Reappraisal of the current resectability criteria and optimal treatment strategies for pancreatic cancer.

Background: Recent advances in anticancer treatment and prolonged survival are the background of this study. The study aimed to reappraise the Japan Pancreas Society (JPS) resectability criteria in pancreatic cancer and to propose optimal treatment strategies. Methods: Three hundred ninety-six consecutive patients with curative-intent surgery for pancreatic cancer from April 2011 to December 2022 were included. Overall survival based on the resectability criteria was analyzed, and Cox regression analyses were performed to identify factors associated with overall survival. Results: The median survival times (MSTs) based on the current resectability status were 37.4, 20.1, and 26.6 months in resectable (R), in borderline resectable (BR), and unresectable (UR) disease, respectively (P<0.001), revealing an inversion phenomenon between BR and UR. Using the International Association of Pancreatology (IAP) criteria, the MST of biological BR disease was demonstrably worse than that of R disease (27.1 vs. 40.7 months, P=0.04), but no difference was observed between classical BR and UR locally advanced disease (18.8 vs. 18.7 months, P=0.97). Rather, ≤180° superior mesenteric artery (SMA) invasion was a more powerful prognostic factor than >180° SMA/celiac artery invasion in multivariate analysis (hazard ratio: 2.101, 95% confidence interval: 1.296-3.404, P=0.003). When biological BR was combined with BR, and BR with artery invasion was considered locally advanced disease as a new resectability criterion, the MSTs were 38.8, 23.5, and 18.5 months in the new R, new BR, and locally advanced groups, respectively (P<0.001). Conclusions: The decision-making and treatment strategies based on our new classification in pancreatic cancer are considered reasonable for clinical practice.

Three Molecular Developmental Pathways of Remnant Pancreatic Cancer after Resection: A Nationwide Project Study of Japan Pancreas Society.

OBJECTIVE: This study aimed to clarify the molecular mechanism of remnant pancreatic cancer (PC) development after primary PC resection. SUMMARY BACKGROUND DATA: Molecular mechanisms of the development of remnant PCs following primary PC resection are largely unknown. METHODS: Forty-three patients undergoing remnant PC resection after primary PC resection between 2001 and 2017 at 26 institutes were retrospectively analyzed. Clinicopathological features and molecular alterations detected by targeted amplicon sequencing of 36 PC-associated genes were evaluated. RESULTS: These patients showed significantly lower body mass indices and higher hemoglobin A1c values at remnant PC resection than at primary PC resection. A comparison of the molecular features between primary and remnant PCs indicated that remnant PCs were likely to develop via three different molecular pathways: successional, showing identical and accumulated alterations (n=14); phylogenic, showing identical and distinct alterations (n=26); and distinct, showing independent distinctive alterations (n=3). The similarity of gene alterations was associated with time to the remnant PC development (r=－0.384, P=0.0173). Phylogenic pathways were significantly associated with the intraductal spread of carcinoma (P=0.007). Patient survival did not differ significantly depending on these molecular pathways. CONCLUSION: Molecular profiling uncovered three pathways for the development of remnant PCs, namely, successional, phylogenic, and distinct pathways. The vast majority of remnant PCs are likely to be molecularly associated with primary PCs either in the successional or phylogenic way. This information could impact the design of a strategy for monitoring and treating remnant PCs.

The survival in octogenarians undergoing surgery for pancreatic cancer and its association with the nutritional status.

PURPOSES: This study explored the association between the nutritional status and survival outcomes after pancreatic cancer surgery and reconsidered surgical indications in octogenarians. METHODS: Three hundred and ninety-three consecutive pancreatic cancer patients who underwent resection were analyzed and grouped according to age (< 70 years old; septuagenarians [70-79 years old], and octogenarians [80-89 years old]). The Charlson age comorbidity index and nutritional parameters were recorded. Survival outcomes and their association with nutritional parameters and prognostic factors were examined. RESULTS: The overall survival was worse in the octogenarians than in other patients. The median overall survivals in the < 70 years old group, septuagenarians, and octogenarians were 27.2, 26.4, and 15.3 months, respectively (P = 0.0828). DUPAN-2 ≥ 150 U/mL, borderline resectable/unresectable tumors, blood loss volume ≥ 500 mL, and blood transfusion were predictors of the overall survival among octogenarians. Nutritional parameter values were worse in the octogenarians than in other patients. The octogenarian age group was not an independent predictor of postoperative complications in a univariate analysis. CONCLUSIONS: Survival outcomes were poor in octogenarians. However, an age ≥ 80 years old alone should not be considered a contraindication for pancreatic cancer surgery. The maintenance of perioperative nutritional status is an important factor associated with the survival.

