An age-stratified cross-sectional study of antidiabetic and non-antidiabetic drugs prescribed to Japanese outpatients with diabetes.

Polypharmacy, common in patients with diabetes, may cause adverse drug reactions. The number of antidiabetic and non-antidiabetic drugs prescribed to patients in different age groups remains unclear. The aim of this study was to examine the number and class of antidiabetics and non-antidiabetics prescribed to Japanese patients with diabetes, stratified by age for reducing polypharmacy. This cross-sectional study examined all prescriptions of patients prescribed antidiabetics at 257 pharmacies of Matsumotokiyoshi Holdings in Japan from May 2018 to March 2019. Total prescription numbers including antidiabetic drugs were 263,915 in this study. Mean numbers of antidiabetic drugs per prescription were 1.71, 2.17, and 1.52 in the patient age groups of 10-19, 50-59, and 90-99 years, respectively. Count of antidiabetics was not related to age. However, the mean total number of drugs prescribed increased with age, which was 2.22 and 7.99 in the age groups of 10-19 and 90-99 years, respectively. The linear regression coefficient (b) according to age was 0.07 (p < 0.001) for 10-99 years. The mean non-antidiabetic number of agents prescribed increased with age among 10-99 years (b = 0.07, p < 0.001). Among outpatients treated for diabetes, dipeptidyl peptidase-4 inhibitors (29%) and antihypertensive, ß-blocking and renin-angiotensin system blocking drugs (32%) were the most prescribed antidiabetics and non-antidiabetics in all ages, respectively. The number of prescribed antidiabetic agents did not increase with age, whereas the total and non-antidiabetic numbers of medications prescribed increased linearly. For reduction of polypharmacy in older people with diabetes, we need to focus on non-antidiabetics.

Sarcoid-Like Granulomatosis of the Lung Related to Durvalumab After Chemoradiation for Pulmonary Squamous Cell Carcinoma.

Sarcoid-like granulomatosis is a unique immune-related adverse event (irAE) in cancer patients treated with immune checkpoint inhibitors (ICIs). This irAE is infrequent, reported to range from 2% to 22.2% of melanoma treated with ICI. In a case of granulomatosis localized in the lung, it is difficult to differentiate granulomatosis from cancer progression or metastases. Herein, we report a case of ICI-induced sarcoid-like granulomatosis of the lung, which was confusable with localized recurrence of the primary lung cancer. A 56-year-old woman with c-stage IIIA of pulmonary squamous cell carcinoma in the right lower lobe received chemo-radiotherapy with two courses of cisplatin and vinorelbine and concurrent thoracic irradiation, followed by 1-year durvalumab consolidation therapy. The tumor in the right S6 grew and presented abnormal uptake by fluorodeoxyglucose positron emission tomography (FDG-PET), 1.5 years after durvalumab. Neither computed tomography (CT) nor FDG-PET found mediastinal and distant metastases. She underwent right lower lobe lobectomy. Histopathologically, the tumor and sampled lymph nodes contained no residue of carcinoma cells but presented diffuse epithelioid granuloma with infiltration of inflammatory cells, partial necrotic lesions and many multinucleated giant cells. In immunohistochemical stains, CD3+ and CD8+ T cells predominantly infiltrated, while there were few CD4+ T cells and a small number of CD20+ B cells. We followed her without steroid and other immunosuppressant drug. We should pay attention to the development of sarcoid-like granulomatosis as a rare irAE, which is difficult to be differentiated from cancer progression.

Pigmented spindle cell variant of a thymic atypical carcinoid in an octogenarian.

