Starlinger, Patrick

Background and Aims: The optimal treatment strategy for de novo perihilar cholangiocarcinoma (pCCA) remains debated. This study compares outcomes between liver transplantation following neoadjuvant chemoradiation (RT+LT) and liver resection (LR), with (LR+VR) and without vascular resection (LR w/o VR). Approach and Results: This single-center, retrospective study included patients with de novo perihilar cholangiocarcinoma treated at the Mayo Clinic Rochester (1993–2023) with curative-intent surgery. Patients underwent either (1) LR, classified as LR+VR or LR w/o VR, or (2) RT+LT following the transplant protocol. Overall survival (OS) and recurrence-free survival were analyzed using as-treated and intention-to-treat approaches, incorporating competing risk analysis and direct matching. In the as-treated analysis, RT+LT showed superior median OS compared with LR w/o VR (78.0 vs. 58.2 mo, p =0.03) and LR+VR (25.8 mo, p <0.001). Considering dropout rates (RT+LT: 41%, LR: 28%), intention-to-treat analysis showed no significant OS difference between LR and RT + LT (31.7 vs. 38.5 mo, p =0.19). In matched as-treated analysis, RT + LT had no significant survival benefit over LR w/o VR (50.6 vs. 140.6 mo, p =0.08) or LR+VR (25.8 mo, p =0.11). Perioperative mortality was 4% (RT+LT), 7% (LR w/o VR), and 8% (LR + VR). Conclusions: Both LR and RT+LT achieve excellent oncological outcomes in selected patients with de novo perihilar cholangiocarcinoma. Key challenges remain dropouts during neoadjuvant therapy in patients planned for LT and high perioperative mortality for patients undergoing LR. OS doubles in patients undergoing LR+VR compared with dropouts, supporting LR+VR as a viable option for patients who are ineligible for LT. Appropriate patient selection is crucial, as those not undergoing surgery suffer from a dismal prognosis.

Abstract Malignant insulinomas are rare pancreatic neuroendocrine tumors characterized by excessive insulin secretion and a high propensity for metastasis, leading to challenging management. This study retrospectively analyzed 57 patients treated for malignant insulinoma at Mayo Clinic sites between 1992 and 2024, focusing on the efficacy of systemic therapies in improving hypoglycemic control and survival outcomes. The most commonly used therapies included somatostatin analogs (SSA), everolimus, capecitabine-temozolomide (CAPTEM), and peptide receptor radionuclide therapy (PRRT). PRRT demonstrated the highest efficacy in controlling hypoglycemia (93%), followed by CAPTEM (68%) and everolimus (62%). SSA, chemotherapy, and streptozocin were less effective, with hypoglycemic improvement seen in 37.5, 33.3, and 28.6% of patients, respectively. Overall survival (OS) was longest with SSA at 84.67 months, followed by CAPTEM at 81.67 months and everolimus at 74.07 months. PRRT demonstrated a median OS of 49.73 months. In contrast, chemotherapy and streptozocin-based therapies had significantly shorter OS times of 15.23 and 8.35 months, respectively. These findings highlight significant variability in systemic therapy efficacy for malignant insulinoma, with PRRT emerging as a promising treatment for refractory hypoglycemia and long survival. Cox regression analysis identified primary tumor resection and a history of benign insulinoma as associated with longer OS. Optimal sequencing of therapies remains unclear, and individualized treatment plans based on hypoglycemic burden and tumor characteristics are critical for improving survival and quality of life in these patients.

Objective: To establish benchmark cutoffs for robotic liver resection (R-LR), encompassing both major and minor resections, and to determine the impact of patient selection on outcomes. Background: R-LR is a key advancement in minimally invasive liver surgery but lacks standardized benchmarks, especially for minor resections. While guidelines endorse R-LR, its role in optimizing outcomes remains unclear. This study establishes the first benchmarks for R-LR, enabling comparisons across surgical modalities and refining patient selection. Methods: This retrospective, multicenter study analyzed consecutive adult patients undergoing R-LR at 30 international centers (2020–2023). Benchmark centers had an annual case volume of ≥15 R-LR. Benchmark criteria included ASA ≤2, no major comorbidities, no prior liver resections, and Child-Pugh A status. Benchmark cutoffs for 14 key outcomes were set at the 50th and 75th percentiles of median values across benchmark centers. Multivariable logistic regression identified predictors of textbook outcomes. Results: Eighteen high-volume centers contributed 4028 cases with 2632 (65.3%) meeting benchmark criteria. Malignancy was the indication in 29.6%, most commonly hepatocellular carcinoma followed by colorectal liver metastases. Major liver resection was performed in 42.6%. The distribution of Iwate difficulty scores was low (25.4%), intermediate (53.9%), advanced (15.9%), and expert (4.9%). Benchmark cutoffs were established for minor and major resection, and stratified by Iwate low (0-3), intermediate (4-6) and high (7-12): Open conversion (≤6.5% minor, ≤10.5% major), major complications within 90 days (≤5.2% minor, ≤16.7% major), R1 resection (≤9.2% minor, ≤6.7% major). Benchmark cases performed at low-volume centers were able to achieve outcomes within the corresponding benchmark cutoffs. In fact, patient selection reflected by the proportion of benchmark patients, rather than case volume, was associated with textbook outcomes. Conclusions: This study defines R-LR benchmarks, emphasizing patient selection over center volume for optimal outcomes. Benchmark cutoffs guide training and support the expansion of R-LR.

