Publications by authors named "Yoko Hiraki"

54 Publications

A comparative study of the lengths of different reconstruction routes used after thoracic esophagectomy.

Esophagus 2021 Jan 19. Epub 2021 Jan 19.

Department of Surgery, Faculty of Medicine, Kindai University, 377-2 Ohno-Higashi, Osaka-Sayama, Osaka, 589-8511, Japan.

Background: A challenge in esophageal reconstruction after esophagectomy is that the distance from the neck to the abdomen must be replaced with a long segment obtained from the gastrointestinal tract. The success or failure of the reconstruction depends on the blood flow to the reconstructed organ and the tension on the anastomotic site, both of which depend on the reconstruction distance. There are three possible esophageal reconstruction routes: posterior mediastinal, retrosternal, and subcutaneous. However, there is still no consensus as to which route is the shortest.

Methods: The length of each reconstruction route was retrospectively compared using measurements obtained during surgery, where the strategy was to pull up the gastric conduit through the shortest route. The proximal reference point was defined as the left inferior border of the cricoid cartilage and the distal reference point was defined as the superior border of the duodenum arising from the head of the pancreas.

Results: This study involved 112 Japanese patients with esophageal cancer (102 men, 10 women). The mean distances of the posterior mediastinal, retrosternal, and subcutaneous routes were 34.7 ± 2.37 cm, 32.4 ± 2.24 cm, and 36.3 ± 2.27 cm, respectively. The retrosternal route was significantly shorter than the other two routes (both p < 0.0001) and shorter by 2.31 cm on average than the posterior mediastinal route. The retrosternal route was longer than the posterior mediastinal route in only 5 patients, with a difference of less than 1 cm.

Conclusion: The retrosternal route was the shortest for esophageal reconstruction in living Japanese patients.
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http://dx.doi.org/10.1007/s10388-020-00805-xDOI Listing
January 2021

A novel method of esophagogastrostomy by overlap anastomosis with placement of the remnant stomach into the lower mediastinum after laparoscopic proximal gastrectomy.

Asian J Endosc Surg 2021 Jan 3. Epub 2021 Jan 3.

Department of Surgery, Kindai University Faculty of Medicine, Osakasayama, Japan.

Introduction: Control of postoperative gastroesophageal reflux (GER) is a critical consideration for patients who undergo proximal gastrectomy. This report describes a new and simple reconstruction method by esophagogastrostomy with placement of the remnant stomach into the lower mediastinum (EG-PRIME). This approach not only suppresses postoperative GER, but it can also be easily performed by total laparoscopy. Detailed herein are the methods for EG-PRIME and the results for three patients with cancer of the upper gastric body.

Materials And Surgical Technique: At the start of the EG-PRIME surgical procedure, a pseudo-fornix and lozenge-shaped gastric conduit were made by cutting the stomach diagonally. Next, the pseudo-fornix was inserted into the esophageal hiatus to form a new angle of His. Then overlap anastomosis was performed and the entry site was closed longitudinally. The outcomes assessed were operative time, intraoperative blood loss, postoperative complications and GER according to 24-hour pH monitoring.

Discussion: The operative times were 339, 288 and 236 minutes; in two patients, intraoperative blood loss was 260 and 343 mL, and in the third, blood loss was minimal. No postoperative complications were observed in any of the three patients. The degree of the GER resulting in fraction time pH<4 was 9.0%, 0.3%, and 2.9%, respectively. No esophagitis by upper gastrointestinal endoscopy was observed in any patient. This EG-PRIME method was technically feasible for reconstruction after proximal gastrectomy by total laparoscopy. This approach may be as simple and useful as esophagogastrostomy for preventing postoperative GER, but more experience with this method is required.
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http://dx.doi.org/10.1111/ases.12906DOI Listing
January 2021

Efficient detection of copy-number variations using exome data: Batch- and sex-based analyses.

Hum Mutat 2021 Jan 11;42(1):50-65. Epub 2020 Nov 11.

Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Japan.

Many algorithms to detect copy number variations (CNVs) using exome sequencing (ES) data have been reported and evaluated on their sensitivity and specificity, reproducibility, and precision. However, operational optimization of such algorithms for a better performance has not been fully addressed. ES of 1199 samples including 763 patients with different disease profiles was performed. ES data were analyzed to detect CNVs by both the eXome Hidden Markov Model (XHMM) and modified Nord's method. To efficiently detect rare CNVs, we aimed to decrease sequencing biases by analyzing, at the same time, the data of all unrelated samples sequenced in the same flow cell as a batch, and to eliminate sex effects of X-linked CNVs by analyzing female and male sequences separately. We also applied several filtering steps for more efficient CNV selection. The average number of CNVs detected in one sample was <5. This optimization together with targeted CNV analysis by Nord's method identified pathogenic/likely pathogenic CNVs in 34 patients (4.5%, 34/763). In particular, among 142 patients with epilepsy, the current protocol detected clinically relevant CNVs in 19 (13.4%) patients, whereas the previous protocol identified them in only 14 (9.9%) patients. Thus, this batch-based XHMM analysis efficiently selected rare pathogenic CNVs in genetic diseases.
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http://dx.doi.org/10.1002/humu.24129DOI Listing
January 2021

Phase II Adjuvant Cancer-specific Vaccine Therapy for Esophageal Cancer Patients Curatively Resected After Preoperative Therapy With Pathologically Positive Nodes; Possible Significance of Tumor Immune Microenvironment in its Clinical Effects.

Ann Surg 2020 Aug 26. Epub 2020 Aug 26.

*Department of Surgery, Kindai University Faculty of Medicine, Osaka, Japan †Department of Surgery, Ohita Nakamura Hospital, Ohita, Japan ‡Life Science Research Institute, Kindai University, Osaka, Japan §Clinical Research Center, Kindai University Hospital, Osaka, Japan ¶Division of Cell Biology, Biomedical Research Center, Juntendo University Graduate School of Medicine, Tokyo, Japan ||Division of Hospital Pathology, Kindai University Hospital, Osaka, Japan **Cancer Precision Medical Center, Tokyo, Japan.

