[365 Days in Newly Opened Cancer Treatment Center in Core Hospital of Mountainous Area].

The declining birthrate and aging population is one of the social issues in mountainous area in Japan. One regional core hospital at Aizu area in Fukushima prefecture opened cancer treatment center in these area in July, 2022. A high-performance radiation therapy system was newly installed and operated with the staff of Fukushima Medical University, and several supportive therapy for cancer chemotherapy including appearance care became possible in the center. The patients living in Aizu area can receive advanced treatments including radiation therapy without moving to long-distant bigger cities now. We report multiple preparations and several trials that we have made during one year since the opening of the center.

Ficus pumila L. improves the prognosis of patients infected with HTLV-1, an RNA virus.

Human T-cell leukemia virus type 1 was isolated as the retrovirus to be identified in humans. Here, we focused on Ficus pumila L. as a factor that be effective against human T-cell leukemia virus type 1. The significant and novel findings is that symptoms of patients with drinking Ficus pumila L. extracts did not worsen despite a lack of aggressive pharmacotherapy against adult T-cell leukemia, a human T-cell leukemia virus type 1-associated myelopathy, or T-cell leukemia virus type 1 uveitis. Twenty-eight of the 194 inpatients who underwent showed high levels of human T-cell leukemia virus type 1.Among human T-cell leukemia virus type 1-infected patients, those who were administered Ficus pumila L. extracts had no human T-cell leukemia virus type 1-related symptoms, while those who were not administered Ficus pumila L. extracts had human T-cell leukemia virus type 1-related diseases and a significantly poorer prognosis. This suggests that the Ficus pumila L. extracts may show some utility against virus infection.

Treatment of lung adenocarcinoma by molecular-targeted therapy and immunotherapy.

Lung adenocarcinoma (LADC) is a cancer treatable using targeted therapies against driver gene aberrations. EGFR mutations and ALK fusions are frequent gene aberrations in LADC, and personalized therapies against those aberrations have become a standard therapy. These targeted therapies have shown significant positive efficacy and tolerable toxicity compared to conventional chemotherapy, so it is necessary to identify additional druggable genetic aberrations. Other than EGFR mutations and ALK fusions, mutations in KRAS, HER2, and BRAF, and driver fusions involving RET and ROS1, have also been identified in LADC. Interestingly, the frequency of driver gene aberrations differs according to ethnicity, sex, and smoking, which leads to differences in treatment efficacy. To date, several molecular-targeted drugs against driver genes have been developed, and several clinical trials have been conducted to evaluate the efficacy. However, targeted therapies against driver-gene-negative cases have not yet been well developed. Efforts to identify a new druggable target for such cases are currently underway. Furthermore, immune checkpoint blockade therapy might be effective for driver-negative cases, especially those with accumulated mutations.

Metastasis of breast cancer cells to the bone, lung, and lymph nodes promotes resistance to ionizing radiation.

BACKGROUND: Metastasis represents the leading cause of breast cancer deaths, necessitating strategies for its treatment. Although radiotherapy is employed for both primary and metastatic breast cancers, the difference in their ionizing radiation response remains incompletely understood. This study is the first to compare the radioresponse of a breast cancer cell line with its metastatic variants and report that such metastatic variants are more radioresistant. MATERIALS AND METHODS: A luciferase expressing cell line was established from human basal-like breast adenocarcinoma MDA-MB-231 and underwent in vivo selections, whereby a cycle of inoculations into the left cardiac ventricle or the mammary fat pad of athymic nude mice, isolation of metastases to the bone, lung and lymph nodes visualized with bioluminescence imaging, and expansion of obtained cells was repeated twice or three times. The established metastatic cell lines were assessed for cell proliferation, wound healing, invasion, clonogenic survival, and apoptosis. RESULTS: The established metastatic cell lines possessed an increased proliferative potential in vivo and were more chemotactic, invasive, and resistant to X­ray-induced clonogenic inactivation and apoptosis in vitro. CONCLUSION: Breast cancer metastasis to the bone, lung, and lymph nodes promotes radioresistance.

