Analysis of the risk factors for osteoporosis and its prevalence after gastrectomy for gastric cancer in older patients: a prospective study.

PURPOSE: Osteoporosis leads to fragility fractures and is a major public health problem. We conducted this study to analyze the prevalence of and risk factors for osteoporosis after gastrectomy in older patients. METHODS: This multicenter prospective trial comprised older patients without recurrence of gastric cancer for > 3 years after curative surgery. The prevalence of osteoporosis was identified using the World Health Organization bone mineral density (BMD)-based definition. Univariate and multivariate analyses were performed to identify the risk factors for osteoporosis. RESULTS: BMD values were measured in 267 of the 271 enrolled patients. The prevalence of osteoporosis was 38.2% (men 24.0%; women 60%). Analysis using FRAX® revealed that 51.7% of patients were candidates for pharmacologic therapy. Female sex (odds ratio [OR] 5.16, 95% confidence interval [CI] 2.61-10.2), age (OR 1.06, 95% CI 1.00-1.12), low body mass index (< 19.0 kg/m2) after gastrectomy (OR 5.31, 95% CI 2.79-10.13), and history of fracture (OR 2.06, 95% CI 1.06-4.02) were independently associated with osteoporosis. CONCLUSIONS: The prevalence of osteoporosis in older patients after gastrectomy was 38.2%. Moreover, female sex, age, low body mass index after gastrectomy, and a history of fracture were risk factors significantly associated with osteoporosis. Thus, older patients undergoing gastrectomy should have proactive surveillance and receive treatment for osteoporosis.

[A Case of Achieving CR through Chemoradiotherapy for Postoperative Oligo Lymph Node Metastasis in Gastric Cancer].

We present a case of oligo lymph node metastasis in a 70s man who had previously undergone subtotal gastrectomy for advanced gastric cancer in the prepylorus. Postoperatively, adjuvant chemotherapy was administered for a duration of 1 year. During the third postoperative year, elevated tumor markers and lymph node enlargement prompted a diagnosis of lymph node metastasis. Subsequent chemoradiotherapy resulted in a complete response(CR), which has been sustained for 2 years without any recurrence. The outcomes of this case indicate that chemoradiotherapy stands as a viable treatment option for oligo lymphatic recurrence in gastric cancer.

[A Case of Neuroendocrine Carcinoma Treated with Salvage Surgery after Systemic Chemotherapy].

A man in his 50s was admitted to our hospital due to hematemesis.Esophagogastroduodenoscopy revealed an 8 cm type 2 gastric tumor.The tumor was histologically diagnosed as a neuroendocrine carcinoma.CT showed that the tumor had directly infiltrated the liver but there was no distant metastasis.We performed open distal gastrectomy, D2 lymph node dissection, partial hepatectomy, and cholecystectomy.Four months after the surgery, metastases of the right adrenal gland and dorsal part of the inferior vena cava were found.Although a significant tumor reduction was obtained by 12 courses of chemotherapy with CDDP plus CPT-11, this effective treatment was discontinued for the patient's convenience.Fifteen months after the surgery, metastasis of the right adrenal gland and dorsal part of inferior vena cava demonstrated re-growth without any further metastasis.After 4 courses of the same regimen, a partial response was obtained for the recurrences.As a salvage surgery, we performed open right adrenal gland and the lymph nodes of dorsal of IVC resection.The patient is alive without recurrence 1 year after the salvage surgery.

[A Case of Lymph Node Recurrence with Invasion to the Trachea after the Resection of Esophageal Cancer Treated by Multidisciplinary Treatment].

A 78-year-old man who underwent esophagectomy for middle thoracic esophageal squamous cell carcinoma(pT1bN0M0, pStage Ⅰ)was diagnosed with lymph node recurrence 12 months after the initial surgery. He received chemoradiotherapy(5- fluorouracil plus cisplatin); however, the treatment was terminated at the middle of the treatment course because of progressive disease. He received chemotherapy(docetaxel plus 5-fluorouracil plus cisplatin)as a second-line treatment, which was also canceled due to serious adverse events. Partial response was achieved after the second therapy; therefore, surgical excision was performed. Thirteen months after the second surgery, he was diagnosed with second local recurrence with invasion to the trachea. Another course of chemotherapy(docetaxel[2-weekly]plus 5-fluorouracil plus cisplatin)was administered, which also achieved a partial response. Thus, surgical excision with partial tracheal resection and mediastinal tracheostomy was performed. He has been alive without recurrence for 6 months after the final operation. In case of postoperative solitary lymph node recurrence of esophageal cancer, long-term survival can be expected with multidisciplinary treatment.