BACKGROUND: A pigmented carcinoid is an extremely rare variant of carcinoid characterized by melanin pigmentation of the tumor, with only five cases described in the literature. In addition, thymic carcinoids are rare in elderly patients and their prognosis after resection of the carcinoid tumor is unclear. CASE PRESENTATION: An anterior mediastinal tumor was incidentally found in an 82-year-old man who had been diagnosed with acute thoracic empyema. The tumor was considered most likely to be a noninvasive thymoma or thymic carcinoma for which surgery was indicated after the resolution of the empyema. The tumor was completely resected 4 months after the empyema surgery, and the patient had an uneventful postoperative course. A cut surface of the resected specimen was extensively pigmented and appeared dark-brownish, with abundant melanin pigmentation later confirmed in the spindle-shaped tumor cells. Based on the histologic examination and immunohistochemical study, melanoma was eliminated as a differential diagnosis and the tumor was diagnosed as a pigmented atypical carcinoid of the thymus. CONCLUSIONS: This report provides additional knowledge on thymic pigmented carcinoids and thymic atypical carcinoids in elderly patients.

Prognosis of patients with recurrence after pulmonary metastasectomy for colorectal cancer.

OBJECTIVES: We investigated the prognosis of patients with recurrence of pulmonary metastases (PM) from colorectal cancer (CRC) after resection. METHODS: We reviewed our surgical series of 101 CRC patients with PM who underwent R0 resection with curative intent. The overall survival (OS) and disease-free survival (DFS) rates after metastasectomy as well as the prognostic factors of survival were analyzed. RESULTS: Fifty-five patients (54%) experienced recurrence, of whom 21 had developed extrapulmonary metastasis (EPM) before lung resection. Multivariate analysis restricted to patients with recurrence identified a disease-free interval (DFI) shorter than a year as an adverse prognosticator of OS (HR, 2.68; 95% CI 1.40-5.51; P < 0.01) and DFS (HR, 8.54; 95% CI 3.0-24.6; P < 0.001). EPM was also identified as an adverse prognosticator of OS for patients with recurrence (HR, 3.16; 95% CI 1.64-5.88; P < 0.001). There was a significant difference in the 5-year OS rate between patients with and without EPM (27.9% vs 64.9%, P < 0.001), and between those with a DFI shorter and longer than a year (40.0% vs 75.0%, P < 0.01). Among these, 31 patients (56%) bore lung-limited recurrence after their first lung resection, of whom 20 (36%) underwent a total of 29 repeat pulmonary metastasectomies, which resulted in a 5-year OS rate of 71.3% after the second lung resection. CONCLUSIONS: Our findings indicate that CRC patients with PM whose DFI is shorter than a year after lung resection or those with prior EPM more frequently experience multisite recurrence.

Randomized Study Comparing Equal Height Staples With Graduated Height Staples in Bronchial Closure.

BACKGROUND: There are two forms of staple cartridge available for lung cancer operations, the flat face with equal height staples and the stepped face with graduated height staples. The objective of the study was to evaluate their stapling ability in lobectomy. METHODS: A randomized prospective study was conducted to compare two types of stapling reloads for bronchial closure. Stapling ability was evaluated by the staple formation on the resected bronchial stump. The stumps were sliced along the staple line, and the shapes of the staples were recorded by roentgenogram. Then, the staple formation was scored as 0 to 4 points with 4 approximating a perfect B-shaped staple. RESULTS: A total of 61 patients were randomly assigned to the equal height staples (n = 30) or the graduated height staples (n = 31). From 61 patients, 183 staple lines, which included 1,144 staples, were evaluated. The case scores were significantly lower in the equal height staples than in the graduated height staples (2.17 versus 2.88, p = 0.0003), respectively. The percentage of staples that formed a complete "B" shape was significantly higher in the graduated height staples than in the equal height staples (25.3% versus 10.0%, p = 0.000). No considerable difference was found between the two groups concerning postoperative complications. No bronchopleural fistula was observed. CONCLUSIONS: The graduated height staples had significantly higher scores of the staple formation on the bronchia stump than the equal height staples. From the clinical point of view, both the equal height staples and the graduated height staples showed acceptable performance in the stapling ability.

Pulmonary lymphoepithelioma-like carcinoma with echinoderm microtubule-associated protein-like 4-anaplastic lymphoma kinase (EML4-ALK) fusion gene.

