Selection of regimens for patients with hepatitis C virus genotype/serotype discrepancy.

In the present study, the usefulness of the resistance-associated variant (RAV) analysis to select direct acting antiviral (DAA) drugs for patients with hepatitis C virus (HCV) genotype/serotype discrepancy was evaluated. The core-genotype and serotype were determined in the 559 patients recruited in the study. The RAV analysis and NS5B-genotype determination were performed in the eight patients who exhibited a genotype/serotype discrepancy. One of these patients exhibited a core-genotype 1b/serotype 2, and detection by RAV analysis was possible in this patient. The other seven patients demonstrated a core-genotype 2/serotype 1, and detection using the RAV analysis was possible in four of them. The NS5B-genotype was 1b in all patients in whom detection using the RAV analysis was possible and was other than 1b in patients in whom detection using the RAV analysis was impossible. The RAV analysis could detect RNA sequences specific to genotype 1b in the NS5A region. Therefore, in patients with genotype/serotype discrepancy in whom detection using the RAV analysis is possible, the treatment regimens should be selected based on the assumption that HCV with genome that is highly homologous to genotype 1b is present in the NS5A region.

[A successful case with TS-1+CDDP chemotherapy for recurrent gastric cancer].

A 64-year-old woman underwent cholecystectomy for treatment of cholecystolithiasis in January 2005. Pathological examination rendered a diagnosis of gallbladder carcinoma. Wedge resection of the liver and dissection of the lymph nodes was performed. No tumor cells in either the liver nodule or lymph nodes were found during pathological examination. At 4 years after surgery, paraaortic lymph node recurrence was confirmed by computed tomography (CT). Gemcitabine was administered once weekly for the first 3 weeks in a monthly cycle, but the tumor continued to increase in size. Gemcitabine was then switched to TS-1, after which it was changed to cisplatin because of continued tumor growth. After 35 courses of chemotherapy, CT showed the disappearance of the paraaortic lymph node, and the patient achieved a complete response. She is currently free of disease at 9 years after surgery.

[A case of recurrent gastric cancer successfully treated with TS-1+CDDP chemotherapy].

A 74-year-old woman underwent distal gastrectomy and D1+ α dissection for the treatment of gastric cancer (pT2a, pN2, H0, P0, M0, Stage IIIA) in February 2008. She was treated with adjuvant postoperative chemotherapy consisting of TS-1. However, 32 months after the operation, paraaortic lymph node recurrence was confirmed by computed tomography (CT). She was treated with combined TS-1 and cisplatin chemotherapy. After 14 courses, CT revealed that the paraaortic lymph node metastasis had disappeared, and a complete response was attained. The patient is currently disease-free, 6 years after the operation.

A Rare Case of Donor-Origin Intrahepatic Cholangiocarcinoma After Liver Transplantation for Hepatocellular Carcinoma: A Case Report.

BACKGROUND: Tumors may develop in the grafted liver after liver transplantation for hepatocellular carcinoma, most of which are hepatocellular carcinoma recurrences and are rarely of donor origin. We report a rare case of donor-origin intrahepatic cholangiocarcinoma in a liver allograft after liver transplantation for hepatocellular carcinoma. METHODS: A man in his 60s underwent liver transplantation for hepatocellular carcinoma with hepatitis C virus cirrhosis. The donor was a braindead woman in her 60s who had no history of malignancy. RESULTS: Three years and 5 months after liver transplantation, a tumor developed in the allograft. Computed tomography scans showed a 40-mm tumor that was atypical for hepatocellular carcinoma. Tumor biopsy was most suggestive of intrahepatic cholangiocarcinoma. Fluorescence in situ hybridization of the tumor showed an XX signal pattern, suggesting that it originated from the donor liver. Whole exome sequencing analysis strongly suggested that the tumor was an intrahepatic cholangiocarcinoma derived from the donor. CONCLUSIONS: Although donor-origin cancer after liver transplantation is extremely rare, it should be considered for adequate treatment.

[A case of hepatoid adenocarcinoma of the stomach].

