Yasuyuki Kawamoto

Polyploid giant cancer cells (PGCCs) are characterized by abnormal enlargement and considerable polyploidy. Though the presence of giant cancer cells has been documented for decades, they remain not fully understood, especially in clinical practice, due to diagnostic challenges, and confusion regarding synonyms for PGCCs still exists. Thus, understanding PGCCs may be a key clue to overcoming them. This review offers a comprehensive overview of PGCCs, integrating insights from basic research and clinical studies to enhance understanding of their complex biology and clinical implications. In basic research, PGCCs are known to emerge under various stressors, including chemotherapy exposure, radiation, viral infection, and hypoxic environments. These cells play crucial roles in tumor progression through multiple mechanisms: enhancing genetic diversity, and facilitating metastatic spread via asymmetrical cell division and genomic instability. In clinical studies, PGCC-containing tumors have been shown to exhibit marked treatment resistance and are associated with a poor prognosis across multiple solid tumor types, including prostate, lung, and pancreatic cancers. Despite these therapeutic challenges, taxane-based chemotherapy has shown promising results in PGCC-containing tumors, such as pleomorphic carcinoma and undifferentiated carcinoma. Furthermore, emerging targeted therapies directed at specific pathways in PGCCs, particularly those involving TP53, represent potential strategies to improve clinical outcomes of patients with PGCC-containing tumors.

Background: Ramucirumab has shown efficacy in combination with paclitaxel in the second-line treatment of advanced gastric cancer (AGC). The efficacy and safety regarding the combination therapy of ramucirumab and docetaxel have not been reported. This treatment could reduce the incidence of neuropathy and patients’ hospital visits. Methods: This was a multicenter, single-arm phase II trial. Patients with AGC who were refractory or intolerant to primary treatment were eligible. Patients received ramucirumab at a dose of 8 mg/kg on day1 and 15, and docetaxel at a dose of 60 mg/m ² on day1 of a 28-day cycle. The primary endpoint was overall response rate (ORR). The secondary endpoints were progression-free survival (PFS), overall survival (OS), relative dose intensity, and safety. Results: A final analysis of efficacy and safety was performed in 35 patients. ORR was 25.7% (90% confidence interval [CI] 14.1–40.6) and disease control rate was 74.3% (90%CI 59.4–85.9). Median PFS and OS were 3.1 months (95%CI 2.1–4.2) and 11.5 months (95%CI 9.2–13.9), respectively. Grade 3 or higher adverse events that occurred in more than 10% of patients were neutropenia, leucopenia, febrile neutropenia, hypertension, and anorexia. The study protocol was amended to allow primary granulocyte-colony stimulating factor (G-CSF) prophylaxis during study period. There was no one incident febrile neutropenia after the protocol amendment. Peripheral sensory neuropathy occurred in 65.7% of all grades, with no incidence of grade 3 or higher. Conclusions: The combination therapy of ramucirumab and docetaxel demonstrated some efficacy for AGC. Caution is required regarding the occurrence of febrile neutropenia. This treatment might be considered as an option for second-line treatment of patients with AGC.

Polyploid giant cancer cells (PGCCs) are characterized by abnormal enlargement and considerable polyploidy. Though the presence of giant cancer cells has been documented for decades, they remain not fully understood, especially in clinical practice, due to diagnostic challenges, and confusion regarding synonyms for PGCCs still exists. Thus, understanding PGCCs may be a key clue to overcoming them. This review offers a comprehensive overview of PGCCs, integrating insights from basic research and clinical studies to enhance understanding of their complex biology and clinical implications. In basic research, PGCCs are known to emerge under various stressors, including chemotherapy exposure, radiation, viral infection, and hypoxic environments. These cells play crucial roles in tumor progression through multiple mechanisms: enhancing genetic diversity, and facilitating metastatic spread via asymmetric cell division and genomic instability. In clinical studies, PGCC-containing tumors have been shown to exhibit marked treatment resistance and are associated with a poor prognosis across multiple solid tumor types, including prostate, lung, and pancreatic cancers. Despite these therapeutic challenges, paclitaxel-containing regimens have shown promising results in PGCC-containing tumors, such as pleomorphic carcinoma of the lung and undifferentiated carcinoma of the pancreas. Furthermore, emerging targeted therapies directed at specific pathways in PGCCs, particularly those involving TP53, represent potential strategies to improve clinical outcomes of patients with PGCC-containing tumors.