A pulmonary lymphoepithelioma-like carcinoma (PLELC) is similar to a lymphoepithelioma, a subtype of nasopharyngeal carcinoma and commonly associated with Epstein-Barr virus infection which is a rare tumour and classified in the group of "other and unclassified carcinoma" in the latest 2015 World Health Organization (WHO) classification. Some reports of lymphoepithelioma-like carcinoma (LELC) have noted an epidermal growth factor receptor (EGFR) mutation, whereas none have noted a mutation of the echinoderm microtubule-associated protein-like 4-anaplastic lymphoma kinase (EML4-ALK) fusion gene. This is the first reported case of PLELC with ALK rearrangement. A 76-year-old woman underwent a right lower lobectomy and complicated partial resection of the upper lobe with lymph node dissection under complete thoracoscopic approach. A histopathological diagnosis of PLELC was made and the stage was classified as T1aN1(#12l) M0, pl0, G2, Ly1, V1. The results of both ALK immunohistochemistry and EML4-ALK fusion gene on fluorescence in situ hybridization (FISH) examinations were positive; however, EGFR mutational analysis results showed wild-type mutation.

Prognostic factors in patients with postoperative brain recurrence from completely resected non-small cell lung cancer.

BACKGROUND: Treatment strategies for brain metastasis from lung cancer have been making progress. The aim of this retrospective analysis was to investigate the post-recurrent prognostic factors in patients with brain metastasis after complete resection of non-small cell lung cancer (NSCLC). METHODS: We retrospectively reviewed the medical records of 40 patients found to have postoperative brain metastasis from NSCLC in our institution from 2002 to 2008. All patients had undergone radical pulmonary resection for the lung cancer. The impact of numerous variables on survival were assessed, including gender, age, carcinoembryonic antigen (CEA), tumor size, N status, histological type, number of brain metastases, tumor size of brain metastasis, presence of symptoms from the brain tumor(s), and use of perioperative chemotherapy. RESULTS: The median follow-up was 20.6 months (range, 3.4-66 months). The five-year survival rate from the diagnosis of brain recurrence was 22.5%. In univariate analysis, the favorable prognostic factors after brain recurrence included a normal range of CEA, no extracranial metastasis, no symptoms from the brain metastasis, brain metastasis (less than 2 cm), and radical treatment (craniotomy or stereotactic radiosurgery [SRS]). The multivariate Cox model identified that a small brain metastasis and radical treatment were independent favorable prognostic factors. CONCLUSIONS: This study found that the implementation of radical therapy for metastatic brain tumor(s) when the tumor is still small contributed to an increase in patients' life expectancy.

Pulmonary metastasectomy: outcomes and issues according to the type of surgical resection.

According to a recent report by the Committee for Scientific Affairs of the Japanese Association for Thoracic Surgery, pulmonary metastasectomy accounted for as many as 10.2 % of all entry cases of general thoracic surgery, and its use is increasing year by year. Accordingly, many studies have examined the surgical procedures used during pulmonary metastasectomy for metastases from primary tumors affecting various organs as well as the outcomes of and indications for such procedures, but some problems remain. In this article, the following questions related to the surgical approach and the type of resection used during pulmonary metastasectomy are reviewed: (1) Wedge resection--what is a safe margin for preventing local recurrence? (2) What is the clinical significance of node sampling/dissection during pulmonary metastasectomy? and (3) When is segmentectomy necessary? In addition, we discuss: (4) open thoracotomy vs. video-assisted thoracoscopic surgery (VATS), (5) repeated metastasectomy for pulmonary metastases, (6) the surgical approach for bilateral pulmonary metastasectomy, (7) pneumonectomy, and (8) pulmonary metastasectomy combined with resection of the neighboring organs.

Pleural recurrence after surgery for pleomorphic adenoma arising from peripheral lung: computed tomography-guided percutaneous needle biopsy as a possible mechanism of local failure.