Impact of molecular surgical margin analysis on the prediction of pancreatic cancer recurrences after pancreaticoduodenectomy.

BACKGROUND: Pancreatic cancer is one of the lethal cancers among solid malignancies. Pathological diagnosis of surgical margins is sometimes unreliable due to tissue shrinkage, invisible field cancerization and skipped lesions like tumor budding. As a result, tumor recurrences sometimes occur even from the pathologically negative surgical margins. METHODS: We applied molecular surgical margin (MSM) analysis by tissue imprinting procedure to improve the detection sensitivity of tiny cancerous cells on the surgical specimen surface after pancreatoduodenectomy. Surgical specimens were collected from 45 pancreatic cancer cases who received subtotal stomach preserving pancreatoduodenectomy at Nagoya University Hospital during 2017-2019. Quantitative methylation-specific PCR (QMSP) of the original methylation marker panel (CD1D, KCNK12, PAX5) were performed and analyzed with postoperative survival outcomes. RESULTS: Among 45 tumors, 26 cases (58%) were QMSP-positive for CD1D, 25 (56%) for KCNK12 and 27 (60%) for PAX5. Among the 38 tumors in which at least one of the three markers was positive, CD1D-positive cancer cells, KCNK12-positive cancer cells, and PAX5-positive cancer cells were detected at the surgical margin in 8 cases, 7 cases and 10 cases, respectively. Consequently, a total of 17 patients had at least one marker detected at the surgical margin by QMSP, and these patients were defined as MSM-positive. They were associated with significantly poor recurrence-free survival (p = 0.002) and overall survival (p = 0.005) than MSM-negative patients. Multivariable analysis showed that MSM-positive was the only significant independent factor for worse recurrence-free survival (hazard ratio: 3.522, 95% confidence interval: 1.352-9.179, p = 0.010). On the other hand, a significant proportion of MSM-negative cases were found to have received neoadjuvant chemotherapy (p = 0.019). CONCLUSION: Pancreatic cancer-specific methylation marker panel was established to perform MSM analysis. MSM-positive status might represent microscopically undetectable cancer cells on the surgical margin and might influence the postoperative long-term outcomes.

Novel prognostic implications of YTH domain family 2 in resected hepatocellular carcinoma.

N6-methyladenosine (m6A), the most abundant internal RNA modification, serves a critical role in cancer development. However, the clinical implications of m6A in hepatocellular carcinoma (HCC) remain unclear. The present study sought to reveal the potential roles of m6A readers, which recognize m6A, in HCC. A total of 177 HCC and paired non-cancerous liver tissues from patients who underwent hepatectomy were analysed using quantitative PCR for the expression of m6A readers: YT521-B homology domain family 1 (YTHDF1) and YT521-B homology domain family 2 (YTHDF2). The expression levels of both YTHDF1 and YTHDF2 were not significantly different between tumour and non-cancerous tissues (P=0.93 and P=0.7, respectively). Analysis of the association between clinical features and m6A reader expression revealed that YTHDF1 expression was associated with formation of capsule (P=0.02), whereas low YTHDF2 expression was associated with septal formation (P=0.02). Furthermore, high YTHDF1 expression and high YTHDF2 expression were significantly associated with shorter recurrence-free survival (RFS) [YTHDF1: Mean survival time (MST), 34.0 vs. 19.0 months, P=0.014; YTHDF2: MST, 30.1 vs. 12.9 months, P=0.0032], whereas YTHDF1 and YTHDF2 expression was not significantly associated with overall survival (OS) (YTHDF1: MST, 99.4 vs. 70.2 months, P=0.74; YTHDF2: MST, 98.4 vs. 64.1 months, P=0.28). According to multivariate analysis, serosal invasion [hazard ratio (HR), 2.39; 95% CI 1.30-4.42; P=0.005), portal vein or hepatic vein invasion (HR, 2.82; 95% CI 1.26-6.28; P=0.01) and YTHDF2 expression in HCC tissues (HR, 1.85; 95% CI 1.09-3.15; P=0.02) were identified as significant independent prognostic factors for RFS. α-fetoprotein (HR, 1.79; 95% CI 1.10-2.92; P=0.02), serosal invasion (HR, 1.99; 95% CI 1.17-3.34; P=0.01) and portal vein or hepatic vein invasion (HR, 3.02; 95% CI 1.38-6.61; P=0.006) were identified as significant independent prognostic factors for OS. In conclusion, the present study revealed that high YTHDF2 expression, an m6A reader, in HCC tissues was associated with cancer recurrence.