[A Case of Adenosquamous Carcinoma of Pancreas Treated with Conversion Surgery after Systemic Chemotherapy].

CASE: A man in his 60s reported upper abdominal pain; close examination revealed a tumor in the body-tail of the pancreas that was suspected to be infiltrating the stomach. Multiple liver lesions(S3, S4)were also detected. Histological examination by EUS-FNA showed poorly-differentiated carcinoma; thus, this case was diagnosed with unresectable pancreatic cancer with liver metastases(cT3, cN1[No. 7], cM1[P0, H1], cStage Ⅳ: JPS 7th). After 2 kinds of systemic chemotherapy(9 courses of GEM plus nab-PTX and 9 courses of modified FOLFIRINOX), obvious distant metastases or local progression did not appear and conversion surgery was scheduled. Although a metastatic lesion was identified at S5 of the liver just before the surgery, it was assumed that an R0 resection could be achieved; therefore, the operation(distal pancreatectomy with combined proximal gastrectomy, left adrenalectomy, lymph node dissection, partial hepatectomy of S5, and cholecystectomy)was performed. Histopathological examination showed squamous metaplasia of the epithelial tissue combined with glandular formation. This case was, thus, diagnosed as adenosquamous carcinoma of pancreas. This patient was discharged 90 days after the operation. The patient is still alive 2 years and 2 months since the first diagnosis.

Skeletal Muscle Loss during Neoadjuvant Chemotherapy Is an Independent Risk Factor for Postoperative Infectious Complications in Patients with Advanced Esophageal Cancer.

OBJECTIVE: Neoadjuvant therapy followed by surgery has been the standard treatment for advanced esophageal cancer. Severe toxicities may influence body composition, including skeletal muscle mass, and increase postoperative complications. The purpose of this study was to evaluate the influence of sarcopenia, changes in body composition, and adverse events during neoadjuvant chemotherapy (NACT) on postoperative complications in esophageal cancer patients. METHODS: A total of 83 patients with esophageal cancer undergoing NACT followed by esophagectomy were included. Body composition was assessed before chemotherapy and before esophagectomy. The relationships between postoperative infectious complications and sarcopenia, changes in body composition, and adverse events during NACT were investigated. RESULTS: Univariate analysis revealed that skeletal muscle loss during NACT, but not preoperative sarcopenia, was significantly higher in the complication (+) group. Febrile neutropenia tended to occur frequently in the complication (+) group. Multivariate analysis demonstrated that skeletal muscle loss was the only factor significantly associated with infectious complications (p = 0.029). Among adverse events, febrile neutropenia was significantly associated with a decrease in skeletal muscle mass. CONCLUSION: Loss of skeletal muscle mass during NACT was a significant risk factor for postoperative infectious complications in patients with esophageal cancer. Prevention of severe adverse events may reduce postoperative infectious complications.

Feasibility of real-time intestinal bloodstream evaluation using probe-based confocal laser endomicroscopy in a porcine intestinal ischemia model.

BACKGROUND: Intestinal ischemia can lead to fatal complications if left unrecognized during surgery. The current techniques of intraoperative microvascular assessment remain subjective. Probe-based confocal laser endomicroscopy (pCLE) has the potential to objectively evaluate microvascular blood flow in real-time setting. The present study evaluated the technical feasibility of real-time intestinal bloodstream evaluation using pCLE in a porcine intestinal ischemia model. METHODS: Seven pigs were used. The intestinal ischemia model was prepared by sequentially dividing the mesenteric blood vessels. The intestinal bloodstream was evaluated on its serosal surface using pCLE (Cellvizio 488 probe, Ultra Mini O) at every 1-cm segment from a vessel-preservation border (i.e., the cut end of the vessel). Images of the blood vessels and flow of red blood cells (RBCs) in each visualized vessel were semi-qualitatively assessed using a 3-scale scoring system. In addition, 25 surgeons blindly assessed the 10 movies recorded at 0, 1, 2, 3, and 5 cm from a vessel-preservation border using a 4-scale scoring system to confirm the consistency of the evaluation of the pCLE system. RESULTS: Images of the blood vessels were successfully obtained from the cut end of the vessel to the segment 4 cm away. Good unidirectional flow of RBCs was observed from the cut end to the 2-cm segment, whereas the flow became bidirectional between 2 and 3 cm segments. Beyond 4 cm, no flow images were obtained. The specimen obtained from the segment beyond 4 cm showed remarkable mucosal color change, which was confirmed as a necrotic change histologically. The evaluations from the cut end of the vessel to the segment 1 cm away by surgeons were excellent or good and it was almost consistent. CONCLUSIONS: Real-time bloodstream evaluation using pCLE is feasible and potentially effective for predicting intestinal ischemia during surgery.

