齋藤 心

BACKGROUND: Intraperitoneal (IP) administration of paclitaxel (PTX) has a great pharmacokinetic advantage to control peritoneal lesions and can be combined with various systemic chemotherapies. In this study, we evaluate the efficacy and tolerability of a combination of IP-PTX and systemic S-1/oxaliplatin (SOX) for induction chemotherapy for patients with peritoneal metastases (PM) from gastric cancer (GC). PATIENTS AND METHODS: Patients with GC who were diagnosed as macroscopic PM (P1) or positive peritoneal cytology (CY1) by staging laparoscopy between 2016 and 2019 were enrolled. PTX was IP administered at 40 mg/m2 on days 1 and 8. Oxaliplatin was IV administered at 100 mg/m2 on day 1, and S-1 was administered at 80 mg/m2/day for 14 consecutive days, repeated every 21 days. Survival time and toxicities were retrospectively explored. RESULTS: Forty-four patients received SOX + IP-PTX with a median (range) of 16 (1-48) courses, although oxaliplatin was suspended due to the hematotoxicity or intolerable peripheral neuropathy in many patients. The 1-year overall survival (OS) rate was 79.5% (95% CI 64.4-88.8%) with median survival time of 25.8 months. Gastrectomy was performed in 20 (45%) patients who showed macroscopic shrinkage of PM with a 1-year OS rate of 100% (95% CI 69.5-100%). Grade 2 and 3 histological responses was achieved in four (20%) and one (5%) patients. Grade 3/4 toxicities included neutropenia (11%), leukopenia (39%), and anemia (14%). There were no treatment-related deaths. CONCLUSIONS: Combination chemotherapy using SOX + IP-PTX regimen is highly effective and recommended as induction chemotherapy for patients with PM from GC.

INTRODUCTION: Gastric leiomyomas are benign mesenchymal tumors, comprising about 2.5% of gastric neoplasms, which can be difficult to differentiate from gastrointestinal stromal tumors which have malignant potential. Granular cell tumors in the abdominal wall are also rare. Since mesenchymal tumors are difficult to diagnose by imaging, further studies are needed to establish the diagnosis. PRESENTATION OF CASE: A 60-year-old asymptomatic woman underwent routine upper endoscopy and was found to have a gastric submucosal lesion. Computed tomography scan also showed an abdominal wall mass. The appearance of both lesions on imaging studies were similar, but it was unclear if the two lesions had the same origin. Endoscopic ultrasound-guided fine needle aspiration biopsy of the gastric lesion was insufficient to establish the diagnosis. Laparoscopic-endoscopic cooperative resection of the gastric lesion and ultrasound-guided core-needle biopsy of the abdominal wall mass enabled pathological diagnosis of both lesions. DISCUSSION: Diagnostic imaging findings of these two lesions were similar. Histologic and immunohistochemical studies are essential to establish a definitive diagnosis. Laparoscopic-endoscopic cooperative surgery may be an effective minimally invasive approach, allowing both pathological diagnosis and complete resection of a gastric submucosal tumor, especially when endoscopic-ultrasound guided fine needle aspiration or biopsy fails to make the diagnosis. CONCLUSION: Laparoscopic-endoscopic cooperative surgery can be an effective minimally invasive approach to resect some lesions. This is first report of the patient with a synchronous gastric leiomyoma and an intramuscular granular cell tumor in the abdominal wall.

