Comprehensive review of undifferentiated carcinoma of the pancreas: from epidemiology to treatment.

Undifferentiated carcinoma (UC) of the pancreas is a rare subtype of pancreatic cancer displaying no definitive direction of differentiation. UC has been reported as a highly aggressive malignant neoplasm, with a median overall survival of <1 year, except for several surgical series. On the other hand, UC tissue sometimes contains non-neoplastic osteoclast-like giant cells (OGCs), and such cases have been reported to have relatively longer survival. Thus, the World Health Organization (WHO) classification histologically distinguishes UC with OGCs (UCOGCs) from UC, and UCs were subclassified into three subtypes: anaplastic UC, sarcomatoid UC and carcinosarcoma. However, still less is known about UC due to its rarity, and such situations lead to further difficulties in treatment for UC. To date, only surgical resection can offer curative treatment for patients with UC, and no clear evidence for chemotherapy exists for them. However, a retrospective cohort study and case reports showed that relatively promising results paclitaxel-containing regimens for treatment of patients with unresectable UC. Furthermore, high programmed cell death protein 1 expression has been reported in sarcomatoid UCs and UCOGCs, and promising responses to anti-programmed death-ligand 1 therapy have been described in case reports of UCOGCs. Recent advances in chemotherapeutic agents and molecular technologies are opening up the possibilities for expanded treatments.

Comparing the Efficacy and Safety of Gemcitabine plus Nab-Paclitaxel versus Gemcitabine Alone in Older Adults with Unresectable Pancreatic Cancer.

BACKGROUND: Gemcitabine plus nab-paclitaxel (GnP) has been a standard treatment for unresectable pancreatic cancer (uPC); however, the current treatment status and usefulness in older adults with uPC remain unclear. Therefore, we aimed to investigate the patient background and compare the efficacy and safety of GnP versus other treatments in older adults with uPC. PATIENTS AND METHODS: In this prospective observational study, we enrolled 233 eligible patients aged ≥76 years with pathologically proven, clinically uPC, and no history of chemotherapy from 55 Japanese centers during September 2018-September 2019. The main endpoints were overall survival (OS), progression-free survival (PFS), and safety. Geriatric assessments were performed upon registration and after 3 months. To adjust for confounders, we conducted propensity score-matched analyses. RESULTS: GnP, gemcitabine alone (Gem), best supportive care, and other therapies were administered to 116, 72, 16, and 29 patients, respectively. In the propensity score-matched analysis, 42 patients each were selected from the GnP and Gem groups. The median OS was longer in the GnP group than in the Gem group (12.2 vs. 9.4 months; hazard ratio [HR], 0.65; 95% CI, 0.37-1.13). The median PFS was significantly longer in the GnP group than in the Gem group (9.2 vs. 3.7 months; HR, 0.38; 95% CI, 0.23-0.64). The incidence of severe adverse events was higher with GnP than with Gem; however, the difference was not significant. CONCLUSION: GnP is more efficacious than Gem in patients aged ≥76 years with uPC despite demonstrating a higher incidence of severe adverse events.

[A case of obstructive jaundice and duodenal stenosis caused by vaginal cancer and retroperitoneal metastasis].

A 76-year-old woman with a history of radiation therapy for vaginal cancer was referred to our hospital because of fever and hepatobiliary dysfunction. Computed tomography showed stenosis of the lower bile duct and edema-like changes in the duodenum from the descending to transverse parts. Endoscopic biliary stenting was performed according to the rendezvous method. Squamous cell carcinoma, similar to vaginal cancer, was found on pathological examination of the duodenum. We accordingly diagnosed obstructive jaundice and duodenal stenosis caused by vaginal cancer and retroperitoneal metastasis. To the best of our knowledge, other such cases have not been reported.

Laparoscopic spleen-preserving distal pancreatectomy for a solid-cystic intraabdominal desmoid tumor at a gastro-pancreatic lesion: a case report.

