Prospective observational study of zinc deficiency symptoms during first-line chemotherapy for gastric and colorectal cancer.

Background: Zinc deficiency during long-term chemotherapy and its related symptoms, including skin rash, taste disorders, and oral mucositis, have not been sufficiently investigated. Methods: This prospective observational study enrolled patients with gastric and colorectal cancer who underwent standard first-line chemotherapy. According to the Practice Guidelines for Zinc Deficiency, zinc deficiency is defined as a serum level of <60 µg/dL. Serum zinc levels were measured before and after (1, 3, and 6 months) chemotherapy, and symptoms were assessed using the Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events version 1.0. Repeated measures were analyzed using a generalized linear mixed model. Results: Of the 61 enrolled patients, 48 who underwent standard first-line chemotherapy with fluoropyrimidine plus oxaliplatin were analyzed. Zinc deficiency was observed in 18 patients (38%) before chemotherapy. The least-squares means of serum zinc levels significantly decreased at 3 and 6 months of chemotherapy in 30 patients without zinc deficiency at the start of chemotherapy (both P<0.01) but not in 18 with zinc deficiency at the beginning. Changes in serum zinc levels during chemotherapy negatively correlated with changes in taste, rash, and itching (all P<0.04) in patients without zinc deficiency before treatment initiation. Conclusions: Serum zinc levels decreased during chemotherapy in zinc-non-deficient patients at the beginning of chemotherapy and correlated with taste changes, skin rash, and itching. Therefore, investigating whether zinc supplementation ameliorates these symptoms is necessary.

Efficacy and Safety of Three-dimensional Conformal Radiotherapy for Macroscopic Vascular Invasion of Hepatocellular Carcinoma.

Chemotherapy is insufficient to treat macroscopic vascular invasion (MVI) of hepatocellular carcinoma (HCC). We retrospectively investigated the treatment outcomes of patients who underwent three-dimensional conformal radiotherapy (3D-CRT) for HCC MVI and analyzed prognostic factors by multivariate analysis using a Cox proportional hazard model. Sixty-five patients were studied. MVI sites were the portal vein (n=48 patients), portal and hepatic veins (n=8), and hepatic vein (n=9). The median irradiation dose was 50 Gy. The median survival time (MST) was 7.5 months. Performance status 2 or 3, modified albumin-bilirubin grade 2b or 3, and massive/diffuse type were poor prognostic factors. Nineteen patients (29%) with a treatment effect of 3 or 4 (≥ 50% of tumor necrosis or regression) at the irradiation sites according to the Response Evaluation Criteria in Cancer of the Liver showed longer survival than those with an effect of 1 or 2 (MST 18.7 vs. 5.9 months, p<0.001). No treatment-related death occurred. The hepatic function reserve was preserved in more than 70% of patients. 3D-CRT controlled HCC MVI safely and was suggested to be a good treatment option.

Clinical Outcomes of S-1 Monotherapy and Modified FOLFIRINOX Therapy after Gemcitabine plus Nab-paclitaxel Therapy in Unresectable Pancreatic Cancer.

Objective S-1 and modified FOLFIRINOX (mFFX) were often used as the second-line chemotherapies after failure of gemcitabine plus nab-paclitaxel (GnP) in unresectable pancreatic cancer (UPC) until nanoliposomal irinotecan plus 5-fluorouracil/leucovorin therapy was approved as an alternative in Japan in 2020. However, the clinical outcomes of S-1 and mFFX after GnP have scarcely been reported. Therefore, we retrospectively studied them. Methods We extracted the clinical data of 86 patients with UPC who received second-line chemotherapy after GnP between 2015 and 2020. Among the patients who had a good organ functions and no massive ascites, 41 patients treated with S-1 and 21 treated with mFFX were enrolled. Results Compared to S-1, mFFX tended to be used for younger patients with a good general condition (median age, 63 vs. 71 years, p<0.01; and performance status 0, 67% vs. 37%, p<0.05). The median progression-free and overall survival were similar between the S-1 (3.7 and 7.2 months, respectively) and mFFX (3.3 and 7.4 months, respectively) groups. The response rate in patients with measurable lesions was 4% (n=1/23) in the S-1 group and 17% (n=2/12) in the mFFX group. The incidence of grade 3 or 4 adverse events was 20% in the S-1 group and 57% (neutrophil count decreased in 43%) in the mFFX group (p<0.01). Conclusion S-1 and mFFX were both acceptable second-line chemotherapies after GnP therapy for UPC, although attention should be paid to myelosuppression during mFFX treatment. Further studies involving nanoliposomal irinotecan plus 5-fluorouracil/leucovorin therapy are necessary to facilitate the selection of the optimal regimen for each patient.