BACKGROUND: Patients with esophageal cancer and a history of gastrectomy or concurrent gastric cancer undergo not only esophagectomy but also total gastrectomy. The goal of this study is to evaluate the postoperative quality of life (QOL) and dysfunction of these patients using two postoperative questionnaires. MATERIALS AND METHODS: From 1999 to 2015, 41 patients underwent concurrent esophagectomy and total gastrectomy. A jejunal pedicle with the subcutaneous supercharge technique was used for reconstruction. Patients were divided into two groups, including those undergoing concurrent esophagostomy and gastrectomy (Group 1), and those undergoing esophagectomy alone (Group 2, history of previous gastrectomy). Patients were analyzed by time interval, including patients within three years of surgery (Group A) and those more than three years after surgery (Group B). RESULTS: Eighteen patients completed the questionnaires. The mean DAUGS20 score was 26.4 ± 13.2. The DAUGS20 scores of groups 1 (N = 7) and 2 (N = 11) were 25.4 ± 12.5 and 27 ± 15.4 (p = 0.58), respectively. Global health status scored by the EORTC QLQC-30 were 71.4 ± 18.5 in group 1 and 67.4 ± 22.8 in group 2 (p = 0.85). DAUGS20 scores of group A (N = 10) and B (N = 8) were 28.1 ± 12.4 and 23.3 ± 14.4 (p = 0.35). No significant differences were found between groups A and B regarding the QLQ-C30 scores. CONCLUSION: DAUGS20 and QLQ-C30 scores showed no significant differences between groups 1 and 2 or groups A and B. These results suggest that postoperative QOL and dysfunction may be influenced more by current status than by surgical history and postoperative interval. Previous reports describe a DAUGS 20 score after gastrectomy of 27.8 and after esophagectomy of 36.1. The DAUGS20 score of these 18 patients is lower than DAUGS20 scores for patients undergoing either operation alone. Reconstruction using a subcutaneously placed jejunal segment seems to be reasonable.

Lung cancer is the leading cause of cancer-related deaths worldwide with over 1 million deaths each year. The overall prognosis of lung cancer patients remains unsatisfactory, with a 5-year overall survival rate of less than 15%. Although most lung cancers are a result of smoking, approximately 25% of lung cancer cases worldwide are not attributable to tobacco use. Notably, more than half of the lung cancer cases in women occur in non-smokers. Among non-small-cell lung cancer (NSCLC) cases, cigarette-smokers have a greater association with squamous cell carcinoma than adenocarcinoma, which is more common in non-smokers. These findings imply that specific molecular and pathological features may associate with lung adenocarcinoma arising in non-smoker female patients. Over the past decade, whole genome sequencing and other '-omics' technologies led to the discovery of pathogenic mutations that drive tumor cell formation. These technological developments may enable tailored patient treatments throughout the course of their disease, potentially leading to improved patient outcomes. Some clinical and laboratory studies have shown success outcomes using epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKI) in patients with EGFR mutations and ALK rearrangements, respectively. In fact, these 2 mutations are predominantly present in female non-smokers with adenocarcinoma. Immunotherapy has also recently emerged as a major therapeutic modality in NSCLC. In this review, we summarize the current understanding of NSCLC biology and new therapeutic molecular targets, focusing on the pathogenesis of non-smoker female NSCLC patients.

Eosinophilic granulomatosis with polyangiitis (EGPA) is a vascular disorder of unknown etiology characterized by severe asthma, eosinophilia, and granulomatous vasculitis. It is sometimes associated with gastrointestinal lesions, although perforations are uncommon. Corticosteroids are commonly used in the treatment of patients with EGPA; however, they may impair tissue repair and induce fibrotic changes in the vascular intima, which can lead to vascular occlusion, ischemia, and perforation. The anti-inflammatory properties of corticosteroids may mask symptoms of gastroduodenal ulcers or other intra-abdominal conditions, which can lead to a delay in diagnosis. From January 1, 2001 to December 31, 2014, 71 patients underwent surgery for small intestinal perforations. Of these, 4 operations were performed on 3 patients with EGPA who were receiving corticosteroids. We retrospectively reviewed the clinical and pathologic features of these patients. All 3 patients with EGPA were men, with a mean age of 56 years. The length of resected intestine ranged from 10 to 60 cm. Histopathologic examination revealed ulcers and perforations of the small intestine associated with vasculitis, compatible with EGPA. All patients had an uneventful postoperative course. Patients with EGPA presenting with abdominal pain must be carefully evaluated for possible intestinal perforation, especially those receiving corticosteroid therapy.