The patient was a 76-year-old man with no chief complaint. He presented to an internist of our hospital for an evaluation of anemia. An upper gastrointestinal endoscopy revealed a type 2 tumor at the lesser curvature of the gastric body. Although the blood analysis showed a high amount of AFP(2, 328 ng/mL), there was no abnormality found in the liver with a CT scan. The tumor was presumed to be an AFP-producing gastric cancer on the basis of the tumor biopsy. We performed total gastrectomy, splenectomy and cholecystectomy. The tumor cells were positive for AFP by immunohistochemistry. The final diagnosis was hepatoid adenocarcinoma, pT3(SS), INF b, ly1, v2, pN1(3/42), pStage II B. Tumor cells were negative for antihepatocyte antibody and anti-HER2 antibody. The amount of AFP normalized postoperatively. After discharge, he was treated with S-1(80mg/day)orally. He is relapse-free now, 14 months after the operation. Hepatoid adenocarcinoma is an extremely aggressive tumor with a poor prognosis, and effective chemotherapy has still not been established. A larger number of analyses, along with a molecular biological approach, is sure to be helpful for the establishment of an effective treatment for hepatoid adenocarcinoma.

[A case of complex (type IV) paraesophageal hiatal hernia with herniation of the small intestine].

A 78-year-old woman was admitted to our hospital because of abdominal pain. She was diagnosed with complex (type IV) paraesophageal hiatal hernia, for which an operation was performed. At laparotomy, a 50 cm long ileum was found to have herniated into the thoracic cavity through the esophageal hiatus along with the sliding hiatal hernia of the stomach. Both the organs were reduced to the abdominal cavity. The hiatal hernia defect (diameter, 7cm) was repaired with a direct suture, and the gastric fundus was sutured to the diaphragm. Presently, 6 years have passed since the operation, there is no sign of recurrence.

[A case of multiple bone metastasis of gastric carcinoma accompanying DIC successfully controlled with combination of S-1 and low-dose CDDP].

The patient was a 50-year-old man who underwent total gastrectomy twelve years ago. Ahigh level of ALP was found in the patient in April 2008. Based on various examinations, the diagnosis of multiple bone metastasis of gastric carcinoma accompanying disseminated intravascular coagulation(DIC)was made. The patient was treated with S-1/CDDP. S-1(80mg/ m / / 2day)was administered for 14 days followed by a 7-day rest period, and a CDDP(20mg/m2)infusion was administered on days 1 and 8. After one course of treatment, the DIC was controlled, and the patient was given a one-year prognosis. The combination of S-1 and low-dose CDDP may be considered effective even for multiple bone metastases of gastric carcinoma with DIC.

A simplified method to quantitatively predict the effect of lenvatinib on hepatocellular carcinoma using contrast-enhanced ultrasound with perfluorobutane microbubbles.

Contrast-enhanced computed tomography (CECT) is generally used to evaluate the response to treatment of hepatocellular carcinoma (HCC); however, CECT is unsuitable for the early prediction of therapeutic effects and frequent monitoring. We aimed to investigate the usefulness of our simplified method for the quantification of tumor vascularity using contrast-enhanced ultrasound (CEUS) with perfluorobutane microbubbles [Sonazoid® (GE Healthcare, Oslo, Norway)] to predict the therapeutic effect of lenvatinib. Among the 13 patients studied, nine who had more than a 20% reduction in tumor vascularity within 2 weeks of starting treatment experienced complete response or partial response at 8-12 weeks as assessed by CECT. In contrast, three patients without reductions and one patient with only a slight decrease in tumor vascularity had a poor response to lenvatinib. Quantitative assessment of tumor vascularity by our simplified CEUS-based method could be a useful predictor of therapeutic responses to lenvatinib in patients with HCC.

Mac-2 binding protein glycosylation isomer predicts tolerability and clinical outcome of lenvatinib therapy for hepatocellular carcinoma.