[Tolerability of Definitive Chemoradiotherapy in Elderly Patients with Esophageal Cancer].

Definitive chemoradiotherapy(CRT)for esophageal cancer is the standard treatment and alternative to surgery. However, the tolerability of CRT in elderly patients is not well known. In this study, we retrospectively analyzed 60 patients with esophageal cancer who were treated with CRT(5-FU 700 mg/m2, cisplatin 70 mg/m2, radiation 60 Gy)at our hospital between January 2015 and September 2017. The patients were divided into 2 groups: an elderly group comprising 16 patients aged >75 years and a non-elderly group comprising 44 patients aged <74 years. The relative dose intensity of cisplatin in the elderly group was significantly lower than that in the non-elderly group. Radiotherapy was successfully executed in both groups. More patients in the elderly(25%)than the non-elderly group(7%)developed pneumonitis, and all patients who developed severe pneumonitis in the elderly group died. Application of definitive CRT and irradiation methods in elderly patients with a subpleural reticular shadow should be carefully considered before initiating therapy.

Ramucirumab after prior sorafenib in patients with advanced hepatocellular carcinoma and elevated alpha-fetoprotein: Japanese subgroup analysis of the REACH-2 trial.

BACKGROUND: The global, randomized, phase 3 REACH-2 study (ClinicalTrials.gov identifier: NCT02435433) found significantly longer overall survival (OS) for second-line ramucirumab versus placebo (hazard ratio [HR]: 0.710, 95% confidence interval [CI] 0.531-0.949, P = 0.0199) in patients with advanced hepatocellular carcinoma (HCC) and alpha-fetoprotein (AFP) ≥ 400 ng/mL. This prespecified subgroup analysis evaluated the efficacy and safety of ramucirumab in the Japanese patients enrolled in the study. METHODS: Patients with advanced HCC and AFP ≥ 400 ng/mL after first-line sorafenib were randomized 2:1 to ramucirumab (8 mg/kg intravenously) or placebo every 2 weeks. Hazard ratios for progression-free survival (PFS) and OS (primary endpoint of the overall study) were estimated using the stratified Cox regression model. We also pooled individual patient data from REACH-2 with data from REACH (NCT01140347) for patients with AFP ≥ 400 ng/mL. RESULTS: In the Japanese REACH-2 subpopulation, there were improvements for ramucirumab (n = 41) versus placebo (n = 18) in PFS (HR 0.282, 95% CI 0.144-0.553) and OS was numerically prolonged (HR 0.599, 95% CI 0.303-1.187), consistent with the significant benefit seen in the overall REACH-2 study population. In the ramucirumab and placebo arms, respectively, the objective response rate was 7.3% and 0%, and the disease control rate was 70.7% and 33.3%. The most frequently reported grade ≥ 3 treatment-emergent adverse event was hypertension (ramucirumab: 15%; placebo: 11%). CONCLUSIONS: Ramucirumab after prior sorafenib improved PFS and OS compared with placebo, with a manageable safety profile, in the Japanese REACH-2 subpopulation, consistent with the overall REACH-2 study results. Ramucirumab is the first agent to demonstrate clinical benefit for Japanese patients with HCC in the second-line setting.

Multicenter cooperative case survey of hepatitis B virus reactivation by chemotherapeutic agents.

AIM: The purpose of this multicenter cooperative study was to elucidate the clinical features of hepatitis B virus (HBV) reactivation by chemotherapeutic agents and the patient outcomes after HBV reactivation by a retrospective review of accumulated patients' medical records. METHODS: Records of a total of 27 patients (hematological malignancy, 14 patients; solid tumor, 13 patients) from 11 institutions who were diagnosed between June 2005 and October 2010 as having HBV reactivation following chemotherapy were reviewed. RESULTS: Of the 27 patients with reactivation, 16 patients were hepatitis B surface antigen (HBsAg) positive and 11 were HBsAg negative prior to the commencement of chemotherapy. Of the 11 patients who were HBsAg negative prior to the chemotherapy, 10 had hematological malignancies and one had a solid tumor. Of the 14 patients with hematological malignancies with HBV reactivation enrolled in the study, the reactivation occurred more than 12 months after the completion of chemotherapy in five patients (36%); on the other hand, none of the patients (0%) with solid tumors developed HBV reactivation more than 12 months after the completion of chemotherapy. Of the 24 patients who had acute liver dysfunction at the diagnosis of HBV reactivation, nine (38%) had severe hepatitis and seven (29%) died of liver failure. CONCLUSION: Most of the patients with HBV reactivation who were HBsAg negative prior to the chemotherapy had underlying hematological malignancies. Furthermore, patients with hematological malignancies often developed late-onset HBV reactivation. The prognosis of patients who develop acute liver dysfunction as a complication of HBV reactivation is extremely dismal.