Genomic and transcriptomic analysis of imatinib resistance in gastrointestinal stromal tumors.

Gastrointestinal stromal tumors represent the most common mesenchymal tumor of the digestive tract, driven by gain-of-function mutations in KIT. Despite its proven benefits, half of the patients treated with imatinib show disease progression within 2 years due to secondary resistance mutations in KIT. It remains unclear how the genomic and transcriptomic features change during the acquisition of imatinib resistance. Here, we performed exome sequencing and microarray transcription analysis for four imatinib-resistant cell lines and one cell line briefly exposed to imatinib. We also performed exome sequencing of clinical tumor samples. The cell line briefly exposed to imatinib exhibited few single-nucleotide variants and copy-number alterations, but showed marked upregulation of genes related to detoxification and downregulation of genes involved in cell cycle progression. Meanwhile, resistant cell lines harbored numerous genomic changes: amplified genes related to detoxification and deleted genes with cyclin-dependent kinase activity. Some variants in the resistant samples were traced back to the drug-sensitive samples, indicating the presence of ancestral subpopulations. The subpopulations carried variants associated with cell death. Pre-existing cancer cells with genetic alterations promoting apoptosis resistance may serve as a basis whereby cancer cells with critical mutations, such as secondary KIT mutations, can establish full imatinib resistance. © 2017 The Authors Genes, Chromosomes and Cancer Published by Wiley Periodicals, Inc.

[Two Cases of Locally Recurrent Rectal Cancer Undergoing Preoperative Chemoradiationtherapy].

Case 1 is a 68-year-old woman with locally recurrent rectal cancer(LRRC)developed 5 years after resection of primary rectal cancer. The tumor seized right lateral side in pelvic. We performed tumor excision after preoperative chemoradiation comprised external beam radiation with oral S-1(tegafur/gimeracil/oteracil). He has been relapse-free for 3 years 3months after surgery. Case 2 is a 74-year-old man with LRRC developed 2 years after resection of primary rectal cancer. The tumor was located dorsal to anastomosis site in pelvic. We performed abdominoperineal resection for LRRC after preoperative chemoradiation with oral S-1. He has been relapse-free for 2 years. It was suggested that preoperative radiotherapy combined with oral FU for local recurrence after rectal cancer may contribute to distant and local control.

Suppressor of cytokine signaling-1 gene therapy induces potent antitumor effect in patient-derived esophageal squamous cell carcinoma xenograft mice.

Chronic inflammation is involved in cancer growth in esophageal squamous cell carcinoma (ESCC), which is a highly refractory cancer with poor prognosis. This study investigated the antitumor effect and mechanisms of SOCS1 gene therapy for ESCC. Patients with ESCC showed epigenetics silencing of SOCS1 gene by methylation in the CpG islands. We infected 10 ESCC cells with an adenovirus-expressing SOCS1 (AdSOCS1) to examine the antitumor effect and mechanism of SOCS1 overexpression. SOCS1 overexpression markedly decreased the proliferation of all ESCC cell lines and induced apoptosis. Also, SOCS1 inhibited the proliferation of ESCC cells via multiple signaling pathways including Janus kinase (JAK)/signal transducer and activator of transcription (STAT) and focal adhesion kinase (FAK)/p44/42 mitogen-activated protein kinase (p44/42 MAPK). Additionally, we established two xenograft mouse models in which TE14 ESCC cells or ESCC patient-derived tissues (PDX) were subcutaneously implanted. Mice were intra-tumorally injected with AdSOCS1 or control adenovirus vector (AdLacZ). In mice, tumor volumes and tumor weights were significantly lower in mice treated with AdSOCS1 than that with AdLacZ as similar mechanism to the in vitro findings. The Ki-67 index of tumors treated with AdSOCS1 was significantly lower than that with AdLacZ, and SOCS1 gene therapy induced apoptosis. These findings demonstrated that overexpression of SOCS1 has a potent antitumor effect against ESCC both in vitro and in vivo including PDX mice. SOCS1 gene therapy may be a promising approach for the treatment of ESCC.