A 75-year-old male was referred to our hospital because of an abnormal shadow found in the right lung 2 years prior that had been increasing in size. Chest computed tomography showed a 1-cm well-defined nodule in the periphery of the right middle lobe. Although a computed tomography-guided percutaneous needle biopsy was performed, the results were indeterminate. In observations over the course of 1 year, the tumor size increased. Surgical resection was finally performed for diagnosis and treatment, and histological findings revealed a pulmonary pleomorphic adenoma. 2 years after surgery, pleural dissemination unfortunately developed. We present here a case of recurrence as pleural dissemination despite complete resection of a pulmonary pleomorphic adenoma arising from peripheral lung tissue. There is a possibility that the local failure is related to percutaneous needle biopsy.

Prognosis associated with surgery for non-small cell lung cancer and synchronous brain metastasis.

PURPOSE: Several reports have described extended survival after aggressive surgical treatment for non-small cell lung cancer (NSCLC) and synchronous brain metastasis. This retrospective analysis assesses the prognostic factors in this population. METHODS: We reviewed retrospectively the medical records of 29 patients with synchronous brain metastasis from NSCLC, who underwent surgical treatment in our institution between 1980 and 2008. All patients underwent chest surgery to remove the primary lesion. The impact of several variables on survival was assessed. RESULTS: The median follow-up period was 9.6 months and the 5-year survival rate from the time of lung cancer resection was 20.6 %. Univariate analysis demonstrated that the carcinoembryonic antigen (CEA) level, primary tumor size, and the presence of lymph node involvement were predictive of overall survival (p < 0.05). Multivariate analysis also identified those factors to be independent favorable prognostic factors. CONCLUSIONS: Although the survival of patients with brain metastasis from non-small cell lung cancer remains poor, surgical resection may benefit a select group of patients, particularly those with a normal CEA level, small tumor size, and node-negative status.

Enhanced cytotoxicity with a novel system combining the paclitaxel-2'-ethylcarbonate prodrug and an HSV amplicon with an attenuated replication-competent virus, HF10 as a helper virus.

We previously demonstrated that HF10, which is a natural, non-engineered HSV-1, has potent oncolytic activity in the treatment of solid malignant tumors in vitro and in vivo [H. Takakuwa, F. Goshima, N. Nozawa, T. Yoshikawa, H. Kimata, A. Nakao, et al., Oncolytic viral therapy using a spontaneously generated herpes simplex virus type 1 variant for disseminated peritoneal tumor in immunocompetent mice, Arch. Virol. 148 (2003) 813-825; S. Kohno, C. Lou, F. Goshima, Y. Nishiyama, T. Sata, Y. Ono, Herpes simplex virus type 1 mutant HF10 oncolytic viral therapy for bladder cancer, Urology 66 (2005) 1116-1121; D. Watanabe, F. Goshima, I. Mori, Y. Tamada, Y. Matsumoto, Y. Nishiyama, Oncolytic virotherapy for malignant melanoma with herpes simplex virus type 1 mutant HF10, J. Dermatol. Sci. 50 (2008) 185-196; A. Nawa, C. Luo, L. Zhang, Y. Ushijima, D. Ishida, M. Kamakura, et al., Non-engineered, naturally oncolytic herpes simplex virus HSV1 HF10: applications for cancer gene therapy, Curr. Gene. Ther. 8 (2008) 208-221]. Previous reports have also shown that a combination of HF10 and paclitaxel (TAX) was more efficacious than either regimen alone for some types of malignant tumors [S. Shimoyama, F. Goshima, O. Teshigahara, H. Kasuya, Y. Kodera, A. Nakao, et al., Enhanced efficacy of herpes simplex virus mutant HF10 combined with paclitaxel in peritoneal cancer dissemination models, Hepatogastroenterology 54 (2007) 1038-1042]. In this study, we investigated the efficacy of gene-directed enzyme prodrug therapy (GDEPT) using a novel system that combines the paclitaxel-2'-ethylcarbonate prodrug (TAX-2'-Et) and an HSV amplicon expressing rabbit-carboxylesterase (CES) with HF10 as a helper virus. This GDEPT system aims to produce high level of CES at the tumor site, resulting in efficient local conversion of the TAX-2'-Et prodrug into the active drug TAX [A. Nawa, T. Tanino, C. Lou, M. Iwaki, H. Kajiyama, K. Shibata, et al., Gene directed enzyme prodrug therapy for ovarian cancer: could GDEPT become a promising treatment against ovarian cancer?, Anti-Cancer Agents Med Chem 8 (2008) 232-239]. We demonstrated that the green fluorescent protein (GFP) gene, as a trace maker, was more efficiently introduced by the HSV amplicon compared to the expression vector, pHGCX, and that the HSV amplicon system expressed an active CES enzyme that could convert TAX-2'-Et to TAX in Cos7 cells. Furthermore, although the cytotoxicity of this amplicon system was not enhanced in virus-sensitive tumor cells, it was significantly enhanced in low virus-sensitive tumor cells in the presence of the prodrug in a concentration-dependent manner, compared to the control virus alone (p<0.05). These results indicate that the addition of a prodrug converting enzyme may be a feasible approach to further enhance the efficacy of HF10 as a cancer therapeutics in low HF10-sensitive malignancies.