Maximum standardized uptake value in 18F-fluoro-2-deoxyglucose positron emission tomography is associated with advanced tumor factors in esophageal cancer.

Positron emission tomography/computed tomography (PET/CT) with 18F-fluoro-2-deoxyglucose (FDG-PET/CT) has become established in cancer imaging, and derived maximum standardized uptake values (SUVmax) add functional information regarding cancer, including esophageal squamous cell carcinoma (ESCC). The aim of the present study was to determine the clinical significance and association of tumor progression using SUVmax derived from PET/CT images in patients with ESCC. In total, 101 patients with ESCC were assessed using FDG-PET/CT and the SUVmax was then compared with the clinical backgrounds and prognoses of the patients. Endoscopic ESCC biopsy specimens were obtained in order to analyze mRNA expression relative to tumor progression. The results showed that values for SUVmax were significantly higher in patients with tumor progression factors, particularly those with lymph node metastasis. Analysis of receiver operating characteristics curves revealed an optimum SUVmax cut-off value of 10.26 for node-positive disease. Patients with SUVmax ≥10.26 had gene alterations with epithelial-mesenchymal transition (EMT) and significantly worse overall survival (P=0.0012). A higher SUVmax in patients with ESCC was associated with lymph node metastasis and a poorer prognosis. Thus, the SUVmax may reflect the potential of EMT in patients with ESCC.

Utility of contrast-enhanced FDG-PET/CT in the clinical management of pancreatic cancer: impact on diagnosis, staging, evaluation of treatment response, and detection of recurrence.

OBJECTIVES: Fluorodeoxyglucose (FDG)-positron emission tomography/contrast-enhanced computed tomography (PET/CE-CT) involving whole-body scanning first by non-CE-CT and FDG-PET followed by CE-CT has been used for detailed examination of pancreatic lesions. We evaluated PET/CE-CT images with regard to differential diagnosis, staging, treatment response, and postoperative recurrence in pancreatic cancer. METHODS: Positron emission tomography/CE-CT was conducted in 108 patients with pancreatic cancer and in 41 patients with other pancreatic tumor diseases. RESULTS: The maximum standardized uptake value (SUV(max)) overlapped in benign and malignant cases, suggesting that differential diagnosis of pancreatic tumors based on the SUV(max) is difficult. In the evaluation of staging in 31 resectable pancreatic cancer by PET/CE-CT, the diagnostic accuracy rate was more than 80% for most factors concerning local invasion and 94% for distant metastasis but only 42% for lymph node metastasis. Significant positive correlations were found between the SUV(max) and tumor size/markers, suggesting that SUV(max) may be a useful indicator for the treatment response. Regarding the diagnosis of the postoperative recurrence, PET/CE-CT correctly detected local recurrence in all the 11 cases of recurrence, whereas abdominal CE-CT detected only 7 of 11 cases, suggesting that PET/CE-CT is superior in this context. CONCLUSIONS: Positron emission tomography/CE-CT is useful for the clinical management of pancreatic cancer.

Des-gamma-carboxy prothrombin identified by P-11 and P-16 antibodies reflects prognosis for patients with hepatocellular carcinoma.

BACKGROUND AND AIMS: Serum des-γ-carboxy prothrombin (DCP) is an established tumor marker in patients with hepatocellular carcinoma (HCC), which can be identified by using MU-3 antibody. The MU-3 antibody mainly reacts with the 9-10 glutamic acid residues of DCP (conventional DCP). Since other variants of DCP with fewer glutamic acid residues can be detected using P-11 and P-16 antibodies (code name: NX-PVKA), we examined the clinical characteristics associated with NX-PVKA, and whether NX-PVKA is a useful measure in HCC patients. METHODS: Participants comprised 197 HCC patients admitted to our hospital between 2001 and 2010. NX-PVKA, conventional DCP, alpha-fetoprotein, and L3 fraction of alpha-fetoprotein were measured prior to initiation of HCC treatment. RESULTS: Of the tumor markers assessed, NX-PVKA was the only significant predictor of prognosis (hazard ratio, 81.32; P < 0.0001). Patients with NX-PVKA level ≥ 100 mAU/mL showed significantly lower survival rates (P < 0.0001). NX-PVKA level was also significantly associated with platelet count, prothrombin time, C-reactive protein, sex, maximum tumor size, number of nodules, and portal venous invasion by HCC. Finally, using NX-PVKA level and other clinical parameters, we established a prognostic model to estimate patient survival time. CONCLUSIONS: NX-PVKA offers the best marker of tumor prognosis among HCC patients, and is strongly associated with tumor factors and hepatic functional reserve. NX-PVKA could be useful for clinical evaluation of tumor severity, as well as the estimated duration of survival among patients with HCC.

