Efficacy and Safety of Trastuzumab Deruxtecan and Nivolumab as Third- or Later-Line Treatment for HER2-Positive Advanced Gastric Cancer: A Single-Institution Retrospective Study.

PURPOSE: Determination of optimal treatment strategies for HER2-positive advanced gastric cancer (AGC) in randomized trials is necessary despite difficulties in direct comparison between trastuzumab deruxtecan (T-DXd) and nivolumab as third or later-line treatments. MATERIALS AND METHODS: This single-institution, retrospective study aimed to describe the real-world efficacy and safety of T-DXd and nivolumab as ≥ third line treatments for HER2-positive AGC between March 2016 and May 2022. Overall, 58 patients (median age, 64 years; 69% male) were eligible for the study (T-DXd group, n=20; nivolumab group, n=38). RESULTS: Most patients exhibited a HER2 3+ status (72%) and presented metastatic disease at diagnosis (66%). The response rates of 41 patients with measurable lesions in the T-DXd and nivolumab groups were 50% and 15%, respectively. The T-DXd and nivolumab groups had a median progression-free survival of 4.8 months (95% confidence interval [CI], 3.3, 7.0) and 2.3 months (95% CI, 1.5, 3.5), median overall survival (OS) of 10.8 months (95% CI, 6.9, 23.8) and 11.7 months (95% CI, 7.6, 17.1), and grade 3 or greater adverse event rates of 50% and 2%, respectively. Overall, 64% patients received subsequent treatment. Among 23 patients who received both regimens, the T-DXd-nivolumab and nivolumab-T-DXd groups had a median OS of 14.0 months (95% CI, 5.0, not reached) and 19.3 months (95% CI, 9.5, 25.1), respectively. CONCLUSIONS: T-DXd and nivolumab showed distinct efficacy and toxicity profiles as ≥ third line treatments for HER2-positive AGC. Considering the distinct features of each regimen, they may help clinicians personalize optimal treatment approaches for these patients.

Single-organ pulmonary metastasis is a favorable prognostic factor in metastatic colorectal cancer patients treated with FOLFIRI and vascular endothelial growth factor inhibitors.

BACKGROUND: Few studies have focused on the impact of single-organ pulmonary metastases on progression-free survival and overall survival in patients with metastatic colorectal cancer. Recognizing differences in prognosis and chemotherapeutic efficacy based on metastasized organs may help in optimizing treatment strategies. The exploratory study was conducted to evaluate the comparative clinical outcomes and prognoses of patients with metastatic colorectal cancer presenting with single-organ pulmonary metastases and treated with folinic acid, 5-fluorouracil, irinotecan, and vascular endothelial growth factor inhibitors as second-line chemotherapy. METHODS: This retrospective study included 289 patients with metastatic colorectal cancer treated with second-line folinic acid, 5-fluorouracil, irinotecan, and vascular endothelial growth factor inhibitors. The response rate, disease control rate, progression-free survival, and overall survival were assessed in the participants. RESULTS: Among the 289 patients enrolled, 26 (9.0%) had single-organ pulmonary metastasis with left-sided primary locations, lower levels of tumor markers at the initiation point of chemotherapy, a significantly higher disease control rate (96.2% vs. 76.7%, P = .02), and a longer progression-free survival (median 29.6 months vs. 6.1 months, P < .001) and overall survival (median 41.1 months vs. 18.7 months, P < .001) than patients with other forms of metastatic colorectal cancer. Multivariate analysis showed that single-organ pulmonary metastasis was an independent predictor of longer progression-free survival (hazard ratio 0.35, P = .00075) and overall survival (hazard ratio 0.2, P = .006). CONCLUSION: Single-organ pulmonary metastasis was a strong predictor of progression-free survival and overall survival in patients with metastatic colorectal cancer treated with folinic acid, 5-fluorouracil, irinotecan, and vascular endothelial growth factor inhibitors as second-line chemotherapy; this provides preliminary evidence for medical guidelines and clinical decision-making on novel therapeutic strategies for these patients.

Potent molecular-targeted therapies for gastro-entero-pancreatic neuroendocrine carcinoma.