Objectives: To elucidate the efficacy of adjuvant vaccine monotherapy using 3 Human Leukocyte Antigen (HLA)-A24-restricted tumor-specific peptide antigens for ESCC, upregulated lung cancer 10, cell division cycle associated 1, and KH domain-containing protein overexpressed in cancer 1.

Summary Of Background Data: ESCC patients with pathologically positive nodes (pN(+)) have a high risk for postoperative recurrence, despite curative resection after preoperative therapy. Subclinical micrometastases are an appropriate target for cancer vaccine.

Methods: This is a non-randomized prospective phase II clinical trial (UMIN000003557). ESCC patients curatively resected after preoperative therapy with pN(+) were allocated into the control and vaccine groups (CG and VG) according to the HLA-A status. One mg each of three epitope peptides was postoperatively injected 10 times weekly followed by 10 times biweekly to the VG. The primary and secondary endpoints were relapse-free survival (RFS) and esophageal cancer-specific survival (ECSS), respectively.

Results: Thirty were in the CG and 33 in the VG. No significant difference was observed in RFS between the CG and VG (5-year RFS: 32.5% vs 45.3%), but the recurrence rate significantly decreased with the number of peptides which induced antigen-specific cytotoxic T lymphocytes. The VG showed a significantly higher 5-year ECSS than the CG (60.0% vs 32.4%, P = 0.045) and this difference was more prominent in patients with CD8 and programmed death-ligand 1 double negative tumor (68.0% vs 17.7%, P = 0.010).

Conclusions: Our cancer peptide vaccine might improve the survival of ESCC patients, which is warranted to be verified in the phase III randomized controlled study.
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http://dx.doi.org/10.1097/SLA.0000000000003880DOI Listing
August 2020

Controlling lymph node micrometastases by neoadjuvant chemotherapy affects the prognosis in advanced esophageal squamous cell carcinoma.

Surg Today 2021 Jan 28;51(1):118-126. Epub 2020 Jun 28.

Department of Surgery, Kindai University Faculty of Medicine, 377-2 Ohno-higashi, Osaka-Sayama, Osaka, 589-8511, Japan.

Purpose: The purpose of this study is to determine the clinical significance of micrometastases after neoadjuvant chemotherapy (NAC) and the difference in controlling micrometastases using different NAC regimens in resectable advanced esophageal squamous cell carcinoma (ESCC).

Methods: We analyzed patients with ESCC who underwent esophagectomy with lymph node dissection after NAC with Adriamycin + cisplatin + 5-fluorouracil (ACF) or docetaxel + cisplatin + 5-fluorouracil (DCF). Micrometastasis was defined as a single isolated cancer cell or cluster of cancer cells on the cervical, recurrent nerve, or abdominal LNs as shown by immunohistochemical staining with anti-cytokeratin antibody (AE1/AE3). The associations between micrometastases, recurrence, prognosis, and regimen differences were investigated.

Results: One hundred and one cases (ACF group: 51 cases; DCF group: 50 cases) were analyzed. Micrometastases occurred in 24 patients (23.8%): 17/51 (33.3%) in the ACF group and 7/50 (13.5%) in the DCF group (p = 0.0403). The 5-year recurrence-free survival (RFS) rates for patients without (n = 77) and with (n = 24) micrometastases were 62 and 32%, respectively, (hazard ratio, 2.158; 95% confidence interval, 1.170-3.980; stratified log-rank test, p = 0.0115). A multivariate analysis showed that stage pN1 or higher and micrometastases were significant risk factors affecting RFS.

Conclusion: In resectable advanced ESCC, controlling micrometastases in the LNs after NAC varied by regimen and may be associated with preventing ESCC recurrence.
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http://dx.doi.org/10.1007/s00595-020-02059-7DOI Listing
January 2021

Risk Factors and Prognostic Impact of Mediastinal Lymph Node Metastases in Patients with Esophagogastric Junction Cancer.

Ann Surg Oncol 2020 Oct 14;27(11):4433-4440. Epub 2020 May 14.

Department of Surgery, Faculty of Medicine, Kindai University, Osaka-Sayama, Osaka, Japan.

Purpose: We retrospectively investigated the risk factors for mediastinal lymph node (MLN) metastasis in esophagogastric junction (EGJ) cancer with an epicenter within 2 cm above and below the anatomical cardia, including both adenocarcinoma (AC) and squamous cell carcinoma (SCC).

Methods: Fifty patients who underwent initial surgery for EGJ cancer from January 2002 to December 2013 were included in this study. We defined metastatic lymph nodes as pathological metastases in resected specimens and recurrence within 2 years postoperatively.

Results: Thirty-four patients had AC and 16 had SCC; 24 patients underwent transhiatal resection and 26 underwent transthoracic resection. MLN metastasis was observed in 13 patients (26%) regardless of the histological type, 9 of whom had metastasis in the upper and middle mediastinum. Metastasis occurred when the esophageal invasion length (EIL) exceeded 20 mm. In addition, 10/13 patients had stage pN2-3 cancer. Multivariable analysis identified EIL ≥ 20 mm and stage pN2-3 as significant risk factors for MLN metastasis. The 5-year overall survival was 38% and 65% in the MLN-positive and -negative groups, respectively (p = 0.12). Multivariable Cox regression analysis showed that only stage pN2-3, and not the presence of MLN metastasis, was a significantly poor prognostic factor.

Conclusion: MLN metastasis in EGJ cancer may have a close association with the EIL of the tumor, but the presence of MLN metastasis itself was not a poor prognostic factor. The significance and indications for MLN dissection should be clarified in prospective clinical trials.
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http://dx.doi.org/10.1245/s10434-020-08579-3DOI Listing
October 2020

[Neoadjuvant Triplet Combination Chemotherapy(UDON Therapy)in Esophageal Cancer Patients with Impaired Renal Function-A Retrospective Study].