Genome-wide identification and characterization of circular RNA in resected hepatocellular carcinoma and background liver tissue.

Circular RNA (circRNA) is a type of non-coding RNA known to affect cancer-related micro RNAs and various transcription factors. circRNA has promise as a cancer-related biomarker because its circular structure affords high stability. We found using high-throughput sequencing that seven candidate circRNAs (hsa_circ_0041150, hsa_circ_0025624, hsa_circ_0001020, hsa_circ_0028129, hsa_circ_0008558, hsa_circ_0036683, hsa_circ_0058087) were downregulated in HCC. The expression of these circRNAs was examined by quantitative PCR in 233 sets of HCC and matched background normal liver tissues, and correlations between candidate circRNA expression and prognosis were evaluated. The results of quantitative PCR showed that expression of hsa_circ_0041150, hsa_circ_0001020 and hsa_circ_0008558 was significantly lower in HCC than in background normal liver tissues. Kaplan-Meier analysis revealed that low expression of hsa_circ_0001020, hsa_circ_0036683, and hsa_circ_0058087 was associated with poor recurrence-free (RFS) and overall survival (OS) in HCC. Additionally, multivariate analysis revealed that low hsa_circ_0036683 expression was a significant prognostic factor, independent from other clinicopathological features, for inferior RFS and OS. There was no significant association between the expression of these circRNAs and hepatitis B/C status or cirrhosis. This study therefore identified circRNAs as potential prognostic markers for patients who undergo curative surgery for HCC and highlighted hsa_circ_0036683 as the most useful biomarker.

Perioperative assessment of indocyanine green elimination rate accurately predicts postoperative liver failure in patients undergoing hepatectomy.

BACKGROUND: This study aimed to evaluate the usefulness of perioperative indocyanine green elimination rate (ICG-K) as a predictive factor of posthepatectomy liver failure (PHLF). METHODS: This study enrolled 193 patients who underwent hepatectomy between 2013 and 2019. We analyzed the relationship between estimated ICG-K (ICG-Krem) calculated by the preoperative ICG-K and the residual liver volume ratio, ICG-K at days 1 and 7 after hepatectomy (ICG-Kpod1, ICG-Kpod7), and grade B or C PHLF. RESULTS: Grade B and C PHLF were observed in eight and two patients, respectively. ICG-Krem and ICG-Kpod1 were highly correlated (correlation coefficient [CC] 0.715), and ICG-Krem and ICG-Kpod7 were moderately correlated (CC 0.653). Receiver-operating characteristic curve analyses indicated that ICG-Krem and ICG-Kpod1 had moderate diagnostic value, while ICG-Kpod7 had high diagnostic value (area under the curve 0.703, 0.845 and 0.937, respectively). Multivariate analysis demonstrated that ICG-Kpod7 (relative risk [RR] 26.04, P = .012) and postoperative bile leakage (PBL) (RR 226.0, P < .001) were independent predictive factors for PHLF. PBL induced PHLF in seven patients, respectively. CONCLUSIONS: ICG-Krem correlated well with postoperative ICG-K, having moderate accuracy as a predictor of PHLF. However, the clinical relevance of postoperatively measuring ICG-K is limited because PHLF is greatly affected by surgical and postoperative factors.

Novel Prognostic Implications of Methylated RNA and Demethylases in Resected HCC and Background Liver Tissue.

BACKGROUND/AIM: N6-Methyladenosine (m6A), the most abundant internal modification of RNA, plays a critical role in cancer development. However, the clinical implications of m6A in hepatocellular carcinoma (HCC) remain unclear. MATERIALS AND METHODS: We analyzed 177 HCC and paired noncancerous liver tissues from patients who underwent hepatectomy according to global m6A quantification and expression of m6A demethylases fat mass and obesity-associated protein (FTO) and alpha-ketoglutarate-dependent dioxygenase alkB homolog 5 (ALKBH5). RESULTS: The global m6A quantification revealed no significant difference between HCC and non-cancerous tissue. The expression of m6A demethylases FTO and ALKBH5, was significantly lower in HCC than in non-cancerous tissues (both p<0.001). Furthermore, low ALKBH5 expression in non-cancerous tissues was significantly correlated with worse recurrence-free survival (median of 16.3 vs. 38.9 months, p=0.001). CONCLUSION: m6A in HCC and its demethylase in surrounding non-cancerous liver tissues might be involved in inherent mechanisms for HCC development and affect malignant potential after HCC resection.

