Covalent targeting of FGFR inhibits metastasis

Therapeutic targeting of late-stage breast cancer is limited by an inadequate understanding of how tumor cell signaling evolves during metastatic progression and by the currently available small molecule inhibitors capable of targeting these processes. Herein, we demonstrate that both β3 integrin and fibroblast growth factor receptor-1 (FGFR1) are part of an epithelial-mesenchymal transition (EMT) program that is required to facilitate metastatic outgrowth in response to fibroblast growth factor-2 (FGF2). Mechanistically, β3 integrin physically disrupts an interaction between FGFR1 and E-cadherin, leading to a dramatic redistribution of FGFR1 subcellular localization, enhanced FGF2 signaling and increased three-dimensional (3D) outgrowth of metastatic breast cancer cells. This ability of β3 integrin to drive FGFR signaling requires the enzymatic activity of focal adhesion kinase (FAK). Consistent with these mechanistic data, we demonstrate that FGFR, β3 integrin and FAK constitute a molecular signature capable of predicting decreased survival of patients with the basal-like subtype of breast cancer. Importantly, covalent targeting of a conserved cysteine in the P-loop of FGFR1-4 with our newly developed small molecule, FIIN-4, more effectively blocks 3D metastatic outgrowth as compared to currently available FGFR inhibitors. In vivo application of FIIN-4 potently inhibited the growth of metastatic, patient-derived breast cancer xenografts and murine-derived metastases growing within the pulmonary microenvironment. Overall, the current studies demonstrate that FGFR1 works in concert with other EMT effector molecules to drive aberrant downstream signaling, and that these events can be effectively targeted using our novel therapeutics for the treatment of the most aggressive forms of breast cancer.

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MALAT1 promotes cancer proliferation and metastasis

Recently, pancreatic ductal adenocarcinoma (PDAC) has emerged as one of the most aggressive malignant tumors with the worst prognosis. Previous studies have demonstrated that long non-coding RNA MALAT1 is increased in pancreatic cancer and is identified as a diagnostic biomarker. Nonetheless, the molecular mechanism of elevated MALAT1 levels and tumor aggressiveness remains unknown. In this study, MALAT1 was found to be highly expressed in PDAC tissues, and elevated expression was associated with poorer prognoses. Additionally, MALAT1 was positively linearly correlated with the expression of LC3B mRNA. Furthermore, several molecules involved in cellular autophagic flux were modulated following the downregulation of MALAT1, including LC3, P62 and LAMP-2. Mechanistically, we found that MALAT1 interacted with RNA binding protein HuR, and silencing of MALAT1 greatly enhanced the posttranscriptional regulation of TIA-1 and had further effects on inhibiting autophagy. MALAT1 was speculated to regulate tumorigenesis via HuR-TIA-1 mediated autophagic activation. Hence, we investigated the biological properties of MALAT1 in terms of tumor proliferation and metastasis by promoting autophagy in vitro. In brief, these data demonstrate that MALAT1 could facilitate the advanced progression of tumors in vivo. Our study highlights the new roles of MALAT1 on pro-tumorigenic functioning and anti-cancer therapy via activating autophagy in pancreatic cancer.

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Expression of CCL21 in Ewing sarcoma shows an inverse correlation with metastases and is a candidate target for immunotherapy

Abstract

Ewing sarcoma is an aggressive neoplasm predominantly occurring in adolescents and has a poor prognosis when metastasized. For patients with metastatic disease in particular, immunotherapy has been proposed as possible beneficial additive therapy. CCL21 activation-based immunotherapy was successful in preclinical studies in other tumor types; therefore, we investigated CCL21 expression in Ewing sarcoma as potential target for immunotherapy. The CCL21 RNA expression was determined in 21 Ewing sarcoma cell lines and 18 primary therapy-naive Ewing sarcoma samples. In the tumor samples, this was correlated with the number and CD4⁺/CD8⁺ ratio of infiltrating T cells and clinical parameters. Higher RNA expression levels of CCL21 significantly correlated with a lower CD4⁺/CD8⁺ T cell ratio (P = 0.009), good chemotherapeutic response (P = 0.01) and improved outcome (P < 0.001). In patients with metastases, CCL21 expression was significantly lower than in patients without (P < 0.0005). CCL21 expression was significantly higher in Ewing sarcoma tissue samples compared to cell lines (P < 0.01), implying the involvement of a stromal factor. Protein expression analysis of CCL21 and its receptor CCR7 in 24 therapy-naïve tumors showed that there was no expression in all bar one Ewing sarcoma cells. In conclusion, CCL21 is expressed in clinical Ewing sarcoma samples by nontumor-infiltrating immune cells. The observed positive correlation with survival implies that CCL21 might be a potential prognostic marker for Ewing sarcoma and marks the potential of CCL21 immunotherapy for use in Ewing sarcoma.

