromboembolism (VTE) prophylaxis with low-molecular-weight heparin (LMWH) or direct oral anticoagulants (DOACs) following cancer surgery. However, these recommendations were based on trials using routine venography, which detects asymptomatic VTEs, and real-life efficacy is not well studied. We aimed to assess the association of extended VTE prophylaxis with the incidence of clinically significant VTE after elective cancer surgery. Patients and Methods: In this retrospective, population-based cohort study, we identified patients who underwent surgical resection for lung, breast, esophageal, gastric, pancreas, and colon cancer from 2010 to 2017 using the SEER–Medicare linked dataset. Patients were divided into 1 of 2 main groups for comparative analyses: those who received extended VTE prophylaxis after cancer surgery and those who did not. Patients who received extended VTE prophylaxis after cancer surgery were identified as those prescribed prophylactic doses of LMWH or a DOAC within 7 days of discharge, as captured in Medicare Part D files. Results: A total of 113,739 Medicare beneficiaries were identified, of whom 1,570 (1.4%) received extended VTE prophylaxis. There was a year-over-year increase in the use of extended VTE prophylaxis during the study period, rising from 0.6% in 2010 to 3.3% in 2017. The overall incidence of VTE was 1.6% at 1 month, 4.3% at 6 months, 5.7% at 12 months, with significant differences observed across cancer types ( P <.001). However, patients who received extended VTE prophylaxis had a higher 1-year cumulative incidence of postoperative VTE compared with those who did not (11.4% vs 5.3%; P <.001), an association that was consistent across cancer sites. In adjusted analyses, extended VTE prophylaxis was independently associated with an increased risk of VTE (hazard ratio, 1.6; 95% CI, 1.3–2.0; P <.001). Extended prophylaxis was also associated with a higher 1-year incidence of bleeding events compared with patients who did not receive prophylaxis (12.0% vs 8.5%; P <.001). Conclusions: The utilization of extended VTE prophylaxis after cancer surgery remains low, although it has increased every year. Paradoxically, patients who received extended VTE prophylaxis had higher incidences of clinically significant VTE and bleeding compared with those who did not, likely reflecting patient selection and surveillance bias after surgery. In light of these findings, national guidelines recommending postoperative extended VTE prophylaxis, and its use as a surrogate for quality of care, should continue to be re-examined.