Appropriate Follow-Up Strategies for Gastrointestinal Stromal Tumor Patients Based on the Analysis of Recurrent Interval and Patterns.

BACKGROUND/AIMS: Previous studies have proposed risk classifications for patients with gastrointestinal stromal tumor (GIST) after resection and have contributed to the prediction of its prognosis. However, optimal postoperative surveillance has not yet been established. METHODS: We retrospectively analyzed data from 115 GIST patients who experienced recurrence after complete resection. The relationships between clinicopathological characteristics and the first recurrence sites, or time to recurrence (TTR), were investigated. We also compared the characteristics between 2 subgroups based on a TTR of ≤5 or >5 years. RESULTS: The first recurrence occurred in the abdomen in 114 of 115 patients (99.1%); one case of esophageal GIST recurred in the lung. Gastric and small intestinal GISTs recurred most frequently in the liver or peritoneum, while the most common recurrences of colorectal GISTs were found to be local. Fourteen patients (12.2%) experienced recurrence after >5 years. Smaller tumors and those categorized as lower risk were significantly more frequent in the TTR >5 years group than in the TTR ≤5 years group. In the TTR >5 years group, local recurrence was the most frequent type of recurrence (42.9%). CONCLUSION: Based on abdominal examination, postoperative surveillance after complete resection for primary GISTs may be recommended for >5 years.

[Investigation of Administration Technique of Regorafenib in Our Center].

Regorafenib is an oral multikinase inhibitor; the CORRECTtrial evaluated its efficacy in patients with metastatic colorectal cancer following disease progression with standard therapies. However, regorafenib has toxicities that develop quickly. Few studies have reported the safe dose and usage of regorafenib to avoid these adverse events in Japanese patients. We examined the side effects and safe administration technique of regorafenib in this study. We administered regorafenib to 15 patients with metastatic colorectal cancer following disease progression with standard therapies. Between August 2013 and January 2014, 5 patients received 160 mg oral regorafenib once daily on days 1-21 of a 28 day course(group A). Between February 2014 and July 2015, 10 patients received initiating therapy with 120 mg regorafenib, with the intention of increasing the dose(group B). We retrospectively assessed side effects, number of dose courses, and total dose of regorafenib in both groups. The median dosing course was 5 coureses in group B, which was more than the 1 course in group A. The median total dose was 10,800 mg in group B, which is about 4 times as much as the 2,400 mg in group A. In group B, 7 out of 10 patients (70%)were successful in the dose escalation of regorafenib from 120 to 160 mg daily over 3-5 courses. The disease control rate was 40% in both groups. The rate of adverse events of Grade 3 or higher was 60% in group A, compared to 40% in group B within 2 courses. The overall survival time was 308 days in group B, which was significantly longer than the 168 days in group A. Initiating therapy with 120 mg regorafenib with the intention of increasing the dose improves safety and allows an increase in dosing courses, as well as in the total dose of regorafenib and overall survival time.

[A Case of Diaphragmatic Metastasis from Adenocarcinoma of the Rectum Treated via Surgical Resection].

A 67-year-oldman underwent lower anterior resection for rectal cancer andresection of liver metastatic tumor 5 years later. Seven years and 2 months after the initial surgery, a soft tissue mass was detected in the left diaphragm. Further retrospective review of CT scan images showedthat the diaphragmatic tumor was present just before the hepatectomy. Partial resection of the left diaphragm was performed, and no relapse has occurred since then for 2 years. Most cases of diaphragmatic metastasis are considered to arise from dissemination, but we considered this case as more likely to be hematogenous. When surgery is chosen to treat metastatic tumors of colorectal cancer, checking for other metastasis via preoperative imaging andperforming curative resection is important.