Non-engineered, naturally oncolytic herpes simplex virus HSV1 HF-10: applications for cancer gene therapy.

Oncolytic HSV-1 has been developed as a novel anticancer agent. According to the properties and functions of HSV-1 encoded proteins, several genes have been targeted for engineering of oncolytic HSV-1. As a result, a variety of strategies have been applied to the engineering of oncolytic HSV-1. Success in cancer therapy for solid tumors requires a maximal oncolytic effect; however, recombinant HSV-1 that has been adapted to meet neurotoxicity requirements for the treatment of brain tumors may be too highly attenuated for effective use in solid tumors outside the brain. Recently, there has been renewed interest in the high potency of naturally oncolytic viruses. In this review, we will overview the engineered oncolytic HSV developed thus far, as well as its mechanism of selectivity and its mode of spreading within tumors. We also discuss the preclinical and clinical studies of HF-10, a non-engineered oncolytic HSV-1 virus, and its potential for use in cancer gene therapy.

Rap1 signal controls B cell receptor repertoire and generation of self-reactive B1a cells.

We previously reported that the mice deficient for SPA-1, a Rap1 GTPase-activating protein, developed hematopoietic stem cell disorders. Here, we demonstrate that SPA-1(-/-) mice show an age-dependent increase in B220(high) B1a cells producing anti-dsDNA antibody and lupus-like nephritis. SPA-1(-/-) peritoneal B1 cells revealed the altered Vkappa gene repertoire, including skewed Vkappa4 usage and the significant Igkappa/Iglambda isotype inclusion indicative of extensive receptor editing. Rap1GTP induced OcaB gene activation via p38MAPK-dependent Creb phosphorylation, and consistently, SPA-1(-/-) immature BM B cells showing high Rap1GTP exhibited the augmented expression of OcaB and Vkappa4 genes. SPA-1(-/-) BM cells could transfer the autoimmunity in association with the generation of peritoneal B220(high) B1a cells in Rag-2(-/-) recipients. Finally, a portion of SPA-1(-/-) mice developed B1 cell leukemia with hemolytic autoantibody. Present results suggest that the regulated Rap1 signal in the immature B cells plays a role in modifying the B cell receptor repertoire and in maintaining the self-tolerance.

Rap1 and SPA-1 in hematologic malignancy.

Rap1 is a member of the Ras family of GTPases and, depending on the cellular context, has an important role in the regulation of proliferation or cell adhesion. In lymphohematopoietic tissues, SPA-1 is a principal Rap1 GTPase-activating protein. Mice that are deficient for the SPA-1 gene develop age-dependent progression of T-cell immunodeficiency followed by a spectrum of late onset myeloproliferative disorders, mimicking human chronic myeloid leukemia. Recent studies reveal that deregulated Rap1 activation in SPA-1-deficient mice causes enhanced expansion of the bone marrow hematopoietic progenitors, but induces progressive unresponsiveness or anergy in T cells. Rap1 and its regulator, SPA-1, could, therefore, provide unique molecular targets for the control of human hematologic malignancy.

