A strategy for low-cost portable monitoring of plasma drug concentrations using a sustainable boron-doped-diamond chip.

On-site monitoring of plasma drug concentrations is required for effective therapies. Recently developed handy biosensors are not yet popular owing to insufficient evaluation of accuracy on clinical samples and the necessity of complicated costly fabrication processes. Here, we approached these bottlenecks via a strategy involving engineeringly unmodified boron-doped diamond (BDD), a sustainable electrochemical material. A sensing system based on a ∼1 cm2 BDD chip, when analysing rat plasma spiked with a molecular-targeting anticancer drug, pazopanib, detected clinically relevant concentrations. The response was stable in 60 sequential measurements on the same chip. In a clinical study, data obtained with a BDD chip were consistent with liquid chromatography-mass spectrometry results. Finally, the portable system with a palm-sized sensor containing the chip analysed ∼40 µL of whole blood from dosed rats within ∼10 min. This approach with the 'reusable' sensor may improve point-of-monitoring systems and personalised medicine while reducing medical costs.

Efficacy of BRAF inhibitor and anti-EGFR antibody in colorectal neuroendocrine carcinoma.

Neuroendocrine neoplasms of the colon and rectum are colorectal epithelial neoplasms with neuroendocrine differentiation. A platinum regimen used for small cell lung cancer is the currently recommended chemotherapy for gastroenteropancreatic neuroendocrine carcinomas (GEP-NECs), regardless of the organ. The BRAF V600E mutation has been recently reported as a druggable driver mutation in colorectal NECs. In BRAF V600E mutant colorectal cancer, a combination of BRAF inhibitor and anti-epidermal growth factor receptor (EGFR) antibody, with or without a MEK inhibitor, is recommended. Here, we report the case of 77-year-old man who had lymph node recurrence after surgery for primary ascending colonic NEC. Two cytotoxic regimens, cisplatin plus irinotecan and modified FOLFOX6, were administered as first- and second-line chemotherapies with no remarkable response observed. At this point, genetic analysis confirmed the tumor harbored a BRAF V600E mutation. Thus, a regimen of BRAF inhibitor plus anti-EGFR antibody was administered. After commencing this regimen, carcinoembryonic antigen levels decreased within normal range, and there was dramatic shrinkage of the lymph node metastases observed by chest and abdominal computed tomography scans. To our knowledge, this is the first reported case of a colorectal NEC responding to a BRAF inhibitor and anti-EGFR antibody.

Age-Based Comparison of Hematological Toxicity in Patients with Lung Cancer.

INTRODUCTION: Because of the increasing age of the general population, there is an increasing number of older patients with lung cancer. Cancer chemotherapy often causes severe hematological toxicity in older patients. OBJECTIVE: This study aimed to explore the risk factors affecting the hematological toxicity of cytotoxic anticancer drugs in patients with lung cancer. METHODS: Data were retrospectively collected from 194 patients with lung cancer at Niigata University Medical and Dental Hospital, Japan, between April 2011 and March 2016, when the patients underwent their first round of cytotoxic chemotherapy. The patients were divided into three groups on the basis of age: <65, 65-74, and ≥75 years. Physiological functions and laboratory data before treatment, as well as hematological adverse events following chemotherapy, were compared among the groups. RESULTS: Patients aged ≥75 years were significantly more likely to experience grade 3 or 4 neutropenia, compared with patients aged <65 years. However, there were no differences in the incidence of anemia or thrombocytopenia among the age groups. The frequency of febrile neutropenia tended to increase with age. Multivariate analysis showed that age ≥75 years, male sex, and a performance status of ≥2 were independent factors for grade 3 or 4 neutropenia. Patients with 2 or 3 of these factors had a significantly higher frequency of neutropenia, compared with patients who had 0 or 1 of these factors. CONCLUSION: We found that age ≥75 years, male sex, and a performance status of ≥2 were independent risk factors for grade 3 or 4 neutropenia.

Success and limitations of plasma treatment in pregnant women with congenital thrombotic thrombocytopenic purpura.