BACKGROUND: We report a case of an intraabdominal desmoid tumor that occurred at a gastro-pancreatic lesion with spontaneous cystic features, and present the successful laparoscopic resection of the tumor. CASE PRESENTATION: A 20-mm retroperitoneal cystic mass with a solid component was found adjacent to the stomach and pancreatic body in a 52-year-old woman with no history of familial adenomatous polyposis. Laparoscopic spleen-preserving distal pancreatectomy with wedge resection of the stomach was performed, and complete resection was achieved without intraoperative and postoperative complications. Histopathological examination by immunohistochemistry enabled diagnosis of a desmoid tumor that had originated from the stomach and invaded the pancreatic parenchyma with a spontaneous cystic change. We herein report an extremely rare case of an intraabdominal desmoid tumor with a spontaneous cystic change. CONCLUSION: Regardless of its rarity, desmoid tumor should be included in the preoperative differential diagnosis of a cystic intraabdominal mass, and laparoscopic function-preserving surgery may be an optimal treatment option.

[Gemcitabine in Combination with Cisplatin in Patients with Unresectable Advanced or Recurrent Biliary Tract Cancer--A Multicenter Prospective Observational Study in Fukuoka].

The standard chemotherapy for the treatment of unresectable advanced and recurrent biliary tract cancers is considered gemcitabine plus cisplatin (GC) on the basis of favorable results reported in the ABC-02 study from the UK and the BT22 study from Japan. However, the GC cohort of the BT22 study consisted of only 42 patients, and we considered it necessary to confirm the effectiveness and safety of GC chemotherapy in a multicenter prospective observational study in Fukuoka. Thirty-seven patients were enrolled in this study, including two patients with recurrent disease. The median patient age was 67.5 years (range, 43-84 years). Twelve patients had intrahepatic cholangiocarcinoma, 13 patients had extrahepatic cholangiocarcinoma, and 12 patients had gallbladder cancer. The median survival time (MST) was 14.9 months, the 1-year survival rate was 54.5%, and the median progression free survival (PFS) was 7.7 months. No chemotherapy-related deaths occurred, and Grade 3/4 adverse events were mainly hematological events including leucopenia in 13 (35.1%) patients and neutropenia in 12 (32.4%). The MST, 1-year survival rate, median PFS, and rate of Grade 3/4 adverse events in our study were similar to those of the BT22 study. In conclusion, this multicenter prospective observational study confirms the effectiveness and safety of GC chemotherapy for the treatment of unresectable advanced and recurrent biliary tract cancers.

Zinc Deficiency as a General Feature of Cancer: a Review of the Literature.

Trace elements are minerals that are present in very low concentrations in the human body and yet are crucial for a wide range of physiological functions. Zinc, the second most abundant trace element, is obtained primarily from the diet. After being taken up in the intestine, zinc is distributed to various target organs, where it plays key roles in processes such as immunity, protein folding, apoptosis, and antioxidant activity. Given the important role of zinc in a wide range of enzymatic reactions and physiological processes, zinc deficiency has been identified in a variety of diseases, notably cancer. In recent years, multiple meta-analyses and reviews looking at zinc levels in individual cancer types have been published, as have a plethora of primary studies demonstrating a link between low zinc levels and specific types of cancer. In this review, we summarize recent evidence implicating low zinc concentrations in serum or tissues as a characteristic in a wide range of cancers. We also discuss preliminary findings indicating that zinc level measurement could ultimately become a useful clinical tool for cancer diagnosis and predicting outcomes in patients with cancer. Finally, we suggest future directions for further elucidating the role of zinc deficiency in cancer development and progression.

[Multiple pyogenic liver abscesses with the decline in neutrophil phagocytic function: a case report].

A 51-year-old man presenting with fever, weight loss and general fatigue was diagnosed with jaundice and liver tumors and admitted to our hospital for further investigation and treatment. We diagnosed multiple pyogenic liver abscesses, obstructive jaundice, and silent syphilis. The patient was successfully treated with endoscopic biliary stenting, endoscopic nasobiliary drainage, percutaneous transhepatic abscess drainage, and, most effectively, transcatheter regional hepatic arterial infusion with antibiotics. We speculated that the decline in neutrophil phagocytic function may concern to occur the pyogenic liver abscess.