Antigen-driven T cell anergy and defective memory T cell response via deregulated Rap1 activation in SPA-1-deficient mice.

SPA-1 is a principal Rap1 GTPase-activating protein in the hematopoietic progenitors and peripheral T cells, and SPA-1-deficient mice develop a spectrum of myeloproliferative stem cell disorders of late onset. In the present study, we show that SPA-1-deficient mice develop age-dependent T cell unresponsiveness preceding the myeloid disorders, whereas the T cell numbers remained unchanged. Progression of the T cell dysfunction was attributed to the age-dependent increase in CD44high T cell population that was unresponsive to T cell receptor stimulation. Younger SPA-1-deficient mice exhibited selectively impaired recall T cell responses against a T-dependent antigen with normal primary antibody response. These results suggested that the unresponsiveness of CD44high T cells was antigen-driven in vivo. T cells from younger SPA-1-/- mice showed much greater and more persisted Rap1 activation by anti-CD3 stimulation than control T cells. Furthermore, freshly isolated T cells from SPA-1-/- mice exhibited progressive accumulation of Rap1GTP as mice aged. T cells from aged SPA-1-/- mice with high amounts of Rap1GTP showed normal or even enhanced Ras activation with little extracellular signal-regulated kinase activation in response to anti-CD3 stimulation, indicating that excess Rap1GTP induced the uncoupling of Ras-mediated extracellular signal-regulated kinase activation. These results suggested that antigenic activation of naïve T cells in SPA-1-/- mice was followed by anergic rather than memory state due to the defective down-regulation of Rap1 activation, resulting in the age-dependent progression of overall T cell immunodeficiency.

Myeloproliferative stem cell disorders by deregulated Rap1 activation in SPA-1-deficient mice.

SPA-1 (signal-induced proliferation-associated gene-1) is a principal Rap1 GTPase-activating protein in hematopoietic progenitors. SPA-1-deficient mice developed a spectrum of myeloid disorders that resembled human chronic myelogenous leukemia (CML) in chronic phase, CML in blast crisis, and myelodysplastic syndrome as well as anemia. Preleukemic SPA-1-deficient mice revealed selective expansion of marrow pluripotential hematopoietic progenitors, which showed abnormal Rap1GTP accumulation. Overexpression of an active form of Rap1 promoted the proliferation of normal hematopoietic progenitors, while SPA-1 overexpression markedly suppressed it. Furthermore, restoring SPA-1 gene in a SPA-1-deficient leukemic blast cell line resulted in the dissolution of Rap1GTP accumulation and concomitant loss of the leukemogenicity in vivo. These results unveiled a role of Rap1 in myeloproliferative stem cell disorders and a tumor suppressor function of SPA-1.

Pretreatment for ovarian endometrial cyst before in vitro fertilization.

Assisted reproductive technology is a widely accepted treatment for infertile women with endometriosis. The presence of an ovarian endometrial cyst reduces the quality of oocytes, while surgical resection of endometrioma may reduce the ovarian reserve for ovarian stimulation by exogenous gonadotropins. To determine what pretreatment should be performed for ovarian endometrial cyst before IVF-ET, we analyzed IVF outcomes with or without pretreatment in patients with endometrioma. Infertile women with endometrioma who underwent IVF-ET were divided into 3 groups, including patients who had received laparotomy or laparoscopy, patients for whom the endometrioma content had been aspirated and treated with or without alcohol fixation, and patients who did not undergo pretreatment. The number of retrieved oocytes, rate of mature oocytes, and fertilization rate were compared among groups. The results showed that pretreatment for endometrioma reduces the number of retrieved oocytes. Although oocyte quality as a rate of mature oocytes was not affected by the presence of an ovarian endometrial cyst, the fertilization rate was improved by cyst aspiration. We propose that surgical pretreatment is not necessary for ovarian endometrial cyst before IVF-ET, but cyst aspiration may be beneficial after several failed attempts of IVF.