BACKGROUND: Congenital thrombotic thrombocytopenic purpura (cTTP), otherwise known as Upshaw-Schulman syndrome, is an extremely rare hereditary disease. Pregnancy is identified as a trigger for TTP episodes in patients with cTTP. OBJECTIVES: To investigate the ideal management of pregnant patients with cTTP. PATIENTS/METHODS: We identified 21 patients with a reproductive history (38 pregnancies) in a Japanese cTTP registry. Fetal outcomes were compared between two groups: group 1 (n = 12), pregnancy after diagnosis of confirmed cTTP by ADAMTS13 gene analysis; and group 2 (n = 26), pregnancy before diagnosis of confirmed cTTP. RESULTS: In group 1, ADAMTS13 activity was closely monitored until delivery in most cases. Among 10 pregnancies in group 1, prophylactic fresh frozen plasma (FFP) infusions during pregnancy were performed to replenish ADAMTS13. In group 2, prophylactic FFP infusions were not administrated in 23 pregnancies and FFP test infusions were performed in only three pregnancies. The live birth rate of group 1 was significantly higher than that of group 2 (91.7% vs 50.0%, respectively, P = .027). The fetal survival rates of women without FFP infusions were dramatically decreased after 20 weeks of gestation. The FFP infusion dosage in group 1 was generally higher than 5 mL/kg/wk by 20 weeks of gestation. CONCLUSIONS: Our results indicate that FFP infusions of more than 5 mL/kg/wk should be initiated as soon as patients become pregnant. However, even with these infusions, patients with repeated TTP episodes before pregnancy might have difficulty giving birth successfully. Recombinant ADAMTS13 products might be new treatment options for pregnant patients with cTTP.

Treatments and outcomes of older patients with esophageal cancer: Comparison with younger patients.

The number of older patients with esophageal cancer (EC) is increasing due to the population aging and increasing life expectancy. However, no optimal treatment strategy for older patients with EC has been established to date. The aim of the present study was to review and compare the treatment modalities and outcomes of 990 younger and older patients diagnosed with EC in our institution. The patients were divided into younger (≤74 years) and older (≥75 years) groups. The majority of the patients in both groups had early-stage EC and were treated by endoscopic submucosal dissection (ESD). The older patients with locally advanced (stage II and III) EC were more likely to undergo chemoradiotherapy rather than esophagectomy. Among the older patients, 22% selected best supportive care. The disease-specific survival rate of the older patients was significantly lower compared with that of the younger patients, which was likely due to the less intense treatment modalities applied. The prognosis following esophagectomy was significantly better compared with that of chemoradiotherapy in the younger, but not in the older patients. In conclusion, the poorer prognosis of older patients (aged ≥75 years) with stage I EC may improve with multidisciplinary treatment after ESD. Although CRT is currently considered the optimal treatment for older patients with stage II/III EC, more efficient treatment modalities are urgently required.

Treatment of Gastric and Gastroesophageal Cancer Patients with Hemodialysis by CapeOX.

Two patients underwent hemodialysis. Case 1 with stage IV gastric cancer was treated with reduced doses of capecitabine (1,000 mg/m2/day, days 1 to 14) and oxaliplatin (65 mg/m2, day 1). Although grade 1 thrombocytopenia occurred in the first cycle, grade 3 thrombocytopenia developed in the second cycle because of increasing dosage. After the dosage was reduced, chemotherapy was continued safely. Case 2 with stage IA gastroesophageal cancer was treated with radiotherapy followed by chemotherapy. Treatment with the same dose of CapeOX therapy as in case 1 resulted in no severe toxicity. We conclude that a half-dose of the CapeOX regimen is safe for gastric cancer patients undergoing hemodialysis.

Cancers among adolescents and young adults at one institution in Japan.

Adolescents and young adults (AYAs) with cancer often live long lives following treatment and face many life events. No detailed studies of cancers in AYAs have described the epidemiology, treatment outcome, and social status in Japan. The present study defined AYAs as those aged 15-29 years old based on the US National Cancer Institute Surveillance, Epidemiology, and End Results (SEER) program. Data was collected from the hospital-based cancer registry and electronic medical charts at Niigata University Medical and Dental Hospital from 2007 to 2015. The present study analyzed the types of cancer, treatment methods and outcomes, fertility preservation, marital status, raising children, school admission, and employment status. A total of 362 (1.9%) cancer cases in AYAs (males 119, females 243) were identified. Carcinoma was the most common type of cancer in both sexes. Females had a high incidence of carcinoma of the genitourinary tract (28.0%). Fertility-sparing surgery (16.0%) was the most common method of fertility preservation. The 5-year survival was better in females (88.4%) than in males (79.9%). The percentage of married AYAs increased following cancer treatment. The proportion of unemployment increased following cancer treatment in all age groups and was greatest (12.6%) in those aged 20-24 years old. Compared with SEER data from the United States, the incidence of carcinoma was high among AYAs, particularly genitourinary tract carcinomas in females, while the incidence of melanoma and skin carcinomas was low. Therefore, AYAs with cancer requires social and economic support.

Trachea Engineering Using a Centrifugation Method and Mouse-Induced Pluripotent Stem Cells.