Serum zinc levels in cancer patients are low and difficult to elevate when complicated by liver cirrhosis: A retrospective study.

In this study, we analyzed blood zinc concentration in patients with various cancer types and the degree of improvement in relation to the underlying disease following treatment with zinc preparations. Serum zinc levels of 530 cancer patients whose blood zinc levels were measured at our hospital from 2016 to 2021 were retrospectively examined in accordance with the primary disease. Changes in zinc levels were analyzed in 155 patients whose zinc levels had been measured on 2 or more occasions in accordance with whether they had received zinc preparations. In addition, the concentration course of zinc before and after zinc formulation administration in 73 patients was examined in accordance with the presence or absence of liver cirrhosis complications. Mean serum zinc levels were below normal in all carcinomas measured, and zinc levels were significantly lower in cirrhosis-hepatocarcinoma cases than in other primary disease cases. Furthermore, serum zinc levels in patients who did not receive zinc preparations decreased significantly over time. In patients who received zinc preparations, the elevated levels of zinc after treatment were significantly lower in patients with cirrhosis than in those without cirrhosis. There was a weak inverse correlation between pre-dose zinc concentration and increased zinc concentration in patients with cirrhosis. In the analysis of covariance, the presence of liver cirrhosis was predominantly correlated with elevated zinc per dose. In summary, serum zinc levels in cancer patients are low and especially low in cancer patients with liver cirrhosis compared with those without cirrhosis after the administration of zinc preparations.

Liver metastasis composed of pure squamous cell carcinoma component from pancreatic pure ductal adenocarcinoma: a case report.

BACKGROUND: Liver metastasis of pure squamous cell carcinoma (SCC) from pancreatic ductal adenocarcinoma has not been previously reported. CASE PRESENTATION: A 66-year-old man underwent a computed tomography scan 3 years after surgery for pancreatic head cancer, and the scan revealed a mass lesion in the right lobe of the liver. A liver tumor biopsy was performed, and SCC was diagnosed. Whole sections of the pancreatic head cancer were re-evaluated, but no areas of SCC-like differentiation were identified. Although the pathology differed between the pancreas and liver, metastasis of adenosquamous carcinoma was considered. Three courses of gemcitabine plus nab-paclitaxel were administered to treat the liver metastasis of pancreatic cancer, but no response was attained. Therefore, primary SCC of the liver was considered and hepatic resection was performed. The tumor had invaded the diaphragm, and S5/6 partial hepatic resection with right diaphragm resection was performed. Pathological examination showed pure SCC of the liver, which differed from the pancreatic cancer. KRAS mutations were evaluated in the pancreatic and liver tumor specimens, and Q61R mutation was identified in both specimens. This pure SCC of the liver was diagnosed as metastasis from pancreatic cancer not by histology but by genetic analysis. CONCLUSIONS: This is the first reported case of pure SCC liver metastasis from pancreatic cancer without a squamous cell component in the primary tumor. Evaluation of KRAS mutations in both specimens was useful for diagnosis.

Loss of adipose tissue or skeletal muscle during first-line gemcitabine/nab-paclitaxel therapy is associated with worse survival after second-line therapy of advanced pancreatic cancer.

AIM: Progression of cachexia indicated by decreased body weight and composition is associated with poor survival of advanced pancreatic cancer (APC). There are limited data concerning the prognostic effect of cachexia on second-line chemotherapy (L2). We aimed to assess the impact of cachexia progression during first-line therapy (L1) on survival after L2. METHODS: We reviewed patients with gemcitabine/nab-paclitaxel (GEM/nabPTX)-refractory APC who underwent L2 with modified FOLFIRINOX or S-1 between 2015 and 2019 in our institution. We determined clinicopathological data including body composition parameters: subcutaneous fat area (SFA), visceral fat area (VFA), and skeletal muscle index (SMI). Correlations of changes in these parameters, as well as their effect on overall survival after L2 (OS2), were examined. RESULTS: Median rates of change in SMI, SFA, and VFA were 0.19%, -4.17%, and -18.39%, respectively, in 59 patients during L1. Although there was moderate correlation in rate of change between SFA and VFA, there was no correlation between SMI and other parameters. We defined loss of SFA, VFA, and SMI as decreases greater than 8.5%, 34.1%, and 8.7%, respectively. Median OS2 of patients with loss in any of these parameters was significantly shorter than in patients without loss (3.83 vs. 8.73 months). Multivariate analysis revealed that loss in any parameters, performance status, and C-reactive protein/albumin ratio were independent negative prognostic factors. CONCLUSION: Loss of adipose tissue or skeletal muscle during L1 had a considerable impact on OS2 in APC refractory to GEM/nabPTX.