Abstract Tumor cells develop various strategies to evade immune surveillance, one of which involves altering the metabolic state of the tumor microenvironment. In response to metabolic stress in the tumor microenvironment, several tumor-infiltrating immune subsets upregulate CD36 to take up lipids. This leads to impaired antitumor immunity, as intratumoral regulatory T cells exhibit increased survival and suppressive activity, whereas CD8+ T cells become more susceptible to ferroptosis and exhaustion. In this study, we develop a humanized anti-CD36 IgG4 antibody, PLT012, against the lipid-binding domain of CD36 with excellent safety and favorable pharmacokinetic features in mice and cynomolgus monkeys. PLT012 alone or in combination with PD-L1 blockade or standard-of-care immunotherapy results in robust antitumor immunity in both immunotherapy-sensitive and -resistant hepatocellular carcinomas (HCC). Notably, PLT012 also reprograms the immune landscape of human HCC ex vivo. Our findings provide proof-of-concept evidence that PLT012 reprograms antitumor immunity in HCC, positioning it as a first-in-class immunotherapy targeting CD36. Significance: Despite the success of cancer immunotherapies, like immune checkpoint inhibitors, many patients still fail to demonstrate significant responses because of metabolic constraints in tumors. PLT012 rejuvenates antitumor immunity by targeting metabolic pathways to reprogram the immune landscape of liver cancer and liver metastasis, with potential to influence future HCC immunotherapy.

Abstract Given the heterogeneous clinical behavior of pancreatic neuroendocrine tumors (pNETs), improved prognostic markers are needed to guide management and post‐resection surveillance. Patients who underwent resection of large (≥3 cm) sporadic well‐differentiated pNETs from 2000 to 2019 were identified. The Ki‐67 proliferation index was determined using immunohistochemistry, and alternative lengthening of telomeres (ALT) status was assessed using fluorescence in situ hybridization. Recurrence‐free and overall survival were estimated using Kaplan–Meier analysis. Multivariable Cox regression analysis evaluated factors associated with recurrence‐free survival. A total of 106 patients were identified. ALT was positive in 57 (54%) and negative in 49 (46%). Ki‐67 was ≥3% in 74 (70%) and <3% in 32 (30%). Tumors with Ki‐67 ≥3% were more likely to be ALT positive (61% vs. 38%, p = .046). Stratifying by ALT status and Ki‐67 proliferation index, median recurrence‐free survival was 4.6 years for patients with ALT‐positive/Ki‐67 ≥3% tumors, 3.1 years for patients with ALT‐positive/Ki‐67 <3% tumors, 12.4 years for patients with ALT‐negative/Ki‐67 ≥3% tumors, and 20.2 years for patients with ALT‐negative/Ki‐67 <3% tumors ( p < .001). Initial recurrence was distant in 82% and locoregional in 18%. Across all groups, overall survival was similar ( p = .19). In multivariable analysis, advanced age, ALT positivity, perineural invasion, and lymph node metastases were associated with increased recurrence risk (all p < .05). ALT and Ki‐67 provide complementary information on post‐resection recurrence risk, which can guide subsequent surveillance and management strategies. These data support the incorporation of ALT testing into routine clinical practice.