Exploration of Exosomal Micro RNA Biomarkers Related to Epithelial-to-Mesenchymal Transition in Pancreatic Cancer.

BACKGROUND/AIM: Epithelial-to-mesenchymal transition (EMT) plays important roles in cancer progression. This study aimed to identify the exosomal miRNA (exo-miRNA) profiles related to the EMT status in pancreatic cancer (PC). MATERIALS AND METHODS: Comprehensive exo-miRNA-expression profiles in the culture media of PC cell lines were analyzed through microarray technology. The identified miRNAs were analyzed to investigate their clinical implication using The Cancer Genome Atlas (TCGA) dataset and clinical samples. RESULTS: We prioritized 291 exo-miRNAs differentially expressed between epithelial and mesenchymal cell types. Among them, survival analysis based on the TCGA dataset revealed that mir-196b and mir-204 significantly stratify the prognosis of PC cases. In addition, analysis of cell lines indicated miR-196b-3p as a mesenchymal marker and miR-204-3p as an epithelial marker. Finally, we demonstrated that miR-196b-3p and miR-204-3p in serum exosomes were differentially expressed among intraductal papillary mucinous neoplasms, mucinous cystic neoplasms, and PC. CONCLUSION: Serum exo-miRNA biomarkers potentially identify the pancreatic tumor status through less-invasive methods.

Novel Prognostic Implications of DUPAN-2 in the Era of Initial Systemic Therapy for Pancreatic Cancer.

BACKGROUND: This study aimed to explore the impact of serum tumor markers on survival for patients with pancreatic cancer (PC) who received initial systemic therapy (IST) followed by surgery. METHODS: Between April 2010 and July 2018, 285 consecutive patients who underwent curative intent surgery for PC were enrolled in the study. The relation between carbohydrate antigen 19-9 and duke pancreatic monoclonal antigen type 2 (DUPAN-2) after IST was analyzed as well as PC prognosis. RESULTS: The study identified 95 patients who underwent systemic chemotherapy with or without radiotherapy as IST from the our prospectively maintained database at the Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, Nagoya, Japan. Survival analysis of the 95 patients showed significant differences in recurrence-free survival (RFS) and overall survival (OS) between the DUPAN-2-normalized (D-normalized) and DUPAN-2-unnormalized (D-unnormalized) groups (median RFS, 24.1 vs. 14.2 months, p = 0.003; median OS, not reached vs. 29.6 months, p = 0.003). In addition, a tendency of differences in survival was observed between the D-normalized and D-unnormalized groups with borderline resectable PC (RFS, 20.1 vs. 14.2 months, p = 0.052; OS, not reached vs. 29.6 months, p = 0.081), and significant differences in survival were observed between the D-normalized and D-unnormalized groups with unresectable PC (RFS, 25.1 vs. 12.1 months, p < 0.001; OS, not reached vs. 11.4 months, p < 0.001). Furthermore, multivariate analysis demonstrated that normalized DUPAN-2 independently predicted survival of resected PC [RFS: hazard ratio (HR) 2.180; 95% confidence interval (CI) 1.16-4.08, p = 0.015; OS: HR 2.806; 95% CI 1.19-6.62, p = 0.018]. CONCLUSIONS: During IST, DUPAN-2 normalization may potentially predict prolonged survival for PC patients and optimal timing for conversion surgery in IST.

Comparison of non-invasive liver reserve and fibrosis models: Implications for surgery and prognosis for hepatocellular carcinoma.

AIM: This study aimed to assess the clinical utility of preoperative evaluation of liver fibrosis using platelet-albumin-bilirubin (PALBI) grade, Fibrosis-4 index (FIB-4), and aspartate transaminase-to-platelet ratio index (APRI) for hepatocellular carcinoma (HCC) patients and explore the clinical impact of these models with regard to perioperative risks and HCC prognosis. METHODS: Between January 2003 and December 2018, 305 consecutive patients who underwent hepatectomy for HCC were enrolled. RESULTS: The APRI showed the most robust diagnostic performance through each fibrosis stage among three models (PALBI, FIB-4, and APRI): fibrosis stage 3 (f3), area under the curve [AUC] = 0.55, 0.72, and 0.76; and f4, AUC = 0.51, 0.71, and 0.76, respectively). In addition, survival analysis revealed that all three models were significantly associated with HCC prognosis. PALBI (grade 1 vs. 2, 3): recurrence-free survival (RFS): median survival time (MST), 34 vs. 17 months, 0.007; overall survival (OS): MST, 115 vs. 68, 0.02. FIB-4 (grade 1, 2 vs. 3): RFS: MST, 34 vs. 22, 0.004, OS: MST, 120 vs. 63, 0.0001. APRI (grade 1, 2 vs. 3), RFS: MST, 30 vs. 20, 0.0005; OS: MST, 107 vs. 55, 0.0003. Among three scoring systems, only PALBI grade was significantly associated with both operative time (median, 303 vs. 340 min, 0.01) and intraoperative blood loss (median, 581 vs. 859 mL, 0.03). CONCLUSIONS: This study showed robust performances of selected liver reserve and fibrosis models to predict HCC prognosis. Of them, PALBI might be used for assessing perioperative risks for hepatectomy for HCC.