Gan To Kagaku Ryoho 2019 Dec;46(13):2173-2175

Dept. of Surgery, Faculty of Medicine, Kindai University.

Background: In Japan, pre-operative 5-FU and cisplatin(CDDP)(FP)combination therapy has been the standard neoadjuvant chemotherapy(NAC)for advanced resectable esophageal cancer(EC); furthermore, the efficacy of the docetaxel (DTX)-containing triplet regimen, FP plus DTX, has been reported. However, patients with impaired renal function should not receive high-dose CDDP. We have been developing a non-CDDP-containing triplet regimen, comprising 5-FU, DTX, and nedaplatin(NED)(UDON), on a phase Ⅰ/Ⅱtrial basis. This retrospective study aimed to investigate the safety and efficacy of NAC with UDON in advanced EC patients with impaired renal function.

Methods: Five patients with advanced resectable EC with impaired renal function were enrolled in this study. Patients received NAC(5-FU, 640mg/m / 2, days 1-5; DTX, 28 mg/m2, days 1 and 15; and NED, 72mg/m2, day 1, q28, 2 courses); following this, they underwent esophagectomy. The primary endpoint was response rate, and the secondary endpoint was adverse event(AE).

Results: The median age was 79 years (range: 58-80 years). The ECOG performance status was 1/2 : 3/2. The main tumor locations were Ce/Ut/Mt : 1/1/3 and the cStages were ⅡA/ⅢA/ⅢC : 1/2/2. The RR(CR/PR/SD/PD : 0/4/1/0)was 80%. The pathological response was grade 1a/1b : 2/3. Major grade 3 or 4 AEs included neutropenia(40%), febrile neutropenia(20%), diarrhea(20%), and hyponatremia( 40%). There was no treatment-related death or reoperation.

Conclusions: NAC with UDON might be feasible and effective in patients with advanced resectable EC with impaired renal function, who are ineligible for high-dose CDDP administration. We are planning a phaseⅡclinical study based on the present results.
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December 2019

A case of a gastric granular cell tumor preoperatively diagnosed and successfully treated by single-incision laparoscopic surgery.

Surg Case Rep 2020 Feb 27;6(1):44. Epub 2020 Feb 27.

Department of Surgery, Kindai University Faculty of Medicine, 377-2 Ohno-higashi, Osaka-Sayama, Osaka, 589-8511, Japan.

Background: Granular cell tumors (GCT) in the gastrointestinal tract are rare. Herein, we describe a case of a gastric GCT diagnosed preoperatively by endoscopic ultrasound-guided fine needle aspiration biopsy (EUS-FNAB) and successfully resected by single-incision laparoscopic surgery (SILS).

Case Presentation: A 46-year-old Japanese woman had a tumor located in the angle of the stomach that was approximately 1.5 cm in diameter. Abdominal computed tomography (CT) revealed a submucosal tumor (SMT), which was finally diagnosed as a gastric GCT using EUS-FNAB. The tumor was not identified by CT 1 year and 4 months before diagnosis; therefore, because there was a possibility that the tumor was malignant, we performed surgical wedge resection using SILS. The patient had an uneventful recovery postoperatively and was discharged without complications 3 days after surgery. The tumor was pathologically diagnosed as a benign GCT that remained within the muscular layer. No recurrence or complications have occurred in the first 16 months since the surgery.

Conclusion: Because gastric GCTs are generally benign and are rarely associated with lymph node metastasis, SILS seems to be a safe and feasible surgical approach for treating GCTs.
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http://dx.doi.org/10.1186/s40792-020-00809-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7046852PMC
February 2020

Skin and hair abnormalities of Cantu syndrome: A congenital hypertrichosis due to a genetic alteration mimicking the pharmacological effect of minoxidil.

J Dermatol 2020 Mar 6;47(3):306-310. Epub 2020 Jan 6.

Department of Dermatology, Kochi Medical School, Kochi University, Nankoku, Japan.

Cantu syndrome is an autosomal dominant disorder, first described by Cantu in 1982, that is characterized by congenital hypertrichosis, characteristic facial anomalies and cardiomegaly. Recent investigations have revealed that this syndrome is caused by mutations of ABCC9, which encodes a regulatory subunit of SUR2, an adenosine triphosphate-mediated potassium channel opener, expressed not only in smooth muscle but also in hair follicles. However, the abnormalities of skin and hair in patients with Cantu syndrome have not been well explored. We herein report three Japanese patients with Cantu syndrome and describe their specific skin manifestations and alterations in the histopathology of their hair follicles and sebaceous glands. Similar alterations were shared among those three patients and may be related to the function of SUR2, namely the regulation of hair follicle growth, because SUR2 is a known pharmacological target of minoxidil.
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http://dx.doi.org/10.1111/1346-8138.15216DOI Listing
March 2020

Gain-of-Function MN1 Truncation Variants Cause a Recognizable Syndrome with Craniofacial and Brain Abnormalities.

Am J Hum Genet 2020 01 12;106(1):13-25. Epub 2019 Dec 12.

Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama 236-0004, Japan. Electronic address:

MN1 was originally identified as a tumor-suppressor gene. Knockout mouse studies have suggested that Mn1 is associated with craniofacial development. However, no MN1-related phenotypes have been established in humans. Here, we report on three individuals who have de novo MN1 variants that lead to a protein lacking the carboxyl (C) terminus and who presented with severe developmental delay, craniofacial abnormalities with specific facial features, and structural abnormalities in the brain. An in vitro study revealed that the deletion of the C-terminal region led to increased protein stability, an inhibitory effect on cell proliferation, and enhanced MN1 aggregation in nuclei compared to what occurred in the wild type, suggesting that a gain-of-function mechanism is involved in this disease. Considering that C-terminal deletion increases the fraction of intrinsically disordered regions of MN1, it is possible that altered phase separation could be involved in the mechanism underlying the disease. Our data indicate that MN1 participates in transcriptional regulation of target genes through interaction with the transcription factors PBX1, PKNOX1, and ZBTB24 and that mutant MN1 impairs the binding with ZBTB24 and RING1, which is an E3 ubiquitin ligase. On the basis of our findings, we propose the model that C-terminal deletion interferes with MN1's interaction molecules related to the ubiquitin-mediated proteasome pathway, including RING1, and increases the amount of the mutant protein; this increase leads to the dysregulation of MN1 target genes by inhibiting rapid MN1 protein turnover.
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http://dx.doi.org/10.1016/j.ajhg.2019.11.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7042485PMC
January 2020

A simple, novel laparoscopic feeding jejunostomy technique to prevent bowel obstruction after esophagectomy: the "curtain method".

Surg Endosc 2020 Nov 9;34(11):4967-4974. Epub 2019 Dec 9.

Department of Surgery, Kindai University Faculty of Medicine, 377-2 Ohnohigashi, Osaka-sayama, Osaka, 589-8511, Japan.

Background: Feeding jejunostomy (FJ) is a common treatment to support patients with esophageal cancer after esophagectomy. However, severe FJ-related complications, such as bowel obstruction, occasionally occur. We investigated the ability of our simple, novel FJ technique, the "curtain method," to prevent bowel obstruction.

Methods: In laparoscopic surgery, the main mechanism of bowel obstruction involves torsion of the mesentery accompanied by migration of the intestine across the fixed FJ through the space surrounded by a triangle comprising the ligament of Treitz, fixed FJ, and spleen rather than adhesion. Our "curtain method" involves closure of this triangle zone with omentum, and the appearance of the lifted omentum resembles a curtain. Sixty patients treated with this modified FJ were retrospectively compared with 13 patients treated with conventional FJ in terms of the incidence of bowel obstruction, peritonitis, stoma site infection, and catheter obstruction.

Results: From 2013 to 2017, 60 patients underwent esophagectomy and gastric conduit reconstruction accompanied by modified laparoscopic FJ. The median observation period, including the period after tube removal, was 644 days. No FJ-associated bowel obstruction, the prevention of which was the primary aim, occurred in any patient. Likewise, no peritonitis or dislodgement occurred. Eight patients (13%) developed a stoma site infection with granulation. The feeding tube became occluded in 11 patients (18%); however, a new feeding tube was reinserted under fluoroscopy for all of these patients. From 2003 to 2012, 13 patients underwent conventional FJ. The median observation period was 387 days. Three patients (23%) developed bowel obstruction by torsion 71 to 134 days after the first surgery, and all were treated by emergency operations. Other FJ-related complications were not different from those in the modified FJ group.

Conclusion: Our simple, novel technique, the "curtain method," for prevention of laparoscopic FJ-associated bowel obstruction after esophagectomy is a safe additional surgery.
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http://dx.doi.org/10.1007/s00464-019-07289-6DOI Listing
November 2020

Simplified percutaneous endoscopic transgastric conduit feeding jejunostomy for dysphagia after esophagectomy.

Dis Esophagus 2020 Mar;33(2)

Department of Surgery, Kindai University Faculty of Medicine, Osaka-sayama, Japan.

Unexpected dysphagia is an important problem affecting life prognosis in patients who have undergone an esophagectomy for esophageal cancer. For nutritional support in patients suffering from dysphagia after a previous esophagectomy, a simplified percutaneous endoscopic transgastric conduit feeding jejunostomy approach was developed that can be performed regardless of the patient's condition. The feasibility of this procedure in 25 patients with esophageal cancer who underwent three-stage esophagectomy with retrosternal gastric conduit reconstruction from April 2009 to December 2016 was evaluated retrospectively. Under fluoroscopy, a percutaneous endoscopic transgastric conduit feeding jejunostomy catheter (9 French) was introduced into the jejunum in the epigastric region using the Seldinger's technique. The following patient data were analyzed retrospectively: operating time, complications, reasons for oral intake difficulty, and clinical data describing patients' nutritional status before and 1 month after percutaneous endoscopic transgastric conduit jejunostomy treatment, such as serum albumin and clinical course. Median patients' age was 68 years (range 50-76 years). Indications for the procedure were late swallowing dysfunction (n = 12), early swallowing dysfunction secondary to surgical complication (n = 8), anastomotic leakage (n = 3), and anorexia (n = 2). Causes of late swallowing dysfunction were radiation injury (n = 8), advanced age (n = 2), or cerebral infarction (n = 2). The median operating time was 29 minutes (range 14-82 minutes). Four patients developed mild erosions at the stoma secondary to bile reflux along the side of the catheter. No patient experienced severe complications such as ileus and peritonitis. Patients were treated for a median of 160 days (range 18-3106 days) with percutaneous endoscopic transgastric conduit jejunostomy. Patient's serum albumin significantly increased from 2.8 to 3.3 g/dl in 1 month. Of the eight patients with early swallowing dysfunction, six successfully regained sufficient oral nutrition after receiving enteral feeding nutritional management. Although all except one late swallowing dysfunction patient could not discontinue tube feeding, five patients were long-term survivors at the time this report was written. This jejunostomy procedure is simple, safe, and useful for patients with unexpected dysphagia and accompanying malnutrition after esophagectomy.
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http://dx.doi.org/10.1093/dote/doz042DOI Listing
March 2020

[Proteinuria in Patients with Gastric Cancer Treated with Ramucirumab].

Gan To Kagaku Ryoho 2019 Feb;46(2):245-249

Dept. of Surgery, Kindai University Faculty of Medicine.

Background: Ramucirumab, an antiangiogenic agent, often causes proteinuria as a characteristic adverse effect. We retro- spectively evaluated proteinuria and clarified the significance of the protein/creatinine ratio by using single urine samples from patients with advanced gastric cancer who were treated with ramucirumab.