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Synergistic effect of MK-2206 and imatinib mesylate in GIST

Purpose: Gastrointestinal stromal tumors (GIST) generally harbor activating mutations in the receptor tyrosine kinase KIT or in the related platelet derived growth factor receptor alpha (PDGFRA). GIST treated with imatinib mesylate (IM) or second-line therapies that target mutant forms of these receptors generally escape disease control and progress over time. Inhibiting additional molecular targets may provide more substantial disease control. Recent studies have implicated the PI3-kinase/AKT pathway in the survival of IM-resistant GIST cell lines and tumors. Experimental Design: Here, we performed in vitro and in vivo studies evaluating the novel combination of IM with the AKT inhibitor MK-2206 in GIST. Whole-transcriptome sequencing (WTS) of xenografts was performed to explore the molecular aspects of tumor response to this novel combination and to potentially identify additional therapeutic targets in GIST. Results: This drug combination demonstrated significant synergistic effects in a panel of IM-sensitive and -resistant GIST cell lines. Furthermore, combination therapy provided significantly greater efficacy, as measured by tumor response and animal survival, in IM-sensitive GIST xenografts as compared to treatment with IM or MK-2206 alone. WTS implicated two neural genes, brain expressed X-linked 1 (BEX1) and neuronal pentraxin I (NPTX1), whose expression was significantly up-regulated in combination-treated tumors compared to tumors treated with the two monotherapies. Conclusion: These studies provide strong preclinical justification for combining IM with an AKT inhibitor as a front-line therapy in GIST. In addition, the WTS implicated the BCL-2/BAX/BAD apoptotic pathway as a potential mechanism for this enhanced combination effect.

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HGF/Met and the Head and Neck Cancer Microenvironment

Studies to date have revealed several major molecular alterations that contribute to head and neck squamous cell carcinoma (HNSCC) initiation, progression, metastatic spread and therapeutic failure. The epidermal growth factor receptor (EGFR) is the only FDA-approved therapeutic target yet responses to cetuximab have been limited. Activation and crosstalk of cellular receptors and consequent activation of different signaling pathways contributes to limited activity of blockade of a single pathway. The hepatocyte growth factor (HGF) receptor, Met has been implicated in HNSCC tumorigenesis and EGFR inhibitor resistance. HGF, the sole ligand of Met, is overexpressed in the tumor microenvironment. The role of HGF/Met signaling in proliferation, metastasis and angiogenesis has been investigated in HNSCC leading to clinical trials with various Met inhibitors and HGF antibodies. However, the role of the HGF/Met signaling axis in mediating the tumor microenvironment has been relatively understudied in HNSCC. In this review we will discuss the functional roles of Met and HGF in HNSCC with a focus on the tumor microenvironment and the immune system.

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New Strategies in Esophageal Cancer

Esophageal cancer remains a highly lethal malignancy in which relatively modest therapeutic advances have been made over the past several decades. Cytotoxic therapy remains the mainstay of treatment for both advanced esophageal adenocarcinoma (EAC) and squamous cell carcinoma (SCC), with incremental benefit conferred by antibodies targeting human epidermal growth factor receptor 2 (HER2) and vascular endothelial growth factor receptor (VEGFR) in select patients. However, intrinsic or acquired resistance in this disease almost invariably occurs and remains a major challenge. Moreover, while large-scale exome and whole genome sequencing efforts have identified a variety of somatic mutations and copy number variations, particularly amplifications, in esophageal cancer, the ability to translate these findings successfully into actionable therapeutic approaches has been elusive. More recently, immunotherapeutic strategies, most notably immune checkpoint inhibitors, have demonstrated benefit to a subset of patients with both EAC and SCC, and represent an area of active clinical investigation. In this article, we discuss some of the insights derived from past trials of esophageal cancer, highlight ongoing research efforts in this arena, and emphasize the need to refine our approach to treating patients based on distinct anatomic, histologic, and molecular features.