The outcomes of tracheal transplantation for the treatment of airway stenosis are unsatisfactory. We investigated the feasibility of regeneration of the trachea using a rat decellularized tracheal scaffold and mouse-induced pluripotent stem (iPS) cells for in vivo transplantation. The rat trachea was first decellularized using a detergent/enzymatic treatment method. We successfully established a centrifugation method that can transplant cells onto the luminal surface of the decellularized rat tracheal scaffold circumferentially. Two types of mouse iPS cells were differentiated into definitive endoderm cells and transplanted onto the luminal surface of the decellularized tracheal matrix scaffold using this centrifugation method. For in vivo study, normal rat tracheas, no-cell rat tracheal scaffolds, or rat tracheal scaffolds recellularized with rat tracheal epithelial cells (EGV-4T) were orthotopically transplanted on F344 rats, and rat tracheal scaffolds recellularized with mouse iPS cells were transplanted on F344/NJc1-rnu/rnu rats. Rats transplanted with no-cell scaffolds or scaffolds recellularized with EGV-4T survived for 1 month, although airway stenosis was observed. One of the F344/NJc1-rnu/rnu rats transplanted with rat trachea regenerated using mouse iPS cells survived over 5 weeks. Histological analysis indicated the cause of death was airway stenosis due to colonic cellular proliferation of undifferentiated iPS cells. Re-epithelialization with numerous ciliated epithelial cells was observed in one of the rats transplanted with trachea bioengineered using iPS cells. In this study, we present a simple and efficient tracheal tissue engineering model using a centrifugation method in a small-animal model. Tissue-engineered trachea using decellularized tracheal scaffolds and iPS cells is potentially applicable for tracheal transplantation.

The Prognostic Nutrition Index Predicts the Development of Hematological Toxicities in and the Prognosis of Esophageal Cancer Patients Treated with Cisplatin Plus 5-Fluorouracil Chemotherapy.

The prognostic nutrition index (PNI), calculated based on serum albumin and lymphocyte counts, predicts the prognosis of several cancers, including operated esophageal cancers. In this study, we determined whether PNI could predict the occurrence of severe adverse events by chemotherapy and chemoradiotherapy, and overall survival in esophageal cancer. We collected data from 191 patients with esophageal cancer treated with at least one course of cisplatin and 5-fluorouracil from 2005 to 2016. We compared the incidences of severe adverse events and overall survival between a high- and a low-PNI group. The optimal cut-off value of the Onodera PNI was 43.2. Patients with low PNIs suffered more frequent severe adverse events than did those with high PNIs, and the latter patients survived longer. The PNI was independently prognostic of overall survival and stage. The PNI predicted the development of severe adverse events caused by chemotherapy or chemoradiotherapy, and overall survival, in esophageal cancer patients.

Peripheral T-cell lymphoma, not otherwise specified: a retrospective single-center analysis.

We retrospectively analyzed clinical and pathological features, treatments, and prognoses in 28 patients with newly diagnosed peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS) in Niigata University Medical and Dental Hospital. Of them, 16 were males and 12 were females, and their median age was 62.5 (range, 26-88) years. The International Prognostic Index was high-intermediate/high in 68% of patients. Twelve patients were treated with CHOP/THP-COP and nine with third-generation chemotherapy regimens. At a median follow-up period of 30 (range: 1-164) months, the 2-year overall survival and progression-free survival rates were 61% and 44%, respectively. Further investigation of novel agents for treating PTCL-NOS is warranted.

Successful umbilical cord blood hematopoietic stem cell transplantation in a patient with adult T-cell leukemia/lymphoma initially achieving complete remission with anti-CC chemokine receptor 4 antibody combined chemotherapy.

A 62-year-old man with CHOP refractory adult T-cell leukemia/lymphoma (ATLL) received anti-CC chemokine receptor 4 antibody (mogamulizumab) combined with CHOP and achieved complete remission. At 71 days after the final administration of mogamulizumab, he received umbilical cord blood transplantation (CBT) using reduced intensity conditioning. Umbilical cord blood engraftment was confirmed on day16. Grade II acute graft-versus-host disease (GVHD) was diagnosed on day60 and was controlled by administration of methylprednisolone. There was no evidence of relapse at 9 months after CBT. Ratios of regulatory T cells in CD4 positive T cells were remarkably low during all of these periods. Since mogamulizumab reduces regulatory T cells, the frequency and severity of acute GVHD were reported to be increased in patients administered mogamulizumab before allogenic stem cell transplantation. Further experiences are needed for selecting optimal donor sources, the portability period and GVHD prophylaxis for patients using mogamulizumab before allogeneic stem cell transplantation.