Treatment Effect and Safety of Nanoliposomal Irinotecan with Fluorouracil and Folinic Acid after Gemcitabine-Based Therapy in Patients with Advanced Pancreatic Cancer: A Multicenter, Prospective Observational Study.

Although the combination of nanoliposomal irinotecan plus fluorouracil/folinic acid (nal-IRI/FF) exhibited survival benefits in gemcitabine-refractory patients with advanced pancreatic cancer (APC) in the phase III NAPOLI-1 trial, there is limited data on the efficacy and safety of this regimen in real-world settings in Japan. This multicenter, prospective observational study enrolled patients with APC who received nal-IRI/FF after a gemcitabine-based regimen from July 2020 to June 2021. We collected and analyzed clinical data and conducted survival and multivariate analyses. Thirty-one (78%) of the 40 patients had metastases. Nal-IRI/FF was the second-line therapy in 36 patients (90%). The median duration was 3.2 months. The disease control rate was 57%. The median progression-free survival and overall survival (OS) were 4.5 months (95% confidence interval [CI]: 2.8−5.5) and 7.4 months (95% CI: 5.1−10.6), respectively. Common ≥grade 3 toxicities included neutropenia (28%) and fatigue (23%). Fatigue led to treatment discontinuation in 6 out of 10 patients. Multivariate analysis showed that a neutrophil-to-lymphocyte ratio > 4 was a significant risk factor for a short OS (hazard ratio (HR) = 3.08, 95% CI: 1.21−7.85, p = 0.02). In conclusion, nal-IRI/FF is an appropriate treatment option for APC following gemcitabine-containing regimens.

[A case of rectal implantation cyst diagnosed by EUS and EUS-guided FNA].

A 73-year-old woman was referred to our hospital complaining of bloody stool. She had undergone high anterior resection with the double stapling technique for a sigmoid colon cancer 2 years prior to this admission. Colonoscopy revealed a soft submucosal tumor, 4cm in size, on the anal side of the previous anastomosis in the rectum. EUS revealed a cystic lesion located in the third and fourth layers of the rectal wall. EUS-FNA was performed, and the content of the cystic lesion was transparent mucinous liquid. Histologically, the specimen revealed PAS and Alcian blue-positive mucinous material and a small number of inflammatory cells such as foamy macrophages. Therefore, this cystic lesion was diagnosed as a rectal implantation cyst.

Adenomyomatous hyperplasia of the extrahepatic bile duct: a systematic review of a rare lesion mimicking bile duct carcinoma.

Adenomyomatous hyperplasia (AH) is a tumor-like inflammatory hyperplastic lesion. In the biliary system, AH commonly arises in the gallbladder, but AH of the extrahepatic bile duct is extremely rare. AH usually develops and is found with symptoms related to biliary stenosis or obstruction, but there are few disease-specific manifestations. It is difficult to make a definitive diagnosis by imaging or cytopathological examination; thus, surgical resections were performed in all past reported cases. The pathophysiological etiology of AH is unknown, but it is considered to be associated with chronic inflammation. According to the epidemiological findings of cases reported to date, the possibility of malignant transformation is considered to be negative. However, the symptoms and imaging findings of AH are difficult to distinguish from those of early-stage bile duct carcinoma. In the current review, we discuss the epidemiology, pathophysiology, diagnosis, and management of AH of the bile duct.

Improved indocyanine green retention after short-term lenvatinib withdrawal in three patients with hepatocellular carcinoma.