BACKGROUND: Many patients with hepatocellular carcinoma present with impaired hepatic function, which often requires interruption or withdrawal of lenvatinib due to associated adverse events. We aimed to identify pre-treatment predictors of tolerability and clinical outcome of lenvatinib therapy. METHODS: Eighty patients who received lenvatinib at our institution between 2018 and 2020 were included in this study. We assessed essential factors associated with prolonged progression-free survival (PFS), using Cox proportional hazards model. We also investigated the correlation between the factor identified as contributing most to PFS and the relative dose intensity (RDI), response rate, and duration of treatment with lenvatinib. RESULTS: Pre-treatment level of Mac-2-binding protein glycosylation isomer (M2BPGi) showed significant association with PFS (hazard ratio = 0.52, P = .0358). Low M2BPGi levels (<1.5) correlated significantly with longer PFS than higher levels (P = .0003). Patients with M2BPGi <1.5 achieved significantly higher RDI, objective response rate, and disease control rate, and maintained lenvatinib treatment for longer than those with baseline values ≥1.5. Patients with M2BPGi ≥1.5 had a higher incidence of adverse events such as fatigue and anorexia. CONCLUSIONS: Baseline M2BPGi levels may predict the tolerability and treatment response to lenvatinib. Patients with high M2BPGi levels may less likely to benefit from lenvatinib therapy.

[Utility of CPT-11 as salvage chemotherapy for progressive or recurrent breast cancer patients with multiple drug resistance].

Salvage chemotherapy is necessary to maintain QOL among progressive or recurrent breast cancer patients with multiple drug resistance. We reported seven Japanese patients who received CPT-11 as salvage chemotherapy. Performance statuses of all patients were 1 or 2, and all patients were managed by ambulatory treatment. CPT-11 was administered at a dose of 80-100mg/m2 weekly on day 1 for 3 consecutive weeks, followed by a 2-week rest period. One patient had a partial response and CPT-11 was administered for 68 weeks. Two patients had grade 3 neutropenia. Grade 3 diarrhea was not observed. CPT-11 is a very useful choice as salvage chemotherapy for breast cancer patients with recurrence or local progression.

Recent Advances in Immunotherapy for Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related death since most patients are diagnosed at advanced stage and the current systemic treatment options using molecular-targeted drugs remain unsatisfactory. However, the recent success of cancer immunotherapies has revolutionized the landscape of cancer therapy. Since HCC is characterized by metachronous multicentric occurrence, immunotherapies that induce systemic and durable responses could be an appealing treatment option. Despite the suppressive milieu of the liver and tumor immunosurveillance escape mechanisms, clinical studies of checkpoint inhibitors in patients with advanced HCC have yielded promising results. Here, we provide an update on recent advances in HCC immunotherapies. First, we describe the unique tolerogenic properties of hepatic immunity and its interaction with HCC and then review the status of already or nearly available immune checkpoint blockade-based therapies as well as other immunotherapy strategies at the preclinical or clinical trial stage.

Branched-chain amino acid to tyrosine ratio is an essential pre-treatment factor for maintaining sufficient treatment intensity of lenvatinib in patients with hepatocellular carcinoma.

BACKGROUND/PURPOSE: Lenvatinib was recently approved as a novel agent for hepatocellular carcinoma. To maximize the therapeutic effect of anticancer drugs, it is essential to maintain treatment intensity by avoiding dose reduction or discontinuation. We aimed to identify essential factors contributing to achieve sufficient treatment intensity of lenvatinib. METHODS: Seventy-one patients who received treatment with lenvatinib were included in this study. We used the delivered dose intensity/body surface area ratio (DBR) to measure treatment intensity of lenvatinib. RESULTS: 2M-DBR (DBR for the first 60 days) of lenvatinib (≥206.7) was strongly correlated with objective response and was the significant factor contributing to prolonged progression-free survival (PFS). Patients with high 2M-DBR had significantly prolonged PFS compared with those who had low 2M-DBR (P < .001). Multivariate analysis revealed that pre-treatment α-fetoprotein and branched-chain amino acid to tyrosine ratio (BTR) were significant factors in maintaining high 2M-DBR of lenvatinib. Furthermore, patients with high pre-treatment BTR (≥4.50) showed significantly longer PFS than those with low BTR (P = .032). CONCLUSIONS: Maintaining high 2M-DBR of lenvatinib is essential to increase response rate and PFS. To achieve high 2M-DBR levels, preservation of pre-treatment BTR is essential, suggesting the importance of nutritional management in the treatment for hepatocellular carcinoma with lenvatinib.