[Myelodysplastic syndrome with refractory hemorrhage due to reduced platelet aggregation activity].

A 75-year-old woman suffered a cat bite 10 months after myelodysplastic syndrome (MDS) diagnosis. She visited our hospital because the internal bleeding of the wound did not improve. Although the wound was treated, the bleeding did not stop. She was hospitalized for emergency medical treatment because the bleeding volume exceeded 200 ml. Although her platelet count was normal, the platelet function test showed a decrease in collagen and arachidonic acid aggregation. After platelet transfusion, her bleeding stopped. Patients with MDS may potentially have platelet dysfunction. In the case of bleeding without thrombocytopenia, a platelet function test should be performed and treatment intervention, such as platelet transfusion, should be considered.

Chromosomal rearrangements in myoepithelial carcinoma of the breast that presented as metachronic double cancer with invasive ductal carcinoma in the ipsilateral breast.

Myoepithelial carcinoma of the breast is an extremely rare tumor composed entirely of malignant spindle cells with myoepithelial differentiation. The majority of previously reported cases have mainly described the clinicopathological features of the disease, and few have presented cytogenetic data. We herein present the case of a 48-year-old woman who was admitted with a left-sided breast lump in the inner upper quadrant that was initially diagnosed as a myoepithelioma with potentially malignant disorder. At 12 months after resection, she complained about a newly developed solid mass in the subareolar region of the ipsilateral breast that was diagnosed as an invasive ductal carcinoma. In addition, 16 months after the initial admission, a re-growing remnant lesion recurred in the inner upper quadrant and was ultimately diagnosed as a myoepithelial carcinoma. Lymph node metastasis of the myoepithelial carcinoma was also observed in her left axillary region 11 months after local recurrence. A cytogenetic analysis showed recurring specific chromosomal alterations both in the locally recurrent and in the lymph-node metastatic lesion: 48, XX, t(5;18)(q13;q23),del(6)(q?),+14. + mar1. To our knowledge, this is the first published report of clonal chromosomal rearrangements in myoepithelial carcinoma of the breast that presented as metachronic double cancer with invasive ductal carcinoma in the ipsilateral breast.

Inhibition of Glutaminolysis Inhibits Cell Growth via Down-regulating Mtorc1 Signaling in Lung Squamous Cell Carcinoma.

BACKGROUND/AIM: Inhibition of glutaminolysis has been reported as a promising therapeutic strategy to target several solid carcinomas. We aimed to investigate the effects of glutaminolysis on cell proliferation in lung squamous cell carcinoma cell lines and to explore the potential of targeting glutaminolysis as an anticancer strategy. MATERIALS AND METHODS: Glutamine (Gln) dependence was assessed in six lung squamous cell carcinoma cell lines. Cell proliferation, mammalian target of rapamycin complex 1 (mTORC1) activity and the induction of autophagy were assessed after inhibition of glutaminolysis via Gln depletion or glutaminase (GLS) inhibition. RESULTS: Five of six lung squamous cell carcinoma cell lines exhibited glutamine-dependence. The extent of dependence was correlated with the mRNA levels of GLS1/GLS2. Inhibition of glutaminolysis inhibited cell proliferation by down-regulating of mTORC1 signaling and inducing autophagy in Gln-dependent lung squamous cell carcinoma cell lines. CONCLUSION: Targeting glutaminolysis may represent a potential therapeutic strategy for the treatment of Gln-dependent lung squamous cell carcinomas.

Myelosuppression by chemotherapy in obese patients with gynecological cancers.

PURPOSE: The American Society of Clinical Oncology provides clinical practice guidelines for appropriate cytotoxic chemotherapy dosing for obese adult patients with cancer. The panel recommends that actual body weight should be used when selecting cytotoxic chemotherapy doses regardless of obesity status. However, there have been no reports regarding the appropriate cytotoxic chemotherapy dosing for obese Japanese patients with cancer. PATIENTS AND METHODS: We collected data from 216 gynecological cancer patients who were treated with at least one course of a paclitaxel and carboplatin (TC) regimen or a docetaxel and carboplatin (DC) regimen at Niigata University Medical and Dental Hospital from July 2006 to April 2014. Patients were divided into three groups according to body mass index (BMI): obese (BMI ≥ 25), normal (BMI 18.5-24.9), and underweight (BMI < 18.5), as defined by the Japan Society for the Study of Obesity. We analyzed hematological toxicities by full weight-based chemotherapy in each group. RESULTS: The rates of grade 3/4 leukocytopenia, neutropenia, and thrombocytopenia were not significantly different among the three BMI groups on all patient analyses. For the TC regimen, the obese and normal groups had significantly lower leukocytopenia (grade 3/4) rates than did the underweight group. Also, significant positive correlations between BMI and the nadirs of leukocytes, neutrophils, platelets, and hemoglobin were observed. For the DC regimen, no significant difference was observed among the BMI groups and the rate of grade 3/4 hematological toxicities. CONCLUSIONS: We did not observe stronger myelosuppression in obese cancer patients compared with non-obese cancer patients. Therefore, the cytotoxic chemotherapy dose should be calculated by the actual body weight and unnecessary dose reduction should be avoided.