Methods: Twenty-three patients who received ramucirumabb etween June 2015 and April 2016 were enrolled. A total of 199 urinalysis specimens were qualitatively analyzed to obtain urine protein levels and the protein/creatinine ratio, and the values were compared.

Results: Frequency of proteinu- ria was 43.5%(grade 1: 26.1%, grade 2: 8.7%, and grade 3: 8.7%). The protein/creatinine ratio was less than 2 in -, ±, and 1+ based on the urine protein qualitative examination; 12.5% of 2+ and 71.4% of 3+ or 4+ had a protein/creatinine ratio over 2.

Conclusions: In patients with gastric cancer, treated with ramucirumab, the protein/creatinine ratio should be examined in cases of 2+, 3+ or 4+ via a qualitative examination.
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February 2019

[A Case of Intestinal Perforation Due to a Catheter for Intraperitoneal Access Port for Intraperitoneal Chemotherapy for Gastric Cancer].

Gan To Kagaku Ryoho 2018 Dec;45(13):2381-2383

Dept. of Surgery, Faculty of Medicine, Kindai University.

The usefulness of intraperitoneal(IP)chemotherapy for gastric cancer with intraperitoneal metastasis has been examined in some clinical trials. We report a case of intestinal perforation caused by a catheter for IP ports. A 75-year-old man had undergone IP therapy for type 4 gastric cancer. After IP therapy, he underwent total gastrectomy. He had no recurrence for 3 years. He complained of high fever and abdominal pain more than 1 week ago. Based on contrast-enhanced CT, we diagnosed him with peritonitis by intestinal perforation due to the catheter, and on the same day, we removed the catheter and performed intraperitoneal drainage by emergent laparotomy. The tube penetrated the ileum 20 cm from the ileocecal portion. We resected the ileocecal area and damaged intestinal tract and removed the subcutaneous IP port. He was discharged on the 25th postoperative day. IP ports should be removed after the completion of IP chemotherapy because the incidence of perforation by IP ports was reported as 0 to 3.5%in a previous report.
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December 2018

[A Case of Advanced Esophageal Cancer Successfully Treated with Neoadjuvant Chemotherapy Containing 5-FU, Docetaxel. and Nedaplatin Combination Therapy].

Gan To Kagaku Ryoho 2018 Dec;45(13):1812-1814

Dept. of Surgery, Faculty of Medicine, Kindai University.

A 71-year-old man with a history of hypertension, diabetes mellitus, and cerebral infarction was admitted to our hospital with dysphagia. Gastroduodenoscopy, thoracoabdominal CT, and PET-CT findings showed type 2 advanced esophageal cancer( squamous cell carcinoma)with upper mediastinal and cervical lymph node(LN)metastasis: cT3N2M1(LYM #104L), cStage Ⅳ. Two courses of neoadjuvant UDONchemotherapy containing 5-FU(640mg/m / 2, days 1-5), docetaxel(28mg/m2, days 1 and 15), and nedaplatin(72mg/m2, day 1)were administered every 4 weeks. UDONtherapy caused grade(Gr)3 febrile neutropenia, Gr 2 diarrhea, and Gr 1 thrombopenia; the tumor and LNs partially responded to the therapy. After 2 courses of UDONtherapy, esophagectomy with right thoracotomy, 3-field LNdissection, and reconstruction of the gastric tube were performed. The postoperative course was almost uneventful besides recurrent nerve palsy, aspiration, pneumonia, and delirium, and the patient was discharged 60 days after surgery. The pathological diagnosis was ypT0N0M0, ypStage 0, and the histological response of the primary tumor and LNs were evaluated as Gr 3. Neoadjuvant UDON therapy is feasible for elderly patients with advanced esophageal cancer and renal failure or comorbidities, for whom CDDP could not be administered. We are planning a clinical trial to assess the effectiveness of neoadjuvant UDONtherapy.
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December 2018

Intraperitoneal and Systemic Chemotherapy for Patients with Gastric Cancer with Peritoneal Metastasis: A Phase II Trial.

Anticancer Res 2018 Oct;38(10):5975-5981

Department of Surgery, Faculty of Medicine, Kindai University, Osaka, Japan.

Aim: To conduct a phase II study of single intraperitoneal (i.p.) administration of paclitaxel followed by paclitaxel, cisplatin, and S-1 (PCS) chemotherapy for patients with gastric cancer with peritoneal metastasis (PM).

Patients And Methods: Staging laparotomy was performed to confirm PM. Initially, patients received i.p. paclitaxel. Beginning 7 days later, PCS was given every 3 weeks followed by second-look laparoscopy. Primary and secondary endpoints were the overall survival (OS) rate, and response rate and patient safety, respectively.

Results: Seventeen patients were enrolled. The overall response rate was 70.5% (12/17). Grade 3/4 toxic effects included neutropenia and leukopenia. After chemotherapy, PM disappearance was confirmed in 11 patients. Gastrectomy was eventually performed in 11 patients. The 1-year OS rate was 82.4% and the median survival time was 23.9 months considering the overall cohort.

Conclusion: Combination chemotherapy with i.p. paclitaxel and PCS is well tolerated and effective in patients with gastric cancer with PM.
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http://dx.doi.org/10.21873/anticanres.12945DOI Listing
October 2018

Intraperitoneal Administration of Paclitaxel Followed by Paclitaxel, Cisplatin, and S-1 Chemotherapy for Cytology-positive Gastric Cancer: A Feasibility Study.

Anticancer Res 2018 Oct;38(10):5969-5974

Department of Surgery, Kindai University Faculty of Medicine, Osaka, Japan.

Background/aim: A preliminary study evaluating the feasibility of single intraperitoneal (IP) administration of paclitaxel followed by paclitaxel and cisplatin with S-1 (PCS) systemic chemotherapy for cytology-positive (CY1) gastric cancer.