[Eribulin Administration Methods to Extend the Survival Time of Patients with Advanced or Recurrent Breast Cancer, Consideringthe Relative Dose Intensity, Time to Treatment Failure, Pretreatment Regimen Number, and Tumor Subtype].

Eribulin is evaluated as the only agent that can extend the survival time of patients with advanced or recurrent breast cancer, when used as or after third-line chemotherapy. We retrospectively analyzed the efficacy of eribulin for the treatment of advanced or recurrent breast cancer in our hospital, considering the relative dose intensity(RDI), time to treatment failure (TTF), pretreatment regimen number, and tumor subtype. Of the 36 patients who were treated with eribulin between December 2011 and August 2016, we studied 31 patients who received eribulin as a single agent. The median RDI was 0.75 (range: 0.44-1). The response rate was 22.5%, the disease control rate was 80.6%, and the clinical benefit rate was 45.2%. Overall survival(OS)was not associated with the RDI, previous regimen number, or tumor subtype; however, OS was affected by the TTF. Eribulin is a novel drug that has a different mechanism of action compared with those of conventional anticancer drugs. Therefore, prolonging the duration of eribulin administration may be more important than maintaining the RDI.

Randomized Phase II Trial of CapOX plus Bevacizumab and CapIRI plus Bevacizumab as First-Line Treatment for Japanese Patients with Metastatic Colorectal Cancer (CCOG-1201 Study).

PURPOSE: The aim of this randomized, multicenter, noncomparative, phase II trial was to investigate the efficacy and safety of two potential first-line treatments, capecitabine and oxaliplatin (CapOX) plus bevacizumab (BEV) and capecitabine and irinotecan (CapIRI) plus bevacizumab, in Japanese patients with metastatic colorectal cancer (mCRC). PATIENTS AND METHODS: Patients with untreated mCRC were randomly assigned to receive either CapOX plus bevacizumab (CapOX/BEV arm: bevacizumab 7.5 mg/kg and oxaliplatin 130 mg/m2 on day 1 and oral capecitabine 2,000 mg/m2 on days 1-14, every 3 weeks) or CapIRI plus bevacizumab (CapIRI/BEV arm: bevacizumab 7.5 mg/kg and irinotecan 200 mg/m2 on day 1 and capecitabine 1,600 mg/m2 on days 1-14, every 3 weeks). The primary endpoint was overall response rate (ORR), and the secondary endpoints included progression-free survival (PFS), overall survival (OS), and safety. RESULTS: A total of 107 patients were enrolled. The intent-to-treat population comprised 54 patients in the CapOX/BEV arm and 53 patients in the CapIRI/BEV arm. The median follow-up period was 35.5 months. ORR was 56% in the CapOX/BEV arm and 55% in the CapIRI/BEV arm. Median PFS and OS were 12.4 and 26.7 months in the CapOX/BEV arm and 11.5 and 28.7 months in the CapIRI/BEV arm, respectively. The frequencies of hematological and nonhematological adverse events above grade 3 were 13% and 30% in the CapOX/BEV arm and 25% and 23% in the CapIRI/BEV arm, respectively. CONCLUSION: CapOX plus bevacizumab and CapIRI plus bevacizumab are equally effective and feasible as the first-line treatments in Japanese patients with mCRC. IMPLICATIONS FOR PRACTICE: The CCOG-1201 study was designed to evaluate the efficacy and safety of capecitabine and oxaliplatin plus bevacizumab and capecitabine and irinotecan plus bevacizumab as a first-line treatment in Japanese patients with metastatic colorectal cancer. This article reports on the trial and efforts to define the role of these regimens, including the effect of KRAS status and UGT1A1 polymorphisms in metastatic colorectal cancer.