Neuroendocrine neoplasms (NENs), which are characterized by neuroendocrine differentiation, can arise in various organs. NENs have been divided into well-differentiated neuroendocrine tumors (NETs) and poorly differentiated neuroendocrine carcinomas (NECs) based on morphological differentiation, each of which has a distinct etiology, molecular profile, and clinicopathological features. While the majority of NECs originate in the pulmonary organs, extrapulmonary NECs occur most predominantly in the gastro-entero-pancreatic (GEP) system. Although platinum-based chemotherapy is the main therapeutic option for recurrent or metastatic GEP-NEC patients, the clinical benefits are limited and associated with a poor prognosis, indicating the clinically urgent need for effective therapeutic agents. The clinical development of molecular-targeted therapies has been hampered due to the rarity of GEP-NECs and the paucity of knowledge on their biology. In this review, we summarize the biology, current treatments, and molecular profiles of GEP-NECs based on the findings of pivotal comprehensive molecular analyses; we also highlight potent therapeutic targets for future precision medicine based on the most recent results of clinical trials.

A multi-institutional observational study evaluating the incidence and the clinicopathological characteristics of NeoRAS wild-type metastatic colorectal cancer.

PURPOSE: As circulating tumor DNA (ctDNA) measurement becomes more widespread, the "NeoRAS" phenomenon, where tissue rat sarcoma viral oncogene homolog (RAS) status converts from mutant (MT) to wild-type (WT) after treatment in metastatic colorectal cancer (mCRC), is gaining attention because ineffective epidermal growth factor receptor (EGFR) inhibitors may made effective. This study investigated its incidence and clinicopathological characteristics. PATIENTS AND METHODS: In total, 107 mCRC patients (refractory or intolerant to previous chemotherapies) with tissue RAS MT were enrolled in four institutions from June 2021 to August 2022. The RAS status in ctDNA was assessed using OncoBEAM™ RAS CRC assay. Clinicopathologic features were compared between patients according to their RAS status in ctDNA, whether WT conversion was noted or not. RESULTS: The incidence rate of NeoRAS WT mCRC was 21.5% (23/107). According to tissue RAS mutation sites, NeoRAS WT frequency in patients with KRAS mutation in exon 2 was significantly lower than those in exon 3 and 4 or NRAS (18.2% [18/99] vs 62.5% [5/8], P = 0.011). Regarding clinical background, there were significant differences in NeoRAS WT frequency between male vs female patients (30.6% [19/62] vs 8.9% [4/45], P = 0.008), and absence vs presence of liver metastasis (38.6% [17/44] vs 9.5% [6/63], P < 0.001). Comparing the two groups divided by the median value, NeoRAS WT was associated with smaller tumor diameter (>60.9 mm vs ≤, 3.8% [2/53] vs 38.9% [21/54], P < 0.001), lower carcinoembryonic antigen level (>38.2 ng/ml vs ≤, 11.3% [6/53] vs 31.5% [17/54], P = 0.018), and lower carbohydrate antigen 19-9 level (>158.0 U/ml vs ≤, 9.4% [5/53] vs 33.3% [18/54], P = 0.004). In the logistic regression multivariate analysis, liver metastasis absence (Odds ratio [OR], 4.62; P = 0.019), smaller tumor diameter (OR, 7.92; P = 0.012), and tissue RAS MT in other than KRAS exon 2 (OR, 9.04; P = 0.026) were significantly related to the conversion to NeoRAS WT in ctDNA. CONCLUSIONS: Original RAS variants in tissue, tumor diameter, and liver metastasis are related to conversion to NeoRAS WT mCRC in ctDNA.

Circulating Tumor DNA: The Dawn of a New Era in the Optimization of Chemotherapeutic Strategies for Metastatic Colo-Rectal Cancer Focusing on RAS Mutation.

Genotyping of tumor tissues to assess RAS and BRAF V600E mutations enables us to select optimal molecularly targeted therapies when considering treatment strategies for patients with metastatic colorectal cancer. Tissue-based genetic testing is limited by the difficulty of performing repeated tests, due to the invasive nature of tissue biopsy, and by tumor heterogeneity, which can limit the usefulness of the information it yields. Liquid biopsy, represented by circulating tumor DNA (ctDNA), has attracted attention as a novel method for detecting genetic alterations. Liquid biopsies are more convenient and much less invasive than tissue biopsies and are useful for obtaining comprehensive genomic information on primary and metastatic tumors. Assessing ctDNA can help track genomic evolution and the status of alterations in genes such as RAS, which are sometimes altered following chemotherapy. In this review, we discuss the potential clinical applications of ctDNA, summarize clinical trials focusing on RAS, and present the future prospects of ctDNA analysis that could change daily clinical practice.