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NTRK1 and ROS1 inhibitors in NSCLC

Purpose: Efforts to discover drugs that overcome resistance to targeted therapies in patients with rare oncogenic alterations, such as NTRK1- and ROS1-rearrangements, are complicated by the cost and protracted timeline of drug discovery. Experimental design: In an effort to identify inhibitors of NTRK1 and ROS1, which are aberrantly activated in some patients with non-small cell lung cancer (NSCLC), we created and screened a library of existing targeted drugs against Ba/F3 cells transformed with these oncogenes. Results: This screen identified the FDA-approved drug cabozantinib as a potent inhibitor of CD74-ROS1 transformed Ba/F3, including the crizotinib-resistant mutants G2032R and L2026M (IC50 = 9, 26, and 11 nM, respectively). Cabozantinib inhibited CD74-ROS1-transformed Ba/F3 cells more potently than brigatinib (wild-type/G2032R/L2026M IC50 = 30/170/200 nM, respectively), entrectinib (IC50 = 6/2,200 /3,500 nM), and PF-06463922 (IC50 = 1/270/2 nM). Cabozantinib inhibited ROS1 autophosphorylation and downstream ERK activation in transformed Ba/F3 cells and in patient-derived tumor cell lines. The IGF-1R inhibitor BMS-536924, potently inhibited CD74-NTRK1 transformed compared to parental Ba/F3 cells (IC50 = 19 nM vs. > 470 nM). A patient with metastatic ROS1-rearranged NSCLC with progression on crizotinib was treated with cabozantinib and experienced a partial response. Conclusions: While acquired resistance to targeted therapies is challenging, this study highlights that existing agents may be repurposed to overcome drug resistance, and identifies cabozantinib as a promising treatment of ROS1-rearranged NSCLC after progression on crizotinib.

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Long-term follow-up results of the multicenter phase II trial of regorafenib in patients with metastatic and/or unresectable GI stromal tumor after failure of standard tyrosine kinase inhibitor therapy

Our study provides the longest follow-up of advanced GIST patients treated with regorafenib in this phase II trial. Particular benefit among exon 11 KIT mutations and SDH-deficient GIST were observed. Liberal use of dose reductions and treatment breaks were required to optimize long-term drug exposure.

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Socioeconomic Inequalities in Diet Quality: from Identifying the Problem to Implementing Solutions

Abstract

In high-income countries, poor diet is both a leading contributor to the burden of disease and strongly socioeconomically and demographically patterned. The many forms of a poor diet, from food insecurity, through a lack of intake of healthy foods to an excess intake of unhealthy food and drink, represent a substantial modifiable driver of inequalities in health and well-being. Here, we review the drivers of these inequalities, with a critical reflection on the interventions most likely to improve inequalities in a healthy diet. Interventions currently exist at the levels of the individual, the community and society that have the potential to improve diet quality across our communities, with greatest benefit for those with greatest need. We conclude that greater attention needs to be paid to the potential impact of specific population nutrition strategies, their sociocultural applicability, their implementation, and their evaluation, if they are to play a significant role in reducing inequalities in diet and health.

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Expression of CCL21 in Ewing sarcoma shows an inverse correlation with metastases and is a candidate target for immunotherapy

Abstract

Ewing sarcoma is an aggressive neoplasm predominantly occurring in adolescents and has a poor prognosis when metastasized. For patients with metastatic disease in particular, immunotherapy has been proposed as possible beneficial additive therapy. CCL21 activation-based immunotherapy was successful in preclinical studies in other tumor types; therefore, we investigated CCL21 expression in Ewing sarcoma as potential target for immunotherapy. The CCL21 RNA expression was determined in 21 Ewing sarcoma cell lines and 18 primary therapy-naive Ewing sarcoma samples. In the tumor samples, this was correlated with the number and CD4⁺/CD8⁺ ratio of infiltrating T cells and clinical parameters. Higher RNA expression levels of CCL21 significantly correlated with a lower CD4⁺/CD8⁺ T cell ratio (P = 0.009), good chemotherapeutic response (P = 0.01) and improved outcome (P < 0.001). In patients with metastases, CCL21 expression was significantly lower than in patients without (P < 0.0005). CCL21 expression was significantly higher in Ewing sarcoma tissue samples compared to cell lines (P < 0.01), implying the involvement of a stromal factor. Protein expression analysis of CCL21 and its receptor CCR7 in 24 therapy-naïve tumors showed that there was no expression in all bar one Ewing sarcoma cells. In conclusion, CCL21 is expressed in clinical Ewing sarcoma samples by nontumor-infiltrating immune cells. The observed positive correlation with survival implies that CCL21 might be a potential prognostic marker for Ewing sarcoma and marks the potential of CCL21 immunotherapy for use in Ewing sarcoma.