Use of lenvatinib, which has a high response rate in advanced hepatocellular carcinoma, sometimes results in tumor shrinkage and resectability of previously unresectable liver cancers. In Asia, including Japan, liver reserve, one of the determinants of resectability, is mainly determined by the indocyanine green (ICG) retention rate. Three patients with advanced liver cancer treated at our institution had very poor ICG retention rates during treatment with lenvatinib. Lenvatinib may reduce blood flow in both cancerous and non-cancerous regions by inhibiting vascular endothelial growth factor. Therefore, accurate determination of liver function likely requires withdrawal of this treatment several days before ICG retention testing.

Risk factors for de novo hepatitis B during solid cancer treatment.

BACKGROUND: Reactivation of hepatitis B virus (HBV) during anticancer treatment is a critical issue. When treating patients with solid tumors, it is unclear whether specific cancer types or treatments affect HBV reactivation in hepatitis B surface antigen (HBsAg)-negative and hepatitis B core antibody (HBcAb)-positive patients, so-called de novo hepatitis B patients. The risk of de novo hepatitis B may vary based on different background factors. AIM: To determine the frequency and risk factors for de novo hepatitis B during solid tumor treatment. METHODS: This retrospective cohort study comprised 1040 patients without HBsAgs and with HBcAbs and/or hepatitis B surface antibodies (HBsAbs). The patients were treated for solid cancer from 2008 to 2018 at the National Kyushu Cancer Center and underwent HBV DNA measurements. Patient characteristics and disease and treatment information were investigated. HBV DNA measurements were performed using TaqMan polymerase chain reaction (PCR). To identify the risk factors associated with HBV DNA expression, the age, sex, original disease, pathology, treatment method, presence or absence of hepatitis C virus (HCV), and HBsAb and/or HBcAb titers of all subjects were investigated. In patients with HBV DNA, the time of appearance, presence of HBsAgs and HBsAbs at the time of appearance, and course of the subsequent fluctuations in virus levels were also investigated. RESULTS: Among the 1040 patients, 938 were HBcAb positive, and 102 were HBcAb negative and HBsAb positive. HBV DNA expression was observed before the onset of treatment in nine patients (0.9%) and after treatment in 35 patients (3.7%), all of whom were HBcAb positive. The HBV reactivation group showed significantly higher median HBcAb values [9.00 (8.12-9.89) vs 7.22 (7.02-7.43), P = 0.0001] and significantly lower HBsAb values (14 vs 46, P = 0.0342) than the group without reactivation. Notably, the reactivated group showed a significantly higher proportion of cancers in organs related to digestion and absorption (79.0% vs 58.7%, P = 0.0051). A high HBcAb titer and cancers in organs involved in digestion and absorption were identified as independent factors for HBV reactivation (multivariate analysis, P = 0.0002 and P = 0.0095). The group without HBsAbs tended to have a shorter time to reactivation (day 43 vs day 193), and the frequency of reactivation within 6 mo was significantly higher in this group (P = 0.0459) than in the other group. CONCLUSION: A high HBcAb titer and cancers in organs involved in digestion and absorption are independent factors that contribute to HBV reactivation during solid tumor treatment.

Lysophosphatidic acid induced nuclear translocation of nuclear factor-kappaB in Panc-1 cells by mobilizing cytosolic free calcium.

AIM: To clarify whether Lysophosphatidic acid (LPA) activates the nuclear translocation of nuclear factor-kappaB (NF-kappaB) in pancreatic cancer. METHODS: Panc-1, a human pancreatic cancer cell line, was used throughout the study. The expression of LPA receptors was confirmed by reverse-transcript polymerase chain reaction (RT-PCR). Cytosolic free calcium was measured by fluorescent calcium indicator fura-2, and the localization of NF-kappaB was visualized by immunofluorescent method with or without various agents, which effect cell signaling. RESULTS: Panc-1 expressed LPA receptors, LP(A1), LP(A2) and LP(A3). LPA caused the elevation of cytosolic free calcium dose-dependently. LPA also caused the nuclear translocation of NF-kappaB. Cytosolic free calcium was attenuated by pertussis toxin (PTX) and U73122, an inhibitor of phospholipase C. The translocation of NF-kappaB was similarly attenuated by PTX and U73122, but phorbol ester, an activator of protein kinase C, alone did not translocate NF-kappaB. Furthermore, the translocation of NF-kappaB was completely blocked by Ca(2+) chelator BAPTA-AM. Thapsigargin, an endoplasmic-reticulum Ca(2+)-ATPase pump inhibitor, also promoted the translocation of NF-kappaB. Staurosporine, a protein kinase C inhibitor, attenuated translocation of NF-kappaB induced by LPA. CONCLUSION: These findings suggest that protein kinase C is activated endogenously in Panc-1, and protein kinase C is essential for activating NF-kappaB with cytosolic calcium and that LPA induces the nuclear translocation of NF-kappaB in Panc-1 by mobilizing cytosolic free calcium.