Endoscopic Bridge-and-Seal of Bile Leaks Using a Fully Covered Self-Expandable Metallic Stent above the Papilla.

BACKGROUND/AIMS: Endoscopic management by endoscopic sphincterotomy with or without plastic stents or fully covered self-expandable metallic stents (FCSEMSs) is widely accepted as the current standard of care for postoperative bile leaks. Biliary stents are placed across the papilla, not above the papilla. We investigated the safety and effectiveness of the bridge-and-seal technique for bile leaks by the placement of FCSEMS above the papilla. METHODS: This was a retrospective study of FCSEMS placement above the papilla for bile leaks between October 2016 and July 2021. FCSEMS was placed above the papilla to bridge and seal the leak. The main outcome measures were the resolution of bile leaks and adverse events. RESULTS: Seven patients with postoperative bile leaks underwent FCSEMS above the papilla. The locations of bile leaks were 1 cystic duct remnant; 2 intrahepatic bile duct; 1 hepatic duct; 2 common bile duct and 1 anastomosis. The technical success rate of FCSEMS placement was 100%, and resolution of bile leaks was achieved in five patients (71.4%). All the adverse events were observed after FCSEMS removal; as follows: 1 moderate cholangitis; 2 mild post-ERCP pancreatitis; and 1 mild remnant cholecystitis. CONCLUSIONS: FCSEMS placement above the papilla can be a treatment option for postoperative bile leaks.

Comparison of Treatment Outcomes Between Gemcitabine With Nab-Paclitaxel and Modified FOLFIRINOX for First-Line Chemotherapy in Metastatic and Recurrent Pancreatic Cancer: Propensity Score Matching.

OBJECTIVES: To compare the treatment outcomes of gemcitabine with nab-paclitaxel (GnP) and modified FOLFIRINOX (mFFX; a combination of fluorouracil, leucovorin, irinotecan, and oxaliplatin) for metastatic pancreatic cancer. METHODS: We retrospectively analyzed consecutive patients with metastatic or recurrent pancreatic cancer treated with GnP or mFFX as the first-line chemotherapy between March 2014 and December 2019 in our hospital. Treatment outcomes were compared using propensity score matching to adjust for age, sex, performance status, carcinoembryonic antigen levels, carbohydrate antigen 19-9 levels, and disease status (metastatic or recurrent). RESULTS: Five hundred sixty-eight patients were included (GnP/mFFX, 456/112). After propensity score matching, 218 patients were extracted. The median age was around 61 years, and the proportion of performance status 0 was approximately 90%. The median overall survival values were 14.6 and 15.5 months (P = 0.45), and the median progression-free survival was 7.4 months (P = 0.53) for GnP and mFFX, respectively. The disease control rates were higher in the GnP group (82.6% vs 67.9%, P = 0.02). In nonhematologic adverse events, grade 3/4 anorexia and diarrhea occurred significantly more frequently in the mFFX group. CONCLUSIONS: Gemcitabine with nab-paclitaxel had a higher disease control rate and lower rates of severe anorexia and diarrhea in our propensity-matched population.

Risk factors for gemcitabine plus nab-paclitaxel-induced interstitial lung disease in pancreatic cancer patients.

BACKGROUND: Drug-induced interstitial lung disease (ILD) is one of the most serious adverse events with a high mortality rate and represents a serious clinical problem. However, gemcitabine plus nab-paclitaxel (GnP)-induced ILD in pancreatic cancer (PC) patients has not been thoroughly investigated. Therefore, we conducted this study to examine the clinical characteristics of GnP-induced ILD and identify risk factors for developing ILD. METHODS: We retrospectively investigated consecutive patients with PC who received GnP between January 2015 and April 2020. We compared the clinical characteristics and overall survival (OS) according to ILD occurrence and explored risk factors including ABO blood type for developing ILD. RESULTS: Of the 910 patients included in this study, ILD occurred in 20 patients (2.2%). PC patients who developed ILD had a significantly higher frequency of blood type B compared to those without ILD (42% vs. 22%, p ˂ 0.05). Other baseline characteristics including smoking history and current/previous lung disease were not different between the two groups. Median time from initiation of GnP to onset of ILD was 80 days. All patients recovered from ILD and OS was not significantly different according to ILD occurrence. Multivariate analysis revealed that blood type B was an independent risk factor for developing ILD. CONCLUSIONS: We demonstrated that GnP-induced ILD occurred in 2.2% of PC patients with no mortality and OS did not differ according to ILD occurrence. Furthermore, we clarified that ABO blood type B was an independent risk factor for developing ILD in PC patients receiving GnP.