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The magnitude of best tumor shrinkage during second-line targeted therapy affects progression-free survival but not overall survival in patients with metastatic renal cell carcinoma

Objective

The present study aimed to evaluate the influence of the magnitude of best tumor shrinkage during second-line targeted therapy after first-line tyrosine kinase inhibitor failure on metastatic renal cell carcinoma prognosis.

Methods

Fifty-two patients were enrolled. The magnitude of tumor shrinkage was assessed according to the Response Evaluation Criteria in Solid Tumors v. 1.1, and evaluated as a continuous variable and by categorical classification: good responders (greater than or equal to –30%), mild responders (–0.1 to –29.9%), poor responders (0 to +19.9%) and non-responders (greater than or equal to +20% or new lesions). Overall survival and progression-free survival after second-line therapy initiation were evaluated according to the categorical classification. Factors predicting overall survival and progression-free survival were also examined.

Results

The mean magnitude of tumor shrinkage was –1.29%, and there were 9, 21, 11 and 11 good responders, mild responders, poor responders and non-responders, respectively. The overall survival and progression-free survival significantly improved as the magnitude of tumor shrinkage increased according to the categorical classification (overall survival: not reached, 27.8, 18.2 and 4.67 months; progression-free survival: 13.4, 8.19, 5.18 and 1.84 months, respectively; P< 0.0001 for both). For overall survival, the magnitude of tomor shrinkage was not demonstrated as an independent indicator in the multivariate analysis (P= 0.0872 for the categorical classification, P= 0.133 for the continuous variable) whereas for second-line progression-free survival, the magnitude of tumor shrinkage according to both the categorical classification and continuous variable was found to be an independent factor in the multivariate analysis (P< 0.0001 for both).

Conclusions

The magnitude of tumor shrinkage is an independent predictive factor for progression-free survival, and may represent a surrogate marker for overall survival.

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An epidermal growth factor receptor exon 19 mutation in a mucin-producing gastric cancer sample from a Chinese patient

Objective

To determine whether a subgroup of gastric cancer patients might benefit from epidermal growth factor receptor-tyrosine kinase inhibitors.

Methods

A total of 103 gastric cancer samples were collected for this study. High-resolution melting and deoxyribonucleic acid sequencing were used to detect epidermal growth factor receptor mutations in exons 19 and 21.

Results

Polymerase chain reaction-high-resolution melting was successfully performed on all 103 samples. Aberrant melting curves were found in only one sample. Sanger sequencing revealed a 15 bp deletion (c.2235_2249del; p.Glu746_Ala750del) in epidermal growth factor receptor exon 19. The sample was from a male patient, and the pathological diagnosis was a mucin-producing gastric cancer with lymph node metastasis. To date, this is the first report on epidermal growth factor receptor exon 19 mutation in gastric cancer.

Conclusions

An epidermal growth factor receptor mutation in exon 19 was identified in mucin-producing gastric cancer sample from a male patient. This mutation indicates that the small subgroup of patients with mucin-producing gastric cancer might benefit from epidermal growth factor receptor-tyrosine kinase inhibitors.

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Patient age was an independent predictor of cancer-specific survival in male patients with upper tract urothelial carcinoma treated by radical nephroureterectomy

Objective

We hypothesized that there may be a prognostic difference in age between the genders and evaluated the influence of gender-adjusted age on prognosis in upper tract urothelial carcinoma patients.

Methods

A total of 839 patients with upper tract urothelial carcinoma from a retrospective multi-institutional cohort were included. The patients were divided into four groups consisting of males (N = 610) and females (N = 229) according to age ((i) <60 years, (ii) 60–69.9 years, (iii) 70–79.9 years and (iv) ≥80 years), and we evaluated the associations of patient age and gender with clinicopathological features and oncological outcomes following radical nephroureterectomy. The median follow-up duration was 34 months.