Intraperitoneal chemotherapy for gastric cancer with peritoneal disease: experience from Singapore and Japan.

Among advanced gastric cancer cases, peritoneal dissemination is a life-threatening mode of metastasis, and any strategy to control peritoneal metastasis will significantly improve treatment outcomes. Since intraperitoneal administration of anticancer drugs can induce an extremely high concentration of drugs in the peritoneal cavity, intraperitoneal chemotherapy would appear to be a reasonable and promising strategy to control the peritoneal dissemination. However, it has been reported in the past that intraperitoneal administration of mitomycin C or cisplatin resulted in no significant clinical effects against peritoneal metastasis of gastric cancer. In contrast, intraperitoneal paclitaxel is expected to remain inside the peritoneal cavity due to its large molecular weight and fat solubility, leading to a high concentration of the drug in the peritoneal cavity. In fact, promising results in several phase II clinical trials using intraperitoneal paclitaxel have been reported, including a median survival time of 16.2-24.6 months and a 1-year overall survival rate of 69-78 %. Thereafter, a phase III randomized control study (PHOENIX-GC trial) with intraperitoneal paclitaxel plus systemic S-1 and intravenous paclitaxel in comparison to systemic S-1 plus cisplatin was conducted in Japan. Moreover, a phase II clinical trial of combination chemotherapy of intraperitoneal paclitaxel with systemic capecitabine plus oxaliplatin is currently ongoing in Singapore. In this review, based on clinical experience from Singapore and Japan, the clinical significance of intraperitoneal chemotherapy for gastric cancer with peritoneal disease is discussed.

Stromal VCAN expression as a potential prognostic biomarker for disease recurrence in stage II-III colon cancer.

To develop prognostic biomarkers that can discriminate stage II-III colorectal cancer patients with high risk of postoperative recurrence, we conducted a genome-wide screening of relapse-related genes utilizing multiple microarray cohorts. Among differentially expressed genes between tumor and nontumor, we identified eight candidate genes associated with relapse in two datasets of stage II-III patients (n = 94 and 145, respectively, P < 0.05). Using datasets of laser-microdissected samples and FACS-purified cell populations, the localization of candidate genes, including COL4A2, COL4A1, VCAN and SERPINE1, were found predominantly in cancer stroma rather than epithelial components. Among those relapse-related stromal genes, VCAN mRNA, specifically expressed in cancer-associated fibroblasts, was further validated to be a prognostic factor in two additional independent datasets, consisting of 453 (P = 0.0334) and 89 (P = 0.0041) stage II-III patients. Furthermore, in our large set of formalin-fixed paraffin-embedded cohort (n = 338), VCAN protein was detected exclusively in cancer stroma by immunohistochemistry, demonstrating a stepwise increase of stromal VCAN from normal tissues through stage 0 to stage IV tumors. Stromal VCAN protein was associated with shorter relapse-free survival (RFS) in stage II-III colon cancer, independent of other clinical factors by multivariate analysis (P = 0.004). Stratified analyses revealed that stromal VCAN was a strong prognostic indicator particularly in stage II colon cancer (P = 0.0029). In all five analyzed cohorts, the expression of VCAN, in transcript or protein levels, was associated with poor RFS in stage II-III patients. We conclude that VCAN is a promising biomarker to identify stage II-III patients at high risk of relapse who may benefit from intensive postoperative management.

Gene aberrations for precision medicine against lung adenocarcinoma.