Overexpression of glypican-1 implicates poor prognosis and their chemoresistance in oesophageal squamous cell carcinoma.

BACKGROUND: Despite the recent improvements in multimodal therapies for oesophageal squamous cell carcinoma (ESCC), the prognosis remains poor. The identification of suitable biomarkers for predicting the prognosis and chemo-sensitivity is required to develop targeted treatments and improve treatment results. METHODS: Proteins highly expressed in ESCC cell lines compared with normal oesophageal cell lines were screened by isobaric tag for relative and absolute quantitation (iTRAQ). We identified glypican-1 (GPC1) as a novel molecule. The clinicopathological characteristics of GPC1 were evaluated by immunohistochemistry using ESCC specimens, and clinical parameters were assessed. The correlation between GPC1 expression levels and chemo-sensitivity were analysed in vitro. RESULTS: In the immunohistochemical assessment of 175 ESCC patients, 98.8% expressed GPC1. These patients demonstrated significantly poorer prognosis compared with patients with low-GPC1 expression by survival assay (P<0.001). Higher chemoresistance was observed in the GPC1 high-expression group. GPC1 expression levels positively correlated with chemo-sensitivity against cis-Diammineplatinum (II) dichloride (CDDP), and are potentially associated with anti-apoptotic function based on alterations in the MAPK downstream signalling pathway and Bcl-2 family member proteins. CONCLUSIONS: GPC1 is an independent prognostic factor in ESCC and is a critical molecule for altering the threshold of chemoresistance to CDDP.

A novel approach of optical biopsy using probe-based confocal laser endomicroscopy for peritoneal metastasis.

BACKGROUND: In digestive cancers, it is mandatory to diagnose peritoneal metastasis prior to selecting therapy. Therefore, exploratory laparoscopy has gained wider clinical acceptance. In laparoscopy, the peritoneal metastasis is pathologically confirmed by excisional biopsy; however, there remain technical difficulties in performing precise diagnosis and adequate biopsy on small peritoneal lesions without damaging organs. We have focused on "optical biopsy" using probe-based confocal laser endomicroscopy (pCLE). The aims of this study were (1) to optimize current CLE system for real-time observation of peritoneal metastases and (2) to assess its potential usefulness as diagnostic modality in preclinical settings. METHODS: To optimize condition and evaluate feasibility, we prepared peritoneal metastasis mice model with gastric cancer cell line (MKN-45). On Day 10 after seeding, the mice were laparotomized and performed pCLE observations with CellvizioLAB (LSU-F 400/488 nm, Mauna Kea Technologies, Paris, France). We evaluated two different CLE probes, three different dyes, and optimal interval time. The detected sites were excised and pathologically evaluated on its morphology. Next, the feasibility and safety were validated in porcine model for clinical usage. After injection of fluorescein, pCLE was applied for the observation of intra-abdominal organs. RESULT: A miniature probe-type pCLE system with 60 µm focal depth (UltraMini O) and 1 % fluorescein dye was chosen for good visualization in mice model. The irregular microarchitecture images suspected to malignancy were obtained from the metastases. In the porcine model, observation of abdominal organs was feasible without any organ injury in the laparoscopic procedures. The dosage of 1 % fluorescein (3 ml/body) was appropriate in observing intra-abdominal organs, and each intra-abdominal organ was clearly observed with the same imaging quality we obtained in mice model. CONCLUSION: The pCLE was feasible and safe and potentially useful for the diagnosis of the peritoneal metastasis in in vivo animal models.

Suppressor of cytokine signalling-1 induces significant preclinical antitumor effect in malignant melanoma cells.

Malignant melanoma is the most aggressive form of skin cancer, responsible for the majority of skin cancer-related deaths. Metastatic melanoma is resistant to surgery, radiation or chemotherapy, and an effective therapy has not yet been established. Our study investigated the therapeutic potential of the suppressor of cytokine signalling-1 (SOCS-1), an endogenous inhibitor of the intracellular cytokine signalling pathway, for treating melanoma. Adenovirus vectors encoding the SOCS-1 gene were used to overexpress SOCS-1 in three melanoma cell lines (G361, SK-MEL5 and SK-MEL28). In G361 and SK-MEL5, overexpression of SOCS-1 significantly reduced cell proliferation and induced apoptosis in vitro and in vivo. Furthermore, we indicated that the antiproliferative effect of SOCS-1 correlated not only with decreased levels of the activation of signal transducer and activator of transcription (STAT)3 but also with increased levels of p53 expression and phosphorylation. These findings indicate the potential for clinical use of SOCS-1 for melanoma treatment.