Results

Disease recurrence occurred in 249 patients and 192 patients died of upper tract urothelial carcinoma. The 3-year cancer-specific survival rates were (i) 84.3%, (ii) 80.2%, (iii) 77.1% and (iv) 71.5% in the entire patient population (P = 0.001); (i) 84.5%, (ii) 81.1%, (iii) 76.8% and (iv) 69.7% in males (P = 0.010); and (i) 83.3%, (ii) 76.9%, (iii) 77.7% and (iv) 72.9% in females (P = 0.287), respectively. No significant differences between disease recurrence and age were found in the male or female population. In multivariate analysis, older age was an independent predictor of cancer-specific survival, in addition to advanced pT stage, the presence of lymphovascular invasion and lymph node involvement in males. In contrast, age was not associated with cancer-specific survival in females, while high grade, advanced pT stage, the presence of lymph node involvement and multifocal tumor were independent predictors.

Conclusion

The results indicate that gender-adjusted age might be a new prognostic factor in upper tract urothelial carcinoma patients.

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Prognostic significance and frequency of EGFR expression and amplification in surgically resected advanced gastric cancer

Objective

The aim of this study is to find the frequency and the role of epidermal growth factor receptor expression as a prognostic biomarker in gastric cancer.

Methods

We evaluated the prognostic value and frequency of epidermal growth factor receptor expression and amplification using immunohistochemistry and silver in situ hybridization in a large cohort of curatively resected gastric cancer.

Results

Of the total of 935 cases, 294 (31.4%), 101 (10.8%) and 36 (3.9%) patients showed epidermal growth factor receptor 1+, 2+ and 3+ expression on immunohistochemistry, respectively. Epidermal growth factor receptor-positive (2+/3+) patients more frequently had intestinal type than epidermal growth factor receptor-negative (0/1+) patients (82.5 vs. 44.1%, P < 0.001). After adjusting for sex, age, stage and adjuvant chemotherapy, epidermal growth factor receptor-positive patients had a favorable overall survival outcome compared with epidermal growth factor receptor-negative patients (hazard ratio, 0.734; 95% confidence interval, 0.541–0.997; P = 0.047), especially in Stage III disease (hazard ratio, 0.676; 95% confidence interval, 0.472–0.968; P = 0.033). Among the 393 cases available for  in situ hybridization, the correlation between immunohistochemistry and in situ hybridization was statistically significant (P = 0.001). Thirteen patients with gene amplification (3.3%) did not show different survival outcome with others (P = 0.359).

Conclusion

Epidermal growth factor receptor positivity was an independent favorable prognostic factor for gastric cancer, especially in Stage III disease.

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Cigarette smoking and the risk of head and neck cancer in the Japanese population: a systematic review and meta-analysis

Objective

Although cigarette smoking is a well-established risk factor for head and neck cancer, the impact of smoking on head and neck cancer might vary among geographic areas. To date, however, no systematic review of cigarette smoking and head and neck cancer in the Japanese population has yet appeared.

Methods

We conducted a systematic review of previous epidemiological studies for cigarette smoking and head and neck cancer among Japanese. Evaluation of associations was based on the strength of evidence ('convincing', 'probable', 'possible' or 'insufficient') and the magnitude of association ('strong', 'moderate', 'weak' or 'no association'), together with biological plausibility as previously evaluated by the International Agency for Research on Cancer. A meta-analysis was conducted to obtain summary estimates for the overall magnitude of association.

Results

We identified five cohort studies and 12 case–control studies. Four of five cohort studies and 11 of 12 case–control studies showed a strong positive association between cigarette smoking and head and neck cancer. Nine of 12 studies indicated a dose–response relationship between cigarette smoking and the risk of head and neck cancer. Meta-analysis of 12 studies indicated that the summary relative risk for ever smokers relative to never smokers was 2.43 (95% confidence interval: 2.09–2.83). Summary relative risks for current and former smokers relative to never smokers were 2.68 (2.08–3.44) and 1.49 (1.05–2.11), respectively.

Conclusions

Cigarette smoking is a convincing risk factor for head and neck cancer in the Japanese population.