Postoperative Neutrophil-to-Lymphocyte Ratio as a Predictor of Long-Term Prognosis after Pancreatectomy for Pancreatic Carcinoma: A Retrospective Analysis.

To clarify the prognostic value of the postoperative blood neutrophil-to-lymphocyte ratio (NLR) in patients undergoing pancreatectomy for pancreatic carcinoma (PAC). A high preoperative NLR has been reported to be a predictor of poor survival in patients with various cancers including PAC. However, it has not been extensively examined in postoperative NLR after pancreatectomy for PAC. This retrospective study enrolled 86 patients who underwent pancreatectomy without preoperative therapy for PAC from 2005 to 2013. Clinicopathological parameters, including postoperative NLR, were evaluated to identify predictors of the overall and recurrence-free survival of patients after pancreatectomy. Univariate and multivariate analyses were performed, using the Cox proportional hazards model. Univariate and multivariate analyses showed that postoperative NLR at one month was an independent prognostic factor in the overall and recurrence-free survival of patients. The 3-year survival rate after pancreatectomy was as follows: 33.9 per cent in patients with a postoperative NLR of less than 3.0 at one month; and 7.3 per cent in those with a postoperative NLR of 3.0 or more at one month (P < 0.001). The overall survival rate after pancreatectomy in the NLR at one month ≥3.0 group was significantly lower than in the NLR at one month <3.0 group: one year, 42.6 versus 81.9 per cent; three year, 7.3 versus 33.9 per cent (P < 0.001). The results of the study suggest that the postoperative NLR at one month is an independent predictor of survival after pancreatectomy in patients with PAC.

The time course of gap-junctional protein connexin 32 expression in the pancreas after the induction of acute pancreatitis by caerulein in rats.

BACKGROUND: We previously demonstrated that the immunostaining of the gap-junction protein, connexin 32 (Cx 32), in the pancreas was markedly reduced in caerulein (Cn)-induced acute pancreatitis. The expression of Cx 32 in the pancreas during the course of acute pancreatitis is unclear. To address this, we examined Cx 32 mRNA and protein expression in the pancreas. METHODS: Cx 32 mRNA and protein expression in the pancreas was examined by Northern blot analysis and Western blot analysis, respectively, 1, 4, 7, and 14 days after the induction of acute pancreatitis. RESULTS: Cx 32 mRNA was identified in normal rat pancreas, and the value for the relative intensity against 18S rRNA was 0.57 +/- 0.15 (mean +/- SD). After the induction of acute pancreatitis by caerulein, the Cx 32 mRNA expression levels were increased on day 1, day 4, day 7, and day 14 compared with levels in the normal pancreas (1.63-fold, 1.61-fold, 1.49-fold, and 1.35-fold, respectively). A significant increase in Cx 32 protein expression was detected on day 1 and day 4 (1.67 +/- 0.15-fold and 1.72 +/- 0.2-fold, respectively), while Cx 32-positive spots, determined by immunohistochemical analysis, were markedly decreased on day 1 and had returned to normal by day 14. CONCLUSIONS: These results show that the expression of Cx 32 increases early on after the induction of pancreatitis by Cn, and that the normalization of Cx 32-immunostained spots in Cn-induced acute pancreatitis occurs after the increase in Cx 32 mRNA and protein expression.