[Intraductal Papillary Mucinous Neoplasm (IPMN) of the Pancreas Showing High Accumulation of 18F-Fluorodeoxyglucose (FDG)--A Case Report].

The diagnosis of intraductal papillary mucinous neoplasms (IPMNs) of the pancreas includes radiographic (CT, MRI) and endoscopic evaluation (ERCP, EUS). The treatment strategy is outlined in the 2012 International Consensus Guidelines (ICG). Herein, we report a case initially not indicated for surgery. Four months after the initial diagnosis, the cystic lesion transformed into a solid mass-like lesion visible on CT. FDG-PET showed abnormal FDG uptake at the same location. Surgical resection was performed immediately, and the tumor was diagnosed as IPMN with inflammation. FDG-PET showed a false-positive diagnosis for the malignancy in this case of IPMN.

[Interventional Radiology for Intra-Abdominal Abscess after Gastrectomy].

Approximately 20% of patients develop some complications after gastrectomy. These complications should be treated appropriately to achieve a positive outcome. The records of 6 patients with postoperative intra-abdominal abscesses treated with interventional radiology (IVR) were analyzed. The cause of abscess was anastomotic leakage in 4 patients and contaminated surgery after gastric perforation in 2 patients. Intra-abdominal abscesses were detected on postoperative day 12 (median), and an IVR-guided drainage tube was inserted with a median interval of 1 day. The drainage tube was kept in place for 26 days (median), and patients were discharged 6.5 days (median) after drainage tube removal. No patients were converted to open surgery. Early IVR-guided drainage was essential and effective for intra-abdominal abscess treatment after gastrectomy.

[Analysis of Chemotherapy with Trastuzumab in Advanced Gastric Cancer].

PURPOSE: Here, we investigated the efficacy of chemotherapy with trastuzumab for patients with advanced or recurrent gastric cancer. MATERIALS AND METHODS: We investigated the progression free survival (PFS) and overall survival (OS) of advanced gastric cancer patients who received first-line chemotherapy with trastuzumab in our hospital. RESULT: After first-line chemotherapy, the median PFS and median OS of patients who received trastuzumab combined with capecitabine/cisplatin chemotherapy was not significantly longer than those of patients who received trastuzumab combined with S-1/cisplatin chemotherapy (PFS, 138 [95%CI: 118-187] vs 169 [95%CI: 83-251] days, p=0.9684; OS, 393 [95%CI: 240-469] vs 466 [95%CI: 256-482] days, p=0.4703). After second-line chemotherapy, the median PFS of patients who received trastuzumab plus irinotecan chemotherapy was not significantly longer than that of patients who received trastuzumab plus paclitaxel chemotherapy (PFS, 63 [95%CI: 52-266] vs 58 [95%CI: 26-184] days, p=0.5447).

[A Case of Unresectable Advanced Gastric Cancer Treated with Radiotherapy and Trans-Arterial Embolization, Resulting in Effective Hemostasis].

We report the case of a 70-year-old man with unresectable advanced gastric cancer because of invasion to the pancreas and multiple liver metastases. He could have continued with fourth-line chemotherapy by controlling intermittent bleeding from the cancer by means of 2 rounds of radiotherapy and trans-arterial embolization. The serum hemoglobin level declined to 4.5 g/dL during second-line chemotherapy. As the venous bleeding from the cancer was difficult to control by endoscopic hemostasis, radiotherapy with 40 Gy/20 fractions was applied to the cancer. We were able to restart chemotherapy after the hemostasis, but 6 months later, the serum hemoglobin level declined to 6.1 g/dL. Additional radiotherapy of 20 Gy/10 fractions was delivered to the tumor, and successful hemostasis was achieved; the serum hemoglobin level reached 7.5 g/dL. However, a contrast-enhanced CT, which was performed 3 weeks later, demonstrated extravasation from the cancer into the gastric cavity. We conducted trans-arterial embolization, and the patient no longer required transfusion. We planned to restart chemotherapy soon, but after 1 month, he died of pneumonia.