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A preoperative low cancer antigen 125 level (

Objective

The purpose of this study is to investigate the clinical characteristics to determine the optimal timing of interval debulking surgery following neoadjuvant chemotherapy in patients with advanced epithelial ovarian cancer.

Methods

We reviewed the charts of women with advanced epithelial ovarian cancer, fallopian tube cancer or primary peritoneal cancer who underwent interval debulking surgery following neoadjuvant chemotherapy at our cancer center from April 2006 to April 2014.

Results

There were 139 patients, including 91 with ovarian cancer [International Federation of Gynecology and Obstetrics (FIGO) Stage IIIc in 56 and IV in 35], two with fallopian tube cancers (FIGO Stage IV, both) and 46 with primary peritoneal cancer (FIGO Stage IIIc in 27 and IV in 19). After 3–6 cycles (median, 4 cycles) of platinum-based chemotherapy, interval debulking surgery was performed. Sixty-seven patients (48.2%) achieved complete resection of all macroscopic disease, while 72 did not. More patients with cancer antigen 125 levels ≤25.8 mg/dl at pre-interval debulking surgery achieved complete resection than those with higher cancer antigen 125 levels (84.7 vs. 21.3%; P< 0.0001). Patients with no ascites at pre-interval debulking surgery also achieved a higher complete resection rate (63.5 vs. 34.1%; P< 0.0001). Moreover, most patients (86.7%) with cancer antigen 125 levels ≤25.8 mg/dl and no ascites at pre-interval debulking surgery achieved complete resection.

Conclusions

A low cancer antigen 125 level of ≤25.8 mg/dl and the absence of ascites at pre-interval debulking surgery are major predictive factors for complete resection during interval debulking surgery and present useful criteria to determine the optimal timing of interval debulking surgery.

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Endobronchial ultrasound-guided transbronchial needle aspiration of hilar and mediastinal lymph nodes detected on 18F-fluorodeoxyglucose positron emission tomography/computed tomography

Objective

Endobronchial ultrasound-guided transbronchial needle aspiration is of diagnostic value in hilar/mediastinal (N1/N2) lymph node staging. We assessed the utility of endobronchial ultrasound-guided transbronchial needle aspiration in lung cancer patients with N1/N2 lymph nodes detected on ¹⁸F-fluorodeoxyglucose positron emission tomography/computed tomography.

Methods

Fifty lung cancer patients with N1/N2 disease on ¹⁸F-fluorodeoxyglucose positron emission tomography/computed tomography underwent endobronchial ultrasound-guided transbronchial needle aspiration for pathological lymph nodes between November 2012 and April 2015. The diagnostic performance of endobronchial ultrasound-guided transbronchial needle aspiration, lymph node site and size, number of needle passes and complications were evaluated retrospectively from patients' medical records. Malignancy was defined as a maximum standardized uptake value (SUV_max) >2.5.

Results

The median longest diameter of the 61 lymph nodes (29 subcarinal, 21 right lower paratracheal, 6 left lower paratracheal, 4 right hilar and 1 upper paratracheal) was 23.4 mm (range: 10.4–45.7); the median number of needle passes was 2 (range: 1–5). There were no severe complications. A definitive diagnosis was made by endobronchial ultrasound-guided transbronchial needle aspiration in 39 patients (31 adenocarcinomas, 3 small-cell carcinomas, 2 squamous-cell carcinomas, 3 large-cell neuroendocrine carcinomas). In the remaining 11 patients, the diagnosis was indefinite: insufficient endobronchial ultrasound-guided transbronchial needle aspiration material was collected in two patients and non-specific lymphadenopathy was confirmed by endobronchial ultrasound-guided transbronchial needle aspiration or thoracotomy in the other nine patients. The mean lymph node SUV_max was 7.09 (range: 2.90–26.9) and was significantly higher in true-positive than in false-positive nodes (P < 0.05, t-test). Non-specific lymphadenopathy was diagnosed by expert visual interpretation of ¹⁸F-fluorodeoxyglucose positron emission tomography/computed tomography images in five of the nine patients.

Conclusion

Endobronchial ultrasound-guided transbronchial needle aspiration accurately diagnoses N1/N2 disease detected on ¹⁸F-fluorodeoxyglucose positron emission tomography/computed tomography.