Dose Intensity/Body Surface Area Ratio is a Novel Marker Useful for Predicting Response to Lenvatinib against Hepatocellular Carcinoma.

Lenvatinib was recently approved as a novel first-line molecular targeted agent (MTA) for treating hepatocellular carcinoma (HCC). The importance of relative dose intensity (RDI) has been shown in the treatment of various types of cancers. However, RDI may not accurately reflect the treatment intensity of lenvatinib, as it is the first oral MTA where the dose is based on the patient's weight. We aimed to evaluate the utility of 2M-DBR (the delivered dose intensity/body surface area ratio at 60 days) by comparing the relationship between 2M-DBR, 2M-RDI (RDI at 60 days), and the therapeutic response. The therapeutic response to lenvatinib was evaluated in 45 patients who underwent computed tomography 8-12 weeks after treatment initiation. We also investigated the clinical factors associated with high 2M-DBR. The area under the receiver operating characteristic of 2M-DBR that predicts the response to lenvatinib was higher than that of 2M-RDI (0.8004 vs. 0.7778). Patients with high 2M-DBR achieved significantly better objective responses and disease control rates than those with low 2M-DBR (p < 0.0001 and 0.0008). Patients with high 2M-DBR experienced significantly longer progression-free survival (PFS) than those with low 2M-DBR (p = 0.0001), while there was no significant correlation between 2M-RDI levels and PFS (p = 0.2198). Patients who achieved higher levels of 2M-DBR had a significantly better modified ALBI grade (p = 0.0437), better CONUT score (p = 0.0222), and higher BTR (p = 0.0281). Multivariate analysis revealed that high 2M-DBR was the only significant factor associated with longer PFS. In conclusion, 2M-DBR could be an important factor that reflects treatment intensity and useful for predicting the response to lenvatinib against HCC, instead of 2M-RDI.

Angiosarcoma arising in the breast following breast-conserving surgery with radiation for breast carcinoma.

We report a case of angiosarcoma arising in the breast following breast-conserving surgery with radiation therapy for breast carcinoma. The patient, a 49-year-old postmenopausal woman, had undergone breast-conserving surgery for invasive ductal carcinoma of the left breast (pT2 pN0 M0 Stage IIA). Adjuvant radiotherapy (50 Gy with a booster dose to the tumor bed of 10 Gy) was then performed for the residual breast tissue and the patient was treated with hormone therapy (tamoxifen, 20 mg daily) for 5 years. She presented with skin erosion with bleeding 10 years after the initial operation. Incisional biopsy revealed angiosarcoma of the breast, and total mastectomy was subsequently performed. The patient was the treated with chemotherapy (weekly paclitaxel, 80 mg/m2 x cycles) and has remained well without evidence of local or distant recurrence.

Sentinel node micrometastasis and distant failure in breast cancer patients.

BACKGROUND: Lymphatic mapping and sentinel lymph node (SN) biopsy has rapidly replaced axillary lymph node dissection for clinically node-negative breast cancers. Because of a short follow-up period when the procedure was new, there were few reports of the clinical recurrence rate in breast cancer patients treated with SN biopsy. The present study attempts to clarify the occurrence of distant failure after SN biopsy, especially in breast cancer patients with SN micrometastasis. METHODS: The subjects consisted of 375 cases with clinically node-negative breast cancer, who had undergone SN biopsies. Chemotherapy and/or hormonal therapy was recommended based on the pathological primary tumor characteristics. The patients with SN micrometastasis also received adjuvant therapy equal to node-positive patients. RESULTS: Examinations of lymph nodes indicated metastases in 73 cases. Among the invasive cancers, 54 cases had macrometastasis, 19 cases had micrometastasis and 241 cases had a tumor free SN. The median follow-up period ws 30 months (range 6 to 66 months). Distant relapse rates per person-years were 0.3% in the cases with tumor free SN and 3.3% among the macrometastatic cases. However, systemic disease was not observed in the cases with SN micrometastasis. CONCLUSIONS: These results may show that upstaging due to SN investigation increases the number of cases who should receive anti-cancer drugs, and consequently reduces the distant relapse rate. Further studies in a large number of cases as well as longer follow-up are needed to determine the prognostic significance of SN micrometastasis.