Gastric cancer is a common malignancy and remains potentially lethal. The prognosis of patients with stage IV gastric cancer is thought to be poor, but new molecular targeted therapy may benefit patients with advanced gastric cancer. Currently, conversion surgery after chemotherapy with a trastuzumab-containing regimen is reported to be effective in these patients. We present 3 patients with human epidermal growth factor receptor 2 (HER2)–positive advanced gastric cancer who underwent conversion surgery after receiving a trastuzumab-containing chemotherapy regimen. Interestingly, the primary lesion acquired resistance to the trastuzumab-containing regimen, although the metastatic lesions maintained a complete response. The reason why the primary lesions became resistant to trastuzumab remains unclear. More studies are needed to clarify the mechanism of resistance. Conversion surgery, made possible by the use of molecular-targeted therapy, may improve the prognosis of patients with stage IV gastric cancer, particularly if metastatic lesions show a complete response to therapy.

INTRODUCTION: Spontaneous esophageal perforation, or Boerhaave's syndrome, is a life-threating condition which usually requires emergent surgery. An upside down stomach is defined as a gastric volvulus in a huge supradiaphragmatic sac. In general, this condition can result in ischemia and perforation of the stomach. This is the first report of a patient with Boerhaave's syndrome and an upside down stomach. CASE PRESENTATION: A 79-year-old woman presented with sudden epigastric pain following hematemesis. Evaluation of the patient showed both an esophageal perforation and an upside down stomach. Surgical drainage and irrigation of the mediastinum and pleural cavities were undertaken emergently. Due to the concurrent gastric volvulus, a gastrostomy was placed to fix and decompress the stomach. The patient had an uneventful hospital course and was discharged. DISCUSSION AND CONCLUSION: Boerhaave's syndrome is a rare but severe complication caused by excessive vomiting, due to a sudden elevation in intraluminal esophageal pressure resulting in esophageal perforation. Acute gastric volvulus can result in ischemia and perforation of the stomach, but has not previously been reported with esophageal perforation. The most likely mechanism associating an upside down stomach with Boerhaave's syndrome is acute gastric outlet obstruction resulting in vomiting, and subsequent esophageal perforation. Perforation of the esophagus as well as perforation of the stomach must be considered in patients with an upside down stomach although both upside down stomach and Boerhaave's syndrome are rare clinical entities.

BACKGROUND: Although advanced esophageal squamous-cell carcinoma (ESCC) is treated using a multidisciplinary approach, outcomes remain unsatisfactory. The microenvironment of cancer cells has recently been shown to strongly influence the biologic properties of malignancies. We explored the effect of supernatant from esophageal fibroblasts on the cell growth and chemo-resistance of ESCC cell lines. METHODS: We used 22 ESCC cell lines, isolated primary human esophageal fibroblasts and immortalized fibroblasts. We first examined cell proliferation induced by fibroblast supernatant. The effect of supernatant was evaluated to determine whether paracrine signaling induced by fibroblasts can influence the proliferation of cancer cells. Next, we examined the effects of adding growth factors HGF, FGF1, FGF7, and FGF10, to the culture medium of cancer cells. These growth factors are assumed to be present in the culture supernatants of fibroblasts and may exert a paracrine effect on the proliferation of cancer cells. We also examined the intrinsic role of HGF/MET and FGFs/FGFR in ESCC proliferation. In addition, we examined the inhibitory effect of lapatinib on ESCC cell lines and studied whether the fibroblast supernatants affect the inhibitory effect of lapatinib on ESCC cell proliferation. Finally, we tested whether the FGFR inhibitor PD-173074 could eliminate the rescue effect against lapatinib that was induced by fibroblast supernatants. RESULTS: The addition of fibroblast supernatant induces cell proliferation in the majority of cell lines tested. The results of experiments to evaluate the effects of adding growth factors and kinase inhibitors suggests that the stimulating effect of fibroblasts was attributable in part to HGF/MET or FGF/FGFR. The results also indicate diversity in the degree of dependence on HGF/MET and FGF/FGFR among the cell lines. Though lapanitib at 1 μM inhibits cell proliferation by more than 50% in the majority of the ESCC cell lines, fibroblast supernatant can rescue the growth inhibition of ESCC cells. However, the rescue effect is abrogated by co-treatment with FGFR inhibitor. CONCLUSION: These results demonstrate that cell growth of ESCC depends on diverse receptor tyrosine kinase signaling, in both cell-autonomous and cell-non-autonomous manners. The combined inhibition of these signals may hold promise for the treatment of ESCC.