A case of percutaneous transhepatic portal vein stent placement and endoscopic injection sclerotherapy for duodenal variceal rupture occurring during chemotherapy for unresectable perihilar cholangiocarcinoma.

Duodenal varices are ectopic varices that are rare but can involve any site along the digestive tract outside the gastroesophageal region. Ectopic variceal bleeding is generally massive and life threatening; the mortality rate is approximately 40%. Up to 17% of ectopic varices occur in the duodenum. However, duodenal varices pose a significant therapeutic challenge due to the lack of standard treatment guidelines. We report a case of duodenal variceal bleeding secondary to portal vein stenosis in a 77-year-old woman receiving chemotherapy for unresectable perihilar cholangiocarcinoma. The patient presented with melena, nausea, vomiting and unstable vital signs suggestive of hemorrhagic shock. Emergency esophagogastroduodenoscopy revealed large nodular varices with a ruptured erosion on top in the superior duodenal angle, and variceal bleeding had stopped by the time of the procedure. Subsequent computed tomography showed the development of portosystemic collaterals; therefore, we performed percutaneous portal vein stent placement to reduce portal vein pressure. Since persistent bleeding was suspected, we also performed endoscopic injection sclerotherapy and achieved successful hemostasis with an improvement in liver function. This case revealed that a combination of portal vein stent placement and endoscopic injection sclerotherapy might be an effective therapy for duodenal variceal bleeding caused by portal vein stenosis.

Modified FOLFIRINOX as a second-line therapy following gemcitabine plus nab-paclitaxel therapy in metastatic pancreatic cancer.

BACKGROUND: There is no established second-line treatment after failure of gemcitabine plus nab-paclitaxel (GnP) therapy for metastatic pancreatic cancer (MPC). The purpose of this study was to evaluate the efficacy and tolerability of the modified FOLFIRINOX (mFFX) as a second-line therapy for MPC and to investigate prognostic factors for survival. METHODS: From 2015 to 2019, we retrospectively reviewed the medical records of consecutive patients receiving mFFX for MPC after failure of GnP therapy. Patients were treated every 2 weeks with mFFX (intravenous oxaliplatin 85 mg/m2, intravenous irinotecan 150 mg/m2, and continuous infusion of 5-fluorouracil 2400 mg/m2 for 46 h without bolus infusion). RESULTS: In total, 104 patients received mFFX. The median overall survival (OS) was 7.0 months (95% confidence interval [CI]: 6.2-9.8) and the progression-free survival (PFS) 3.9 months (95% CI 2.8-5.0). The objective response rate was 10.6% and the disease control rate 56.7%. The median relative dose intensities of oxaliplatin, irinotecan, and infusional 5-FU were 80.0% (range 21.5-100%), 77.2% (range 38.1-100%), and 85.9% (range 36.9-100%), respectively. Grade 3-4 toxicities were reported in 57 patients (54.8%), including neutropenia, leukopenia, anemia, febrile neutropenia, and peripheral sensory neuropathy. Glasgow prognostic score and carcinoembryonic antigen level were independently associated with survival. Our prognostic model using these parameters could classify the patients into good (n = 38), intermediate (n = 47), and poor (n = 19) prognostic groups. The median OS and PFS time was 14.7 (95% CI 7.6-16.3) and 7.6 months (95% CI 4.1-10.5) for the good prognostic factors, 6.5 (95% CI 5.5-10.0) and 3.6 months (95% CI 2.7-4.8) for the intermediate prognostic factors and 5.0 (95% CI 2.9-6.6) and 1.7 months (95% CI 0.9-4.3) for the poor prognostic factors, respectively. CONCLUSIONS: The mFFX showed to be a tolerable second-line treatment for MPC after GnP failure. Our prognostic model might be useful for deciding whether mFFX is indicated in this setting.