Molecular subtypes of lung adenocarcinoma present distinct immune tumor microenvironments.

Overcoming resistance to immune checkpoint inhibitors is an important issue in patients with non-small-cell lung cancer (NSCLC). Transcriptome analysis shows that adenocarcinoma can be divided into three molecular subtypes: terminal respiratory unit (TRU), proximal proliferative (PP), and proximal inflammatory (PI), and squamous cell carcinoma (LUSQ) into four. However, the immunological characteristics of these subtypes are not fully understood. In this study, we investigated the immune landscape of NSCLC tissues in molecular subtypes using a multi-omics dataset, including tumor-infiltrating leukocytes (TILs) analyzed using flow cytometry, RNA sequences, whole exome sequences, metabolomic analysis, and clinicopathologic findings. In the PI subtype, the number of TILs increased and the immune response in the tumor microenvironment (TME) was activated, as indicated by high levels of tertiary lymphoid structures, and high cytotoxic marker levels. Patient prognosis was worse in the PP subtype than in other adenocarcinoma subtypes. Glucose transporter 1 (GLUT1) expression levels were upregulated and lactate accumulated in the TME of the PP subtype. This could lead to the formation of an immunosuppressive TME, including the inactivation of antigen-presenting cells. The TRU subtype had low biological malignancy and "cold" tumor-immune phenotypes. Squamous cell carcinoma (LUSQ) did not show distinct immunological characteristics in its respective subtypes. Elucidation of the immune characteristics of molecular subtypes could lead to the development of personalized immune therapy for lung cancer. Immune checkpoint inhibitors could be an effective treatment for the PI subtype. Glycolysis is a potential target for converting an immunosuppressive TME into an antitumorigenic TME in the PP subtype.

Impact of Surgical Margin Status on Survival and Recurrence After Pancreaticoduodenectomy for Distal Cholangiocarcinoma: Is Microscopic Residual Tumor (R1) Associated with Higher Rates of Local Recurrence?

BACKGROUND: Patients undergoing macroscopically curative resection for distal cholangiocarcinoma (DCC) have high recurrence rates and poor prognoses. This study aimed to investigate the impact of surgical margin status on survival and recurrence after resection of DCC, specifically focusing on microscopic residual tumor (R1) and its relationship to local recurrence. PATIENTS AND METHODS: This was a retrospective analysis of patients who had undergone pancreaticoduodenectomy (PD) for DCC between 2005 and 2021. Surgical margin was classified as R0, R1cis (positive bile duct margin with carcinoma in situ), and R1inv (positive bile duct margin with an invasive subepithelial component and/or positive radial margin). RESULTS: In total, 29 of 133 patients (21.8%) had R1cis and 23 (17.3%) R1inv. The 5-year overall survival (OS) for R0 (55.7%) did not differ significantly from that for R1cis/R1inv (47.4%/33.6%, respectively). The 5-year recurrence-free survival (RFS) for R0 was significantly longer than that for R1inv (50.1% vs. 17.4%, p = 0.003), whereas RFS did not differ significantly between those with R0 and R1cis. R1cis/R1inv status was not an independent predictor of OS and RFS in multivariate analysis. Cumulative incidence of isolated distant recurrence was significantly higher for R1cis/R1inv than for R0 (p = 0.0343/p = 0.0226, respectively), whereas surgical margin status was not significantly associated with rates of local or local plus distant recurrence. CONCLUSIONS: Surgical margin status does not significantly impact OS and RFS in patients undergoing PD for DCC following precise preoperative imaging evaluation. Additionally, R1 status is significantly linked to higher isolated distant recurrence rather than local recurrence, highlighting the importance of multidisciplinary therapy.

Pathological complete response of initially unresectable multiple liver metastases achieved using combined peptide receptor radionuclide therapy and somatostatin analogs following pancreatic neuroendocrine tumor resection: a case report.