Relationship between HMGB1 and PAI-1 after allogeneic hematopoietic stem cell transplantation.

BACKGROUND: Conditioning regimens including total body irradiation (TBI) or cyclophosphamide can mobilize high-mobility group box 1 (HMGB1) to peripheral blood. Additionally, increased plasminogen activator inhibitor (PAI)-1 levels are associated with post-allogeneic hematopoietic stem cell transplantation (aHSCT). However, changes to circulating levels of HMGB1 after aHSCT are poorly understood. MATERIALS AND METHODS: The study cohort included 289 patients who underwent aHSCT at one of 25 institutions in Japan. We have investigated the relationship between HMGB1 and PAI-1 following aHSCT. A significant increase in HMGB1 levels occurred after conditioning treatment. Additionally, levels of HMGB1 at day 0 were significantly increased in TBI+ patients and cyclophosphamide/TBI patients. CONCLUSION: Our data revealed that an increased level of HMGB1 at day 0 following aHSCT correlates with increased PAI-1 after aHSCT, which is consistent with previous reports. Increased HMGB1 at day 0 after a conditioning regimen may play a role in transplantation-associated coagulopathy following aHSCT, because PAI-1 can accelerate procoagulant activity.

A case of pancreatic neuroendocrine tumors.

Pancreatic neuroendocrine tumors (pNETs) are an uncommon malignancy arising from the neuroendocrine cells of pancreas. Most cases of pNETs present with metastatic disease, but there are few reports in the literature describing pNETs metastasis to the lung and mediastinal lymph nodes [1]. Moreover, although a multimodal treatment including surgical resection and chemotherapy is acceptable for management of pNETs, advanced pNETs still remain a difficult therapeutic challenge [2, 3]. Radiotherapy or combined chemoradiotherapy has not been standard in the treatment of pNETs. An 80-year-old female was admitted to our hospital with cough and anorexia. She had been diagnosed and resected pNETs 8 years ago. Mass shadow was pointed out with chest X-ray, and endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) was performed. Pathological examination revealed neuroendocrine tumors, so the lung mass was considered as metastasis of pNETs. Then, we discussed her treatment at Cancer Board, and radiotherapy was chosen. We hope this case suggests that radiotherapy will be one of the treatment options for metastatic pNETs.

The association of level of reduction of Wilms' tumor gene 1 mRNA transcript in bone marrow and outcome in acute myeloid leukemia patients.

We focused on the level of reduction of Wilms' tumor gene 1 (WT1) mRNA in bone marrow as minimal residual disease during chemotherapies in adult acute myeloid leukemia (AML) patients. Forty-eight patients were enrolled in this study. Log levels of reduction of WT1 mRNA transcript after induction therapy compared with those at diagnosis were associated with disease-free survival (DFS) (P=0.0066) and overall survival (OS) (P=0.0074) in patients who achieved complete remission. Also log levels of reduction of WT1 mRNA transcript after final consolidation therapy compared with those at diagnosis were associated with DFS (P=0.015) and OS (P=0.012). By multivariate analysis, log levels of reduction of WT1 mRNA transcript after induction therapy and after final consolidation therapy compared with those at diagnosis were extracted as risk factors for outcome. Our results suggest that early and deep reduction of tumor burden may be important for the outcome of AML patients. In addition, it may be useful for the decision to proceed with allogeneic SCT as post-remission therapy.

Late onset post-transfusion hepatitis E developing during chemotherapy for acute promyelocytic leukemia.

We herein report the case of a leukemia patient who developed hepatitis E seven months after undergoing a transfusion with contaminated blood products. The latency period in this case was significantly longer than that of typical hepatitis E. Recently, chronic infection with hepatitis E virus (HEV) genotype 3 has been reported in immunocompromised patients. There is a possibility that our patient was unable to eliminate the virus due to immunosuppression following chemotherapy and the administration of steroids. The prevalence of HEV in healthy Japanese individuals is relatively high and constitutes a critical source of infection via transfusion. Hepatitis E is an important post-transfusion infection, and immunocompromised patients may exhibit a long latency period before developing the disease.