Patients And Methods: Staging laparoscopy was performed to confirm CY1 and P0 status. Initially, patients received IP paclitaxel. Beginning 7 days later PCS was given every 3 weeks followed by second-look laparoscopy.

Results: Nine patients were enrolled. The toxic effects of IP and systemic chemotherapy were acceptable. After chemotherapy, 8 patients converted from CY1P0 to CY0P0 and 1 patient from CY1P0 to CY1P1. Gastrectomy was performed on 8 patients except for the CY1P1 patient. Four patients were alive without recurrence. The 2-year overall and progression-free survival rates were 76% and 65%, respectively.

Conclusion: Combination chemotherapy with IP paclitaxel and sequential PCS is safe and may be effective for CY1 gastric cancer.
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http://dx.doi.org/10.21873/anticanres.12944DOI Listing
October 2018

[A Case of Emergency Resection of Esophageal Cancer Which is on the Brink of Perforation after Neoadjuvant Chemotherapy].

Gan To Kagaku Ryoho 2017 Nov;44(12):1943-1945

Dept. of Surgery, Kindai University Faculty of Medicine.

According to the Guidelines for Diagnosis and Treatment of Carcinoma of the Esophagus in Japan, the standard treatment of esophageal cancer with cStage II / III is preoperative chemotherapy and radical resection. But when the tumor has deep ulcer, the perforation of it is sometimes occurred due of the anti-tumor effect and we are forced to change the standard treatment. In this time, we report a case of emergency resection of esophageal cancer which is on the brink of perforation after neoadjuvant chemotherapy. A 62-year-old woman had locally advanced esophageal cancer(cT4N2M0)and performed neoadjuvant chemotherapy(NAC). After 2 courses of NAC, the patient got into critical condition that the esophageal cancer was on the brink of perforation, thus we immediately performed emergency resection of the tumor. Unfortunately, the tumor was not completely resected because of invasion to the Botallo ligament, but we were able to avoid a critical state such as mediastinitis or penetration to the aorta. In multimodality therapy for locally advanced tumor, immediate response to oncologic emergency is significantly required, impacting on the prognosis and quality of life.
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November 2017

[A Case Report on Successful Larynx-Preserving Surgery for a Cervical Esophageal Cancer That Invaded the Hypopharynx].

Gan To Kagaku Ryoho 2017 Nov;44(12):1844-1846

Dept. of Surgery, Kindai University Faculty of Medicine.

The patient was a 58-year-old man suffering from dysphagia. He was diagnosed with T3 cervicalesophagealcancer that invaded the posterior hypopharyngealwal lwith lymph node metastasis. The patient received neoadjuvant chemoradiotherapy (30 Gy with CDDP/5-FU), followed by larynx-preserving surgery(LPS)for cervicalesophagealcancer. Two techniques for successfulLPS consist of the dissections of cricopharyngealmuscl e and the inferior pharyngealsphincter, and the complete division of the bilateral infrahyoid muscles attached to the sternum(CDBIMS). The former technique of releasing the esophagus from the trachea at the cricoid cartilage level results in the extension of the oral surgical margin. The latter technique is expected to prevent postoperative aspiration pneumonia, as the lack of flexibility of scarred infrahyoid muscles is regarded as one of the major causes of dysfunction in swallowing. Free jejunum was transferred for cervical reconstruction. Pathological examination indicated degenerated squamous cell carcinoma(ypT2, INF b, ly0, v0, PM0, ypN0, ypStage II A). Although the patient had recurrent nerve palsy, he could eat meals without aspiration. He returned to normal life after discharge from the hospital. Five years after surgery, no recurrence had been observed.
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November 2017

[Radical Resection of Huge Gastrointestinal Stromal Tumor of the Stomach Following Neoadjuvant Chemotherapy with lmatinib - ACase Report].

Gan To Kagaku Ryoho 2017 Nov;44(12):1723-1725

Dept. of Surgery, Kindai University Faculty of Medicine.

The usefulness and safety of imatinibfor neoadjuvant chemotherapy for resectable gastrointestinal stromal tumor(GIST) has not been established. We reported a case of a huge GIST of the stomach that was safely resected following preoperative imatinibtherapy. A 69-year-old man was hospitalized with abdominal fullness which increased rapidly from a month ago. A CT scan showed a huge tumor containing solid and cystic component which was accompanied by an extra-wall nodule. The tumor was strongly suspected to be originated from the stomach and EUS-FNA revealed GIST. We diagnosed GIST of the stomach and initiated preoperative adjuvant chemotherapy with imatinib because there was a risk for the break of tumor capsule and composite resection of the other organs without prior chemotherapy. After the administration of imatinib4 00 mg/day for 6months, the solid component was decreased in size and its' activity by PET-CT had declined, but the size of the cystic component was not changed and the patient's complaint of fullness was not reduced. Then, after a week cessation of imatinib, we performed surgical removal of the tumor with partial gastrectomy without surgical complication during and after the operation. Imatinibwas resumed 2 weeks later postoperatively and 1 year and 8 months has passed since the operation without recurrence. Neoadjuvant chemotherapy with imatinibhas the potential to become an important therapeutic option for the treatment of huge GISTs.
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November 2017

[A Case of Locally Advanced Thoracic Esophageal Cancer with Larynx Preservation and Curative Resection via Combined Modality Therapy].

Gan To Kagaku Ryoho 2017 Nov;44(12):1720-1722

Dept. of Surgery, Kindai University Faculty of Medicine.