The growth, invasiveness and metastasis of human cancers are determined not only by cancer cells, but also by their microenvironment. Activated stromal fibroblasts promote tumor progression by secreting growth factors. In the present study, we focused on interrelations between cancer and fibroblasts, the main component of tumor stroma. We retrospectively analyzed the relations of mortality to clinical, pathological, and α-smooth muscle actin (α-SMA) characteristics in 97 consecutive patients with esophageal squamous cell carcinoma (ESCC). In vitro, we used TE-11, KYSE150 and KYSE220 ESCC cell lines and isolated esophageal stromal fibroblasts, some of which were immortalized. Migration assays were conducted to assess the effects of fibroblasts on cancer-cell migration and 3-dimensional organotypic cultures. In vivo, TE-11 and KYSE220 cells plus immortalized fibroblasts were co-transplanted subcutaneously in Nod/Scid mice to assess the effects of fibroblasts on tumorigenicity. Clinicopathologically, the α-SMA expression of cancer stroma was correlated with venous invasion (p<0.01), nodal involvement (p=0.02), recurrence (p=0.01), and was a predictor of survival in patients with stage I and II ESCC (p=0.04). In vitro, the presence of fibroblasts strongly promoted the migration of TE-11, KYSE150 and KYSE220 cells. On organotypic culture, stromal invasion was observed only in the presence of immortalized fibroblasts. In vivo, tumors developed or grew in a fibroblast‑dependent manner after implantation. Our findings provide evidence that stromal fibroblasts and tumor cells interact to promote tumor progression in ESCC. In patients with earlier stage ESCC, α-SMA may be a predictor of mortality. Inhibition of paracrine systems associated with tumor fibroblasts may slow or reverse tumor progression, potentially leading to the development of new targeted therapies.

OBJECTIVE: Adenosquamous carcinoma originating in the stomach is an unusual neoplasm with few existing histological studies. This study was aimed to gain insight into the histogenetic and clinicopathological characteristics of gastric cancer with squamous cell carcinoma (SCC) components. METHODS: From January 2001 to June 2010 a total of 1735 patients underwent a resection of gastric cancer. Histopathologically, eight patients had adenocarcinoma containing SCC components, in which the proportion of SCC components was above 25% of the total tumor mass in four patients. The immunohistochemical and clinicopathological characteristics of these eight patients were analyzed. RESULTS: The median survival duration was 22 months. Adenocarcinoma was present at the superficial layer of all tumors and SCC was primarily present at sites with deep invasion. Immunohistochemically, adenocarcinoma components were positive for cytokeratin (CK) 8/18/19 and CK7 in all cases. SCC components were positive for carcinoembryonic antigen and CK7 in more than 60% of patients. Expression patterns of p53 product were identical in both components. SCC components were positive for 34βE12 and adenocarcinoma components were negative for 34βE12 in all patients. CONCLUSIONS: SCC components are derived from squamous metaplasia in a pre-existing adenocarcinoma. A gastric adenocarcinoma with SCC components is associated with various patterns of metastasis and both SCC and adenocarcinoma components have the potential for metastasis. Gastric cancer with SCC components is a clinically aggressive tumor.

67歳女.主訴は食欲低下,嘔気,吐血であった.内視鏡検査で上切歯列より25cm遠位に粘膜の脱落と著明な狭窄を認めた.また,胃体中部に多発する潰瘍が認められた.食道ブジーを行いながら,複数回の生検を施行したが,異型細胞は認められず,病態の原因を明らかにできなかった.家族を含めた詳細な問診により「熱い粥を冷まさずに食べる生活習慣」があることが判り,反復性の熱傷が原因と考えられた.この食習慣を禁止し,投薬とブジーを繰返す治療によりほぼ正常な食生活が可能になった.発症より1年4ヵ月後の内視鏡検査では狭窄は認めたが,食道の粘膜面は再生し,胃の多発性潰瘍は瘢痕となっていた