Lung adenocarcinoma (LADC), the most frequent histological type of lung cancer, is often triggered by an aberration in a driver oncogene in tumor cells. Examples of such aberrations are EGFR mutation and ALK fusion. Lung adenocarcinoma harboring such mutations can be treated with anticancer drugs that target the aberrant gene products. Additional oncogene aberrations, including RET, ROS1, and NRG1 fusions, skipping of exon 14 of MET, and mutations in BRAF, HER2, NF1, and MEK1, were recently added to the list of such "druggable" driver oncogene aberrations, and their responses to targeted therapies are currently being evaluated in clinical trials. However, approximately 30% and 50% of LADCs in patients in Japan and Europe/USA, respectively, lack the driver oncogene aberrations listed above. Therefore, novel therapeutic strategies, such as those that exploit the vulnerabilities of cancer cells with non-oncogene aberrations, are urgently required. This review summarizes the current status of research on precision medicine against LADC and enumerates the research priorities for the near future.

[Primary Malignant Melanoma of the Gallbladder].

Primary malignant melanoma of the gallbladder is a rare disease, and 37 cases have been reported in the literature.The current patient was a 78-year-old man who was admitted with a pelvic tumor and left leg edema due to compression of the external iliac vein by the pelvic tumor.The edema improved following resection of the tumor, which was diagnosed at pathology as a malignant melanoma.After surgery, the patient became anorexic and complained of discomfort in the upper right abdomen.A whole body FDG-PET scan demonstrated significant uptake in the gallbladder and in the lymph nodes of the lower abdomen.The patient underwent open cholecystectomy, and the pathological diagnosis was malignant melanoma. Junctional activity was seen in the gallbladder, suggesting that this was the primary site.No melanocytic lesions of the skin or eyes were detected, further supporting the diagnosis of primary malignant melanoma of the gallbladder.Chemotherapy was initiated, but the patient died on February 28, 2016.

[A Case of Port Site Recurrence after Laparoscopic Distal Gastrectomy for Advanced Gastric Cancer].

It has been suggested that port site recurrence is a potential complication after laparoscopic distal gastrectomy for gastric cancer, especially considering the increased number of laparoscopic surgeries being performed. We encountered a case of an 84-year-old man who was diagnosed with 2 port site recurrences at the navel and right hypochondrium after laparoscopic distal gastrectomy(D2). Pathological diagnosis for the original tumor was tub2, pT4a, pN1(1/38), M0, pStage III A, and HER2(0). As first-line chemotherapy with S-1 plus CDDP for the port site recurrence failed, second-line chemotherapy with ramucirumab plus paclitaxel(RAM plus PTX)was administered. Although RAM plus PTX therapy induced shrinkage of the port site recurrence, liver metastasis was detected as a new lesion. RAM mono-therapy maintained good QOL for 18 months after surgery.

[Risk Evaluation and Prognostic Prediction of Colorectal Cancer in Elderly Patients Over 80 Years of Age].

This study aimed to investigate risk factors and prognosis ofcolorectal cancer in patients over 80 years ofage. Surgical risk was evaluated by colorectal POSSUM(CR-POSSUM)and prognosis by Glasgow prognostic score(GPS). The analysis included 56 patients aged over 80 years with colorectal cancer during 2002-2012. Mean operation time, blood loss, and period ofhospitalization were 130 min, 111 mL, and 19.9 days, respectively. Postoperative complications occurred in 26 patients (46.4%; complications group). The 5-year overall survival rate for patients with complication scores above 2 was 51.1%, compared to 82.3% in a control group, and patients in the complication group also exhibited a poorer prognosis. CR-POS SUM scores were significantly higher in the complication group than in the control group in PS, OS, and PMR. Further analysis revealed that patients with GPS 0 or 1 had a significantly higher 5-year survival rate(84.9%)than those with GPS2(38.9%, p <0.05).

[A Case of Primary Poorly Differentiated/Small Cell Carcinoma of the Breast in a Patient with Von Recklinghausen's Disease].