[Gemcitabine plus S-1 combination therapy (GS therapy) for pancreatic cancer patients with high-grade hepatic metastasis].

Pancreatic cancer shows the worst prognosis among the solid tumors, and survival for patients with high-grade liver metastasis is estimated at around a few months. We reported the effects of combination therapy with gemcitabine and S-1 (GS therapy) on pancreatic cancer patients with high-grade hepatic metastasis. Patients with severe metastatic pancreatic cancer received chemotherapy comprising S-1 (30mg/m² p.o. b.i.d., days 1-14) and gemcitabine (1000mg/m² on days 1 and 8), repeated every 3 weeks. Fourteen patients (7 men, 7 women) received treatment at a mean age of 56.5 years (range, 39-76 years), achieving complete response in 1 patient, partial response in 5 patients, and stable disease in 3 patients and progressive disease in 5 patients. The response rate was thus 43%. Median progression-free survival was 186 days (95% confidence interval, 40-247 days). Median overall survival was 261 days (95% confidence interval, 162-358 days). GS therapy appears to be well-tolerated and effective in patients with high-grade hepatic metastasis.

Primary extranodal non-Hodgkin's lymphoma of the common bile duct manifesting as obstructive jaundice: report of a case.

Primary non-Hodgkin's lymphoma (NHL) of the common bile duct (CBD) manifesting as obstructive jaundice is extremely rare: to our knowledge, only 22 cases of primary NHL arising from the CBD have been reported. The patient in this case report was a 63-year-old man who presented with obstructive jaundice. Abdominal sonography, positron emission tomography, and computed tomography showed a mass with abnormal 18-fluorodeoxyglucose uptake in pancreatic head. Magnetic resonance cholangiopancreatography demonstrated a strictured segment of the CBD with proximal bile duct dilatation. We performed pancreaticoduodenectomy for a presumptive diagnosis of pancreatic head carcinoma or cholangiocarcinoma of the CBD. However, the histological diagnosis was a primary, diffuse, large B-cell lymphoma of the CBD. He received three courses of combination chemotherapy, including rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). The patient remains well, without evidence of tumor recurrence, 8 months after surgery. In summary, primary NHL of the CBD, despite its rarity, should be considered in the differential diagnosis of obstructive jaundice. An accurate histopathologic diagnosis and complete surgical resection, followed by combination chemotherapy plus rituximab may be effective.

Brain metastasis from hepatocellular carcinoma treated with a cyber-knife.

A 70-year-old right-handed Japanese man who had undergone surgical resection for hepatocellular carcinoma (HCC) 2 years earlier was diagnosed with lung metastasis 3 months before consulting our hospital with a headache and visual field disturbance. Head computed tomography revealed a brain tumor with an intracerebral hemorrhage. Using (99m)Tc-PMT (pyridoxal-5-methly-triptophan) scintigraphy, we determined that the brain tumor was metastasis from the HCC and utilized the cyber-knife for treatment. The prognosis of patients with brain metastasis from HCC has been reported to be poor. Use of the cyber-knife was non-invasive, and proved to be effective for improving prognosis and quality of life.

Characteristics of geographic distributions and route of infection for hepatitis B virus genotype D in Ehime area in western Japan.

AIMS: Hepatitis B virus genotype D (HBV/D) is rare in Japan, and has been shown to circulate in Ehime prefecture in western Japan. HBV/D is suspected to have been transferred into Ehime from Russia as a result of the Japanese-Russian War. This study examined the current geographic spread and infectious route for HBV/D in Ehime. METHODS: HBV genotype was determined for 508 patients with chronic HBV infection and 46 patients with acute HBV infection hepatitis (acute hepatitis, AH), all of whom were living in Ehime. Ehime was divided into three areas and genotypic distributions were studied. RESULTS: The ratio of genotypes A,B,C and D in chronically infected patients were 1.8%, 4.5%, 87.8% and 5.9%, respectively. Most patients chronically infected with HBV/D lived in the central area. Only two patients lived in the east and south-west areas, and both had lived in the central area in childhood. Patients with AH due to HBV/D were found only in the central area. CONCLUSION: HBV/D has not yet spread widely to areas other than central Ehime, although small numbers of infected people have moved to other areas. The major infectious route for patients with AH is sexual transmission, regardless of HBV genotype.