Prognosis of locally advanced esophageal cancer is poor. The greatest prognostic factor of locally advanced esophageal cancer is a local control. We experienced a case of T4 locally advanced thoracic esophageal cancer who was successfully resected without any combined resection after multimodality therapy. A male in 75-year-old. was diagnosed with type 3 locally advanced upper thoracic esophageal cancer whose metastatic right recurrent laryngeal lymph node invaded into the trachea. Definitive chemoradiation therapy(CRT)was performed, leading to a significant shrinkage of the main tumor, but T4 lesion remained. Next, adding DCF therapy(docetaxel, CDDP and 5-FU), a relief of T4 was finally obtained. Then, salvage surgery with subtotalesophagectomy and retrosternalesophagealreconstruction with gastric tube was performed, resulting in R0 resection without any combined resection. The postoperative course was uneventful, and the patient has been alive without recurrence for 1 year after surgery. In locally advanced cancer, focusing on T4 downstaging, it is significantly important in terms of safety, curativity and organ preservation to perform surgery after a sure sign of T4 relief by multimodality therapy.
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November 2017

[Resection of the Distal Part of the Gastric Tube for the Gastric Tube Cancer after Esophagectomy - A Case Report].

Gan To Kagaku Ryoho 2017 Nov;44(12):1577-1579

Dept. of Surgery, Kindai University.

A 76-year-old man was admitted to our hospital for treatment of gastric tube cancer(cT2N0M0, cStage II A)detected by a screening upper gastrointestinal endoscopy. Seven years previously, he had undergone subtotal esophagectomy for esophageal cancer with gastric pull-up via the retrosternal route. At that time, he experienced cardiopulmonary arrest due to ventric- ular tachycardia. He was in a state of poor nutrition(BMI 15 kg/m2). Therefore, reducing operative stress as much as possible, minimizing complications after surgery, and aiming for a satisfactory postoperative course are all important goals. Based on his past history, we performed distal gastrectomy(resection of the distal part of the gastric tube)without excision of the right gastroepiploic artery. The postoperative course was uneventful. He was discharged 40 days after surgery. By considering the risks of surgery due to cardiac dysfunction and malnutrition, we were able to provide effective and safe therapy for the patient.
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November 2017

[Combination Chemotherapy Including Intraperitoneal(IP)Administration of Paclitaxel(PTX)followed by PTX, CDDP and S-1Triplet Chemotherapy for CY1P0 Gastric Cancer].

Gan To Kagaku Ryoho 2017 Nov;44(12):1355-1357

Dept. of Surgery, Faculty of Medicine, Kindai University.

Background And Objectives: We evaluate the feasibility and efficacy of combination chemotherapy including single intraperitoneal( IP)administration of paclitaxel(PTX), followed by triplet chemotherapy(PTX, cisplatin[CDDP]and S-1: PCS)for CY1P0 gastric cancer.

Methods: First of all, we performed staging laparoscopy and confirmed CY1P0, and secondary, administrated PTX intraperitoneally. Thirdly, patients received PCS chemotherapy for 2 courses. After antitumor effect had been confirmed, we performed second look laparoscopy. In the case of CY0P0, we performed gastrectomy with D2 lymph nodes dissection.

Results: Total 4 patients were enrolled. Grade 3 leukopenia and neutropenia were observed in one patient while intraperitoneal and systemic-chemotherapy. One patients showed PR and 3 patients showed SD. All patients underwent second look laparoscopy. CY0P0 was observed in all patients and gastrectomy with D2 dissection was performed for all patients. Postoperative complications were observed in 2 patients. Two patients were still alive without recurrence, while the remaining 2 had died of liver metastasis and #16 LN metastasis.

Conclusions: Combination chemotherapy including single IP PTX followed by PCS systemic-chemotherapy for CY1P0 gastric cancer is feasible and efficient.
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November 2017

[A Case of Recurrent Gastric Cancer with Grade 3 Proteinuria Caused by Ramucirumab plus Paclitaxel Therapy].

Gan To Kagaku Ryoho 2017 Nov;44(12):1080-1082

Dept. of Surgery, Kindai University Faculty of Medicine.

Proteinuria is one of the characteristic adverse events by ramucirumab(RAM)plus paclitaxel(PTX)combination therapy for advanced gastric cancer. We reported a case of recurrent gastric cancer with grade(gr)3 proteinuria caused by RAM plus PTX therapy. 77-year-old woman was underwent distal gastrectomy in 76 years old for gastric cancer that was diagnosed mucinous adenocarcinoma, fStage III C(T4aN3H0P0CY0M0)and received adjuvant chemotherapy of S-1 for 1 year. She suffered from peritoneal recurrence with ascites after 1 year and 4 months of the operation and RAM(8mg/kg; day 1 and 15)plus PTX(80mg/m2; day 1, 8 and 15)therapy was administrated as second-line chemotherapy. After 1 course, weekly PTX has been continued for gr 3 proteinuria and the ascites disappeared after 4 courses. This successful case might indicate that it was important for patients with gr 3 proteinuria as adverse event to consider discontinuance of RAM and continuation of PTX according to the proper usage guide of RAM.
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November 2017

Integrative Analyses of De Novo Mutations Provide Deeper Biological Insights into Autism Spectrum Disorder.

Cell Rep 2018 01;22(3):734-747

Department of Human Genetics, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan. Electronic address:

Recent studies have established important roles of de novo mutations (DNMs) in autism spectrum disorders (ASDs). Here, we analyze DNMs in 262 ASD probands of Japanese origin and confirm the "de novo paradigm" of ASDs across ethnicities. Based on this consistency, we combine the lists of damaging DNMs in our and published ASD cohorts (total number of trios, 4,244) and perform integrative bioinformatics analyses. Besides replicating the findings of previous studies, our analyses highlight ATP-binding genes and fetal cerebellar/striatal circuits. Analysis of individual genes identified 61 genes enriched for damaging DNMs, including ten genes for which our dataset now contributes to statistical significance. Screening of compounds altering the expression of genes hit by damaging DNMs reveals a global downregulating effect of valproic acid, a known risk factor for ASDs, whereas cardiac glycosides upregulate these genes. Collectively, our integrative approach provides deeper biological and potential medical insights into ASDs.
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http://dx.doi.org/10.1016/j.celrep.2017.12.074DOI Listing
January 2018

[Techniques for Preventing Postoperative Complication in Esophageal Salvage Surgery].