We report a case of neuroendocrine carcinoma and poorly differentiated/small cell carcinoma ofthe breast in a patient with von Recklinghausen's disease. The patient was a 46-year-old woman who was diagnosed with von Recklinghausen's disease when she was 22 years old. She presented with left breast pain, and physical examination revealed a firm mass in the left breast. A core needle biopsy of the tumor revealed triple negative breast cancer with neuroendocrine features. We performed a simple mastectomy with lymph node dissection. We did not plan neoadjuvant chemotherapy because the tumor would be possibly inoperative if neoadjuvant chemotherapy was not effective for this neuroendocrine cancer. The tumor was diagnosed as a neuroendocrine carcinoma and poorly differentiated/small cell carcinoma. The patient was treated with CDDP and CPT- 11, which is a regimen often used to treat small cell lung cancer.

Water intake disorder in a DEND syndrome afflicted patient with R50P mutation.

In this study, we present a case of developmental delay, epilepsy and neonatal diabetes (DEND) syndrome in a young male patient with the R50P mutation located in the Kir6.2 subunit of the ATP-sensitive K(+) (KATP) channel. Whereas most patients with DEND syndrome are resistant to sulfonylurea therapy, our patient was responsive to sulfonylurea, lacked the most common neurological symptoms, such as epilepsy, but refused to drink water. His serum electrolytes and plasma osmolarity were normal but the serum vasopressin level was increased. To investigate the underlying mechanism of his water intake disorder, a 5 µL aliquot of 340 µM KATP channel opener diazoxide or 100 µM KATP channel inhibitor glibenclamide was injected into the third ventricle of the rat brain, and water intake was monitored. Although the injection of glibenclamide had no effect, injection of diazoxide significantly increased water intake by about 1.5 fold without affecting food intake. This result indicates that the KATP channel activity in the brain may have an influence on water intake. Here, we present the first case of a DEND syndrome-afflicted patient with water intake disorder and increased serum vasopressin level, possibly related to altered KATP channel activity.

[A Case of Gastrointestinal Perforation in a Patient with Colon Cancer and Stent Placement during Bevacizumab Treatment, Alleviated with Conservative Therapy].

The case involved a 52-year-old man. He was diagnosed with sigmoid colon cancer and multiple liver and lung metastases. After placement of a metallic stent for circumferential stricture, 5-fluorouracil/Leucovorin/oxaliplatin (FOLFOX4) plus bevacizumab therapy was introduced. After 17 courses, gastrointestinal perforation was noted at the site of stent placement, but this was alleviated with conservative therapy. Although gastrointestinal perforation is known to be a serious complication that occurs during chemotherapy combined with bevacizumab, further studies are needed to investigate the incidence of gastrointestinal perforation after stent placement more fully.

[Treating Side Effects of FOLFIRINOX--A Study of the Effect of Hange-Shashin-To on Preventing Diarrhea].

OBJECTIVES: FOLFIRINOX is an effective therapy for unresectable advanced pancreatic cancer. However, FOLFIRINOX has side effects of blood and gastrointestinal toxicity. Diarrhea, one of the side effects of CPT-11, sometimes becomes serious. We studied whether Hange-shashin-to could prevent diarrhea caused by CPT-11. METHODS: Seven patients who were diagnosed with unresectable pancreatic cancer, either Stage Ⅳor recurrent disease, were enrolled. They took 2.5 g of Hange-shashin-to before each meal starting one day before FOLFIRINOX, and continued taking it for one week. We examined the occurrence of diarrhea by using CTCAE retrospectively. RESULTS: The median age was 61 years. The median number of chemotherapy courses was 4. The frequency of diarrhea was lower, compared to the results of ACCORD11 trial and the domestic phaseⅡ clinical trials. In addition, Grade 3 or more serious diarrhea was not observed, even in the patients with genetic polymorphisms of UGT1A1. CONCLUSION: The incidence of diarrhea in patients treated with Hange-shashin-to in our department was lower compared to the ACCORD11 trial and domestic phase Ⅱ clinical trials. Hange-shashin-to is useful to allay the severity of diarrhea caused by CPT-11 in FOLFIRINOX therapy.

[A Long-Term Survival Case of Unresectable Hilar Bile Duct Cancer Treated with Gemcitabine].