The prognosis of sarcopenia is poor in cancer patients. Recently, urinary titin, a biomarker of muscle damage, has been suggested as a potential marker for sarcopenia. However, its utility in patients with unresectable digestive malignancies remains unclear. In addition, sex differences have been reported in the association between sarcopenia and urinary titin levels. This study aimed to evaluate urinary titin as a diagnostic marker for unresectable digestive malignancies, focusing on sex differences. This retrospective study enrolled 96 patients (58 males, 38 females; median age 70), and urinary titin was evaluated as a diagnostic biomarker in relation to clinical factors (e.g., age, Eastern Cooperative Oncology Group performance status [ECOG PS], albumin [Alb]) and muscle indicators (e.g., psoas muscle index [PMI], handgrip strength). In male patients, urinary titin levels were significantly higher in the sarcopenia subgroup (5.78 vs. 2.79 pmol/mgCr, p = 0.008), and multivariate analyses identified urinary titin as an independent predictor of sarcopenia (odds ratio 13.4, p = 0.028). The receiver operating characteristic (ROC) analysis demonstrated fair diagnostic performance (area under the curve [AUC] 0.729), with an optimal cutoff value of 3.676 pmol/mgCr. Urinary titin may serve as a useful non-invasive diagnostic biomarker for sarcopenia in patients with unresectable digestive malignancies, particularly in males. These findings suggest that sex-specific approaches are required for sarcopenia assessment with urinary titin.

Purpose Pancreatic ductal adenocarcinoma (PDAC) has a poor prognosis. Despite the use of aggressive combination chemotherapy regimens, outcomes remain unsatisfactory. Schlafen family member 11 (SLFN11) has been reported to regulate the DNA damage response and influence tumor sensitivity to certain chemotherapeutic agents. This study aimed to investigate the expression of SLFN11 in PDAC and its potential as a biomarker for predicting treatment efficacy and survival outcomes. Methods This retrospective observational cohort study included 158 patients with unresectable or borderline resectable PDAC who received palliative chemotherapy. Patients were classified into three groups: metastatic, locally advanced, and borderline resectable PDAC. Immunohistochemical staining for SLFN11 was performed on biopsy specimens, and expression levels were quantified using the histo-score (H-score). Associations between SLFN11 expression and clinical outcomes, including progression-free survival and overall survival, were analyzed using Kaplan–Meier methods and Cox regression models. Results SLFN11 expression was observed in 54.4% of PDAC tissues. The median H-score for SLFN11 expression was higher in metastatic cases than in locally advanced and borderline resectable cases. However, no significant association was found between SLFN11 expression and the efficacy of chemotherapy or clinical outcomes. Conclusion Despite the hypothesized role of SLFN11 as a predictive biomarker for chemotherapy efficacy, no significant association was found between SLFN11 expression and clinical outcomes in PDAC. Further studies with larger cohorts and more detailed staging are needed to clarify the potential utility of SLFN11 as a therapeutic biomarker in PDAC.

PURPOSE: This study aimed to investigate the clinicomolecular profiles and the efficacy of human epidermal growth factor receptor 2 (HER2)-targeted therapy in HER2 -amplified biliary tract cancer (BTC). METHODS: This study was an international collaboration that used combined data from the prospective SCRUM-Japan GOZILA and MONSTAR-SCREEN in Japan and retrospective reviews in the United States; patients with advanced BTC who had received systemic therapy were included. The clinicomolecular profiles were evaluated in an exploratory cohort, whereas the efficacy of HER2-targeted therapy was assessed in a biomarker-selected cohort. RESULTS: Of the 439 patients in the exploratory cohort, 43 (10%) had HER2 amplification. The frequencies of coalterations were higher in patients with HER2 amplification versus patients without HER2 amplification including HER2 mutations (26% v 5%, P < .001), TP53 mutations (84% v 61%, P = .003), and BRAF amplification (9% v 2%, P = .030). There were no KRAS mutations identified in patients with HER2- amplified BTC. No significant difference in overall survival (OS) was observed between patients with and without HER2 amplification (median, 17.7 v 16.9 months; hazard ratio [HR], 0.95 [95% CI, 0.65 to 1.40]). Of the 60 patients with HER2 -amplified BTC in the biomarker-selected cohort (43 from Japan and 17 from the United States), the OS was significantly longer in 29 patients who received HER2-targeted therapy than in those who did not receive HER2-targeted therapy (median, 24.3 v 12.1 months; HR, 0.39 [95% CI, 0.23 to 0.82]). Multivariate analysis identified HER2-targeted therapy as an independent prognostic factor for OS (HR, 0.29 [95% CI, 0.14 to 0.58]; P < .001). CONCLUSION: HER2 amplification was found in 10% of advanced BTC and was not identified as an independent prognostic factor for OS. Patients with HER2 -amplified BTC derive significant benefit from HER2-targeted therapy.

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.

Due to the widespread use of cancer genetic testing in gastrointestinal cancer, the BRCA1/2 genetic mutation has been identified in biliary tract cancer as well as pancreatic cancer. Niraparib is a... Plain language summary – A clinical study to confirm the efficacy and safety of niraparib for people with advanced biliary tract, pancreatic and other abdominal cancers with the BRCA genetic mutati...