Ultrasound Demonstration of Mammographically Detected Microcalcifications in Patients with Ductal Carcinoma in situ of the Breast.

BACKGROUND: Breast microcalcifications are difficult to depict by ultrasound (US). However, recent advances in US equipment and the refinement of breast imaging techniques have improved the detection and characterization of small breast lesions. The present study attempts to determine whether US examination is able to demonstrate nonpalpable breast lesions associated with mammographically detected microcalcifications without mass density or distortion, and to evaluate the clinical reliability of US-guided procedures, especially in cases of ductal carcinoma in situ(DCIS)of the breast. METHODS: The subjects consisted of 73 patients with breast cancer diagnosed preoperatively as DCIS by stereotactic core needle biopsies, all of whom had microcalcifications without other abnormalities on mammography. The radiological appearance and size of the clustered microcalcifications were evaluated. US examinations were performed preoperatively, and the detection rates were assessed. Sonographically detected lesions underwent US-guided wire localization followed by surgical excision. RESULTS: The lesions associated with microcalcifications were identified sonographically in 54 of 73 cases (74%), and the pathological examination revealed breast cancer in all of the corresponding specimens. Lesions with linear-branching shape, segmental-linear distribution and category-5 calcifications on mammography had a high level of visibility on US. The US visible cases had a larger size of calcified area on mammography when compared with US invisible cases. Pathologically, the lesions were more frequently seen on US in cases with minimally invasive cancer or with comedo type DCIS. CONCLUSIONS: US examination is an effective method for identifying and localizing breast microcalcifications, and can be used as an alternative to stereotactic localization in selected patients with early breast cancer.

A rare case of esophageal cancer (T2N0) with a solitary cerebellar metastasis.

A 72-year-old man with a history of distal gastrectomy was diagnosed with esophageal cancer (EC). A subtotal esophagectomy and the residual total gastrectomy were performed via a right-sided thoracotomy and laparotomy with D2 lymph node dissection followed by reconstruction with a retrosternal right colonic interposition. The pathological diagnosis was Mt, 65 mm, moderately differentiated squamous cell carcinoma, pT2, ly0, v2, pN0, sM0, pStage II. The patient suddenly developed neurological symptoms 10 days after the operation, and brain magnetic resonance imaging detected a single solid left cerebellar tumor. This tumor was completely excised, and pathological diagnosis confirmed the tumor as an EC metastasis. He received adjuvant chemotherapy with cisplatin + 5-fluorouracil. Seven months later, he developed multiple brain metastases; however, no evidence of local recurrence or other metastatic sites was found. He died 8 months after the surgery. Solitary cerebellar metastasis from EC in which the primary tumor is T2N0 is rare, and the mechanism of this metastatic pattern is of particular interest. Our case study suggests that even if the primary tumor is in the limited stage and other metastatic sites are not identified at presentation, it seems reasonable to perform preoperative imaging of the brain for all patients with EC.

Pharmacokinetic analysis of ductal carcinoma in situ of the breast using dynamic MR mammography.

The purpose of this study was to assess the relationship between functional parameters derived from dynamic MR imaging and the histological findings of breast ductal carcinoma in situ (DCIS) and DCIS with invasive foci, and to evaluate whether these parameters might predict DCIS patient outcome. Two parameters, amplitude A and k(21), were determined from multicompartmental pharmacokinetic analyses of dynamic MR mammography in 39 patients with needle biopsy-proven primary DCIS. After surgery, the histological tumor characteristics, including microvessel density (MVD) (anti-CD-34), vascular permeability (anti-VEGF antigen) and histological grade, were evaluated. Histology revealed 27 pure DCIS and 12 DCIS with invasive foci. In pure DCIS, positive correlations between MVD and amplitude A (r=0.56, P<0.0025) and between MVD and k(21) (r=0.43, P=0.02) were found. As for histological grade, the differences in both functional parameters of grade 1 versus grade 2 and grade 1 versus grades 2 and 3 combined were significant (P<0.05). No significance was found in the analysis of DCIS with invasive foci. Our results indicated that functional MRI-based parameters might possess the potential to predict the outcome of patients with DCIS. Further study will be needed with larger series over longer periods.