A 69-year-old woman was diagnosed with liver dysfunction on blood testing in a nearby clinic. Computed tomography revealed stenosis of the hilar bile duct. Accordingly, an endoscopic nasobiliary drainage tube was inserted in the left hepatic duct and she was referred to our hospital for diagnostic examinations and treatment. The endoscopic retrograde cholangiopancreatography findings revealed obstruction of the cystic duct and stenosis of the hilar bile duct due to inflammation of the cystic duct or inflammation of the clamping type by cholecystitis. Considering the possibility of malignant tumor, surgical operation was performed. Radical resection was considered impossible and we instead performed cholecystectomy and resection of a bile duct wall specimen for diagnosis. The pathological diagnosis was poorly differentiated tubular adenocarcinoma. The patient was treated with gemcitabine as systemic chemotherapy for unresectable hilar bile duct cancer. Currently, 78 months after the start of chemotherapy, the patient is alive and well, without tumor progression.

[Curative Surgery for Advanced Gastric Cancer with Extensive Lymph Node Metastasis after Long-Term Chemotherapy].

A 65-year-old man was diagnosed with HER2-positive gastric cancer considered unresectable owing to multiple distant lymph node metastases. After long-term chemotherapy, the original lesion disappeared, while peri-gastric lymph node metastases remained. Therefore, we performed lower mediastinal lymph node dissection, total gastrectomy with regional lymph node dissection (D2) and cholecystectomy. Pathological evaluation indicated that the main gastric tumor showed complete response, while there was metastasis in the No.3 lymph nodes, which showed HER2 positivity (3+). At present, the patient has received Xeloda plus trastuzumab and remains relapse-free 5 months after conversion surgery.

[Two Cases of Digestive Organ Cancer in Patients with Situs Inversus Treated with Laparoscopic Surgery].

Case 1: A 53-year-old woman had a positive fecal occult blood test during an examination performed in June 2014, and she visited our department in August. Colonoscopic examination showed a type 2 rectal cancer 4 cm from the anal verge. CT showed situs inversus totalis. We performed laparoscopic abdominoperineal resection (D2) for a diagnosis of cT1b, N0, M0, Stage Ⅰrectal cancer. Case 2: A 60-year-old man had a positive fecal occult blood test. Colonoscopic examination showed a type 2 cancer of the ascending colon. Chest radiography showed dextrocardia, but the arrangement of the organs in the abdomen was normal. We performed laparoscopic ileocecal resection (D3) for a diagnosis of cT2, N0, M0, StageⅠ colon cancer. Laparoscopic surgery can be performed safely in patients with situs inversus totalis.

AP-1 clathrin adaptor and CG8538/Aftiphilin are involved in Notch signaling during eye development in Drosophila melanogaster.

Clathrin adaptor protein complex-1 (AP-1) and its accessory proteins play a role in the sorting of integral membrane proteins at the trans-Golgi network and endosomes. Their physiological functions in complex organisms, however, are not fully understood. In this study, we found that CG8538p, an uncharacterized Drosophila protein, shares significant structural and functional characteristics with Aftiphilin, a mammalian AP-1 accessory protein. The Drosophila Aftiphilin was shown to interact directly with the ear domain of γ-adaptin of Drosophila AP-1, but not with the GAE domain of Drosophila GGA. In S2 cells, Drosophila Aftiphilin and AP-1 formed a complex and colocalized at the Golgi compartment. Moreover, tissue-specific depletion of AP-1 or Aftiphilin in the developing eyes resulted in a disordered alignment of photoreceptor neurons in larval stage and roughened eyes with aberrant ommatidia in adult flies. Furthermore, AP-1-depleted photoreceptor neurons showed an intracellular accumulation of a Notch regulator, Scabrous, and downregulation of Notch by promoting its degradation in the lysosomes. These results suggest that AP-1 and Aftiphilin are cooperatively involved in the intracellular trafficking of Notch during eye development in Drosophila.