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Nivolumab-induced thyroid dysfunction

Nivolumab (ONO-4538) is an anti-programmed death-1 specific monoclonal antibody, which has become a standard treatment for metastatic malignant melanoma. Nivolumab induces autoimmune adverse events, defined as immune-related adverse events. Herein, we report a case of nivolumab-induced thyroid dysfunction in the clinical setting. Fourteen patients were treated with nivolumab at our institute, of which three developed thyroid dysfunction, an incidence higher than previously reported in the initial clinical trials. Interestingly, one patient achieved complete remission; suggesting that in some patients, the occurrence of immune-related adverse events, including thyroid dysfunction, might reflect the drug's antitumour efficacy. No patient died or discontinued nivolumab treatment owing to thyroid dysfunction. Although thyroid dysfunction first appeared to be asymptomatic, two of the three patients developed symptoms related to hypothyroidism soon after, requiring hormone replacement therapy. Another patient developed hyperthyroidism that was initially asymptomatic; the patient subsequently developed myalgia with fever >39.5°C after two additional courses of nivolumab. Treatment with nivolumab was therefore discontinued, and treatment with prednisolone was initiated. Symptoms resolved within a few days, and thyroid function normalized. Thyroid dysfunction is sometimes difficult to diagnose because its symptoms similar to those of many other diseases. In addition, thyroid-related immune-related adverse events may present with unique symptoms such as myalgia with high fever, abruptly worsening patients' quality of life. Consequently, thyroid dysfunction should be considered as a possible immune-related adverse event. Thus, it is important to test for thyroid dysfunction at baseline and before the administration of each nivolumab dose if possible.

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The effect of Clostridium butyricum MIYAIRI on the prevention of pouchitis and alteration of the microbiota profile in patients with ulcerative colitis

Abstract

Purpose

Ulcerative colitis (UC) is a chronic, relapsing, and refractory disorder of the intestine. Total proctocolectomy with ileal pouch anal anastomosis (IPAA) is the preferred and standard surgical procedure for patients' refractory to medical therapy. Pouchitis is one of the most common long-term complications after IPAA. In the present study, the safety and efficacy of Clostridium butyricum MIYAIRI (CBM) as a probiotic were examined.

Methods

A randomized and placebo-controlled study was performed. Seventeen patients were recruited from 2007 to 2013. Nine tablets of MIYA-BM^® or placebo were orally administered once daily. The cumulative pouchitis-free survival, pouch condition (using the modified pouch disease activity index), and blood parameters were evaluated. A fecal sample analysis was also performed.

Results

Subjects were randomly allocated to receive MIYA-BM or placebo (9 and 8 subjects, respectively). One subject in the MIYA-BM group and four subjects in the placebo group developed pouchitis. No side effects occurred in either group. Characteristic intestinal flora was observed in each group.

Conclusions

Our results suggest that probiotic therapy with CBM achieved favorable results with minimal side effects and might be a useful complementary therapy for the prevention of pouchitis in patients with UC who have undergone IPAA.

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Three-dimensional simulation of pancreatic surgery showing the size and location of the main pancreatic duct

Abstract

Purpose

We performed three-dimensional (3D) surgical simulation of pancreatic surgery, including the size and location of the main pancreatic duct on the resected pancreatic surface.

Methods

The subjects of this retrospective analysis were 162 patients who underwent pancreatic surgery. This cohort was sequentially divided into a "without-3D" group (n = 81) and a "with-3D" group (n = 81). We compared the pancreatic duct diameter and its location, using nine sections in a grid pattern, with the intraoperative findings. The perioperative outcomes were also compared between patients who underwent pancreaticoduodenectomy (PD) and those who underwent distal pancreatectomy (DP).

Results

There were no significant differences in the main pancreatic duct diameter between the 3D-simulated values and the operative findings. The 3D-simulated main pancreatic duct location was consistent with its actual location in 80 % of patients (65/81). In comparing the PD and DP groups, the intraoperative blood loss was 1174 ± 867 and 817 ± 925 ml in the without-3D group, and 828 ± 739 and 307 ± 192 ml in the with-3D group, respectively (p = 0.024, 0.026).

Conclusion

The 3D surgical simulation provided useful information to promote our understanding of the pancreatic anatomy, including details on the size and location of the main pancreatic duct.

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