5 Background: Metastatic anal squamous cell carcinoma is rare and associated with a poor prognosis. There is limited evidence on the impact of local interventions on survival outcomes in patients with metastatic disease. We aimed to evaluate the survival of patients with liver-only metastatic anal cancer following definitive local management of liver lesions. Methods: This is a single-institution retrospective cohort study of patients with liver-limited metastatic anal cancer who underwent curative-intent local therapy. Clinical characteristics were collected and analyzed. The Kaplan-Meier method was used to calculate disease-free survival (DFS) and overall survival (OS). Prognostic factors associated with DFS and OS were assessed using Cox-proportional hazards models. Results: Twenty-five patients were included, median age was 59 years, and 92% were female. None of the patients had known HIV infection, 92% had HPV-positive disease and 76% had metachronous liver metastases following locoregional disease. All patients received chemoradiation for the primary lesion Unilobar hepatic involvement was present in 76% of the patients, with 56% having a single metastatic lesion. Pre-intervention systemic therapy was provided to 52% of the patients, including 8 who received carboplatin and paclitaxel, with a median duration of 3 months and ORR of 69%. Definitive treatment of metastatic disease included surgical resection (60%), non-surgical interventions (20%), and multimodal therapy (20%). All patients had viable tumor in the pathological specimen. With a median follow-up of 22 months, median DFS was 7.3 months, and median OS was 51.3 months. An ECOG performance status of 2, poorly differentiated histology, and extrahepatic recurrence were identified as significant prognostic factors in the univariate analysis, but not in the multivariate analysis. Conclusions: Our results demonstrate potential for long-term survival in liver-limited metastatic anal squamous cell carcinoma amenable to local therapeutic intervention combined with systemic therapy. These findings warrant further prospective study of local therapy in oligometastatic anal cancer. Characteristics N=25 (%) Median number of liver metastases (range), lesions- 1- 2-3- >3 1 (1-20)14 (56)8 (32)3 (12) Median maximal diameter of liver metastases (range), cm 3 (0.9-11.9) Best response of liver metastases to chemotherapy (N=13)- Complete response- Partial response- Stable disease- Progressive disease 2 (15)7 (54)3 (23)1 (8) Surgical procedure (N=20)- Right/left hemi-hepatectomy- Segmentectomy- Wedge resection 4 (20)14 (70)2 (10) Non-surgical procedure (N=10)- Local ablation- Radiotherapy- Other 5 (50)3 (30)2 (20) Hepatic surgical margins (N=20)- Positive margins- Close margins (<1mm)- Negative margins 02 (10)18 (90) Recurrent disease- Yeso Intrahepatico Extrahepatic- No 20 (80)14 (70)6 (30)5 (20)

Abstract Background Atezolizumab plus bevacizumab (A/B) received FDA approval as the first-line therapy for patients with advanced hepatocellular carcinoma (HCC) in 2020. However, optimal subsequent treatment options are unclear. Here, we describe clinical outcomes of advanced HCC patients following first-line treatment with A/B. Patients and Methods We conducted a multi-site analysis of patients with HCC treated with first-line A/B between January 2018 and December 2022 at Mayo Clinic. This study cohort included all patients receiving second-line systemic therapy after A/B. Median overall survival (OS) and time-to-treatment discontinuation (TTD) were estimated using the Kaplan-Meier method. Child Pugh (CP) scores are also described at diagnosis, prior to first line, and prior to second-line therapy. Results Of the 342 patients who received A/B, 107 (31.3%) received second-line treatments including anti-VEGF therapy or immune checkpoint inhibitor (ICI) and were included in the final analysis. Median OS for all patients was 11.1 months from initiation of second-line therapy. Median OS was 10.7 months (95% CI: 7.2-12.8) and 15.7 months (95%CI: 6.8-NE) for those receiving anti-VEGF inhibitors and ICI ( P = .50). Median TTD for second-line therapies was 2.4 months (95% CI: 1.7-3.3) and 2.6 months (95% CI: 1.5-5.1) for anti-VEGF inhibitors and ICI, respectively (P = .87). In multivariate analyses, CP was significantly associated with survival. Conclusion Following first-line A/B treatment, there is no statistically significant difference in survival between ICI and anti-VEGF therapy, nor in time to treatment discontinuation. CP score remains an important prognostic tool.