BACKGROUND: Peptide receptor radionuclide therapy (PRRT) serves as a novel and effective treatment option for somatostatin receptor-positive unresectable liver metastases of pancreatic neuroendocrine tumors (PNETs). However, there are few reported cases of surgical resection for initially unresectable liver metastases of PNET that were converted to resectable after PRRT. Here we report a case where PRRT and somatostatin analogs (SSAs) led to a pathological complete response of initially unresectable multiple liver metastases following PNET resection. CASE PRESENTATION: A 52-year-old man underwent pylorus-preserving pancreaticoduodenectomy for PNET at age 40 and subsequent hepatectomies for resectable liver metastases at 44 and 47 years of age. At age 48, a follow-up examination revealed unresectable multiple liver metastases, and PRRT with 177Lu-DOTATATE therapy was initiated. After four cycles of PRRT, most liver metastases diminished according to imaging studies, and the remaining two hepatic lesions continued to shrink with additional lanreotide. Conversion surgery for liver metastases was successfully performed, revealing no viable tumor cells in tissue specimens. Seventeen months after surgery, imaging showed no detectable residual tumor or recurrence. We present a review of the relevant literature that highlights the significance of our findings. CONCLUSIONS: This rare case highlights the pathological complete response of initially unresectable multiple liver metastases achieved by PRRT and SSAs following PNET resection, suggesting their potential as a multimodality treatment option for unresectable PNET.

Diagnostic performance of EUS-guided tissue acquisition for solid pancreatic lesions ≤10 mm.

Background and Objectives: EUS tissue acquisition (EUS-TA) is the standard diagnostic method for solid pancreatic lesions (SPLs); however, there are few reports on EUS-TA results for SPLs ≤10 mm. Furthermore, given the recent advent of fine-needle biopsy, the current diagnostic accuracy of EUS-TA for SPLs ≤10 mm is unknown. This study aimed to evaluate the diagnostic accuracy and efficacy of EUS-TA for SPLs ≤10 mm. Methods: We retrospectively analyzed the data of 109 patients with SPLs ≤10 mm who underwent EUS-TA. All patients underwent rapid on-site specimen evaluation. Results: The median tumor diameter was 8 mm (range, 2.5-10 mm), and the technical success rate was 99.1% (108/109). Adverse events were observed in 3 patients (2.8%). The diagnostic performance was as follows: sensitivity, 90.1% (64/71); specificity, 97.3% (36/37); accuracy, 92.6% (100/108); positive predictive value, 98.5% (64/65); and negative predictive value, 83.7% (36/43). Multivariate analysis revealed that the number of punctures (odds ratio, 7.03; 95% confidence interval, 1.32-37.5; P = 0.023) and tumor type (odds ratio, 11.90; 95% confidence interval, 1.38-102.0; P = 0.024) were independent risk factors for inaccurate EUS-TA results. The diagnostic accuracy of EUS-TA for pancreatic ductal adenocarcinoma was 87.5% (14/16). No EUS-TA-related needle-tract seeding was observed in patients with pancreatic ductal adenocarcinoma during the observation period. Conclusions: EUS-TA for SPLs ≤10 mm showed adequate diagnostic accuracy and was safe for use with rapid on-site specimen evaluation in all cases.

Trastuzumab Deruxtecan in Human Epidermal Growth Factor Receptor 2-Expressing Biliary Tract Cancer (HERB; NCCH1805): A Multicenter, Single-Arm, Phase II Trial.

PURPOSE: Treatment options for patients with unresectable or recurrent biliary tract cancer (BTC) who progress on a gemcitabine-containing regimen are limited. In addition, the significance of anti-human epidermal growth factor receptor 2 (HER2) therapy in HER2-expressing BTC has not been sufficiently investigated. METHODS: In this phase II trial, participants from five institutions in Japan were enrolled. Eligible patients had pathologically confirmed unresectable or recurrent BTC with centrally confirmed HER2-positive (immunohistochemistry [IHC]3+ or IHC2+ and in situ hybridization [ISH]+) or HER2-low (IHC2+ and ISH-, IHC1+, and IHC0 and ISH+) and were refractory or intolerant to a gemcitabine-containing regimen. The patients received 5.4 mg/kg trastuzumab deruxtecan (T-DXd) once every 3 weeks until disease progression or unacceptable toxicity. The primary end point was the confirmed objective response rate (ORR) in HER2-positive BTC by an independent central review (threshold ORR, 15%; expected ORR, 40%). RESULTS: A total of 32 patients were enrolled and treated. Among these patients, 22 with HER2-positive disease comprised the primary efficacy population and had a confirmed ORR of 36.4% (90% CI, 19.6 to 56.1; P = .01), meeting the primary end point. Eight with HER2-low disease comprised the exploratory population and had a confirmed ORR of 12.5%. The most common ≥grade 3 treatment-related adverse events were anemia (53.1%) and neutropenia (31.3%). Eight patients (25.0%) had interstitial lung disease (ILD), including two grade 5 events. CONCLUSION: T-DXd showed promising activity in patients with HER2-positive BTC and a signal of efficacy in patients with HER2-low BTC. Although the safety profile was generally manageable, ILD requires careful monitoring and early intervention.