Background: Treatment of symptomatic splenomegaly in myelofibrosis (MF) was revolutionized by JAK2 inhibitors (JAKi), with ruxolitinib inducing a &gt;35% spleen volume reduction in 42% of patients at 24 weeks (N Engl J Med 2012;366). However, the benefit is often transient with a median duration of spleen response of three years (N Engl J Med. 2011;365). Treatment modalities for the management of MF-associated splenomegaly resistant to JAKi treatment includes surgical resection and involved-field radiotherapy. In the current study, we describe our experience with the former. Methods: Study patients were retrospectively recruited from Mayo Clinic (USA) databases based on the following criteria: i) diagnosis according to the International Consensus Classification (Blood 2022;140:1200); ii) documentation of JAKi therapy exposure followed by splenectomy; iii) availability of information before and after splenectomy. Splenectomy was performed as an open (n=29) or laparoscopic (n=5) surgery. Conventional statistical methods were employed for data analysis (JMP Pro 17.0.0, SAS Institute, Cary, NC, USA). Results: A total of 34 patients (median age 62.5 years, range 43-79; 59% males) were identified with splenectomies performed between 2011-2024. Mutation distribution included JAK2 62%, CALR 26%, MPL 3%, and triple negative 9%. ASXL1 mutation was present in 37% and SRSF2 mutation was present in 26% of 19 informative cases. Karyotype was very high risk in 15% and unfavorable in 12%. Median time from diagnosis to JAKi initiation was 7.5 years (0-31). Majority (76%) were treated with one JAKi; 18% had been exposed to 2 different JAKi and 6% with three JAKi. JAKi included ruxolitinib (n=27), momelotinib (n=5), pacritinib (n=3), fedratinib (n=3), and BMS-911543 JAKi (n=5). Two patients underwent allogeneic stem cell transplant (ASCT) three and six months prior to splenectomy. Prior treatment included splenic radiation in 4 patients (median 0.6 years (0.2-1.2)). Pre-operative splenic embolization was performed in 4 patients on same day of splenectomy; one patient had embolization 10 months prior to splenectomy. Median interval from diagnosis to splenectomy was 10.3 years (1.0-35.4) and from initiation of JAKi therapy to splenectomy 1.8 years (0.03-12.1). Most patients had multiple indications for splenectomy including 76% with symptomatic splenomegaly, 50% with significant cytopenia, and 18% in preparation of ASCT. At time of splenectomy, median spleen size on imaging was 25.1 cm (14.7-36) and 55% were red cell transfusion-dependent (Revised international working group criteria). Postoperative complications were reported in 22 (65%) of patients. Major bleeding occurred in 11 (32%) (of which 7 (64%) required repeat surgical exploration) and thrombosis in 9 (26%); 5 patients experienced both major bleeding and thrombosis. Other complications included infection (n=5), renal injury (n=3), and pneumothorax (n=2). At a median follow up of 1.7 years (0.01-10.2) post-splenectomy, 12 (35%) ASCT were documented at a median of 2.3 years (1.5-26.4) post-procedure. Median post-splenectomy survival was 4.3 years (5-year survival 44%) and significantly longer in transplanted patients (median not reached vs 2.6 years; 5-year survival 65% vs 22%; p=0.02). Among patients without post-splenectomy ASCT (n=22), 12 (55%) deaths (including 2 from post-operative complications) and 3 leukemic transformations were recorded. Additionally, 13 of the 22 had transfusion-dependent anemia at splenectomy and subsequently 6 (46%) became transfusion-independent (TI) (≥12 weeks without transfusion) with median TI response duration of 2.8 years (0.3-7.1). In addition, among 5 non-transplanted patients with baseline thrombocytopenia (&lt; 50 x 109/L (16-42 x 109/L)), 4 (80%) had platelet count &gt; 100 x 109/L (median; 170 x 109/L, range: 119-279 x 109/L) within 3 months post-procedure. Conclusions: Splenectomy following JAKi-resistant or intolerant MF is associated with improvement of transfusion-dependent anemia (46% response), resolution of severe thrombocytopenia (80%), and may allow for successful transition to ASCT (35%). However, the procedure is associated with significant perioperative complications occurring in the majority of patients and underscores the need for future collaborative studies to develop selection criteria and evaluate alternative treatment modalities.

ABSTRACT Background Surgical resection for pancreas ductal adenocarcinoma (PDAC) remains the mainstay of treatment. Regardless of enhanced survival rates, disparities in patient outcomes and experiences driven by the social determinants of health (SDH) persist. The area deprivation index (ADI) comprises 17 indicators related to education, employment, housing‐quality, and poverty. We sought to examine the impact of ADI on surgical outcomes of PDAC patients. Methods Patients who underwent pancreatoduodenectomy or distal pancreatectomy for PDAC between January 2011 and December 2022 were identified. ADI was calculated using patient zip codes and categorized into quartiles, with the highest indicating the most marginalized. The primary outcome was loss to follow‐up after surgical resection. To account for confounders, a competing risk multivariable regression analysis was used. Results A total of 1001 patients had a mean age of 66.6 (±9.64), with 46.3% ( n = 463) of patients being female. A majority, 94.6% ( n = 947), identified as white, and 64.1% ( n = 641) had at least a college degree. The median length of follow‐up after surgery was 1.8 years (interquartile range: 0.9–3.5). Multivariable analysis adjusting for competing risk of death, showed that patients who are least marginalized are 1.57 times more likely to have their follow‐up than those most marginalized (hazard ratio: 1.57, 95% confidence interval: 1.08–2.29, p = 0.017). Conclusion SDH impact many aspects of patient's care including a higher risk of loss to follow‐up for marginalized patients after surgery for PDAC. Future efforts should seek to identify and lower barriers faced by marginalized patients with system‐level changes to ensure equitable access.