Kyobu Geka 2017 07;70(8):720-727

Department of Surgery, Division of Esophago-Gastric Surgery, Kindai University Faculty of Medicine, Osakasayama, Japan.

Patients with esophageal cancer are often treated with definitive chemoradiotherapy (dCRT). Regardless of arrival at dCRT, the risk of local/regional recurrence during follow-up is significant. Many patient are faced with limited options for therapy once dCRT has failed. Salvage surgery is the only way for complete cure of patients with local/regional recurrent esophageal cancer after dCRT. However, salvage surgery has a significant high risk of fatal complications. We examine our preventive measures to reduce the incidence of postoperative complications after salvage surgery for thoracic esophageal cancer. The points of our preventive measures are them; I. the ingenuity of surgery, II. the securement of blood supply for the respiratory tract, III. standard lymphadenectomy, IV. countermeasures of anastomotic failure, V. countermeasures of dead space, VI. countermeasures of respiratory complications, VII. perioperative managements. Salvage surgery is a reasonable option to treat patients with local/regional recurrence after failed dCRT. Our preventive mesures are effective, therefore, we have to make the further technological developments and the safety of salvage surgery.
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July 2017

A case of incisional hernia repair using Composix mesh prosthesis after antethoracic pedicled jejunal flap reconstruction following an esophagectomy.

Surg Case Rep 2017 Dec 29;3(1):79. Epub 2017 Jun 29.

Department of Surgery, Kindai University Faculty of Medicine, 377-2 Ohno-higashi, Osaka-Sayama, Osaka, 589-8511, Japan.

Background: An incisional hernia in a case of antethoracic pedicled jejunal flap esophageal reconstruction after esophagectomy is a very rare occurrence, and this hernia was distinctive in that the reconstructed jejunum had passed through the hernial orifice; a standard surgical treatment for such a presentation has not been established. Herein, we describe a case of repair using mesh prosthesis for an atypical and distinctive incisional hernia after antethoracic pedicled jejunal flap esophageal reconstruction.

Case Presentation: A 77-year-old woman with a history of subtotal esophagectomy who had undergone antethoracic pedicled jejunal flap reconstruction complained of epigastric prominence and discomfort without pain. On examination, she had an abdominal protrusion between the xiphoid process and the umbilicus that contained the small bowel. Computed tomography showed that the fenestration of the abdominal wall that was intentionally created for jejunum pull-up was dehisced in a region measuring 9 × 15 cm and the small intestine protruded through it into the subcutaneous space without strangulation. Because the hernial orifice was too large and the reconstructed jejunum was passing through the hernial orifice in this case, we applied a parastomal hernia repair method that was modified from the inguinal hernia repair using the Lichtenstein technique. After 3 years and 5 months following surgery, the patient has recovered without hernia recurrence or other complications.

Conclusion: We consider this to be the first case of repair using Composix mesh prosthesis for repair of an atypical and distinctive incisional hernia after an antethoracic pedicled jejunal flap reconstruction. This method seems to be useful and could potentially be widely adopted as the surgical treatment for this condition.
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http://dx.doi.org/10.1186/s40792-017-0353-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5491424PMC
December 2017

Critical involvement of ZEB2 in collagen fibrillogenesis: the molecular similarity between Mowat-Wilson syndrome and Ehlers-Danlos syndrome.

Sci Rep 2017 04 19;7:46565. Epub 2017 Apr 19.

Department of Dermatology, Kochi Medical School, Nankoku 783-8505, Japan.

Mowat-Wilson syndrome (MOWS) is a congenital disease caused by de novo heterozygous loss of function mutations or deletions of the ZEB2 gene. MOWS patients show multiple anomalies including intellectual disability, a distinctive facial appearance, microcephaly, congenital heart defects and Hirschsprung disease. However, the skin manifestation(s) of patients with MOWS has not been documented in detail. Here, we recognized that MOWS patients exhibit many Ehlers-Danlos syndrome (EDS)-like symptoms, such as skin hyperextensibility, atrophic scars and joint hypermobility. MOWS patients showed a thinner dermal thickness and electron microscopy revealed miniaturized collagen fibrils. Notably, mice with a mesoderm-specific deletion of the Zeb2 gene (Zeb2-cKO) demonstrated redundant skin, dermal hypoplasia and miniaturized collagen fibrils similar to those of MOWS patients. Dermal fibroblasts derived from Zeb2-cKO mice showed a decreased expression of extracellular matrix (ECM) molecules, such as collagens, whereas molecules involved in degradation of the ECM, such as matrix metalloproteinases (MMPs), were up-regulated. Furthermore, bleomycin-induced skin fibrosis was attenuated in Zeb2-cKO mice. We conclude that MOWS patients exhibit an EDS-like skin phenotype through alterations of collagen fibrillogenesis due to ZEB2 mutations or deletions.
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http://dx.doi.org/10.1038/srep46565DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5396187PMC
April 2017

[Three Cases of Bleeding from Advanced Gastric Cancer during Chemotherapy Treated with Transcatheter Arterial Embolization(TAE)].

Gan To Kagaku Ryoho 2016 Nov;43(12):1920-1922

Dept. of Surgery, Sakai City Medical Center.

Case 1: An 71-year-old man underwent chemotherapy with S-1 plus trastuzumab to treat type 3 gastric cancer that was diagnosed as Stage IV tubular adenocarcinoma(T4b[Panc], N3, H0, CY1, P0, M1). For anemia and active bleeding from the tumor, transcatheter arterial embolization(TAE)was performed with metallic coils on the splenic artery. Infarction of the spleen and left pleural effusion were observed. Second-line paclitaxel(PTX)chemotherapy was administered 4 weeks after TAE. Case 2: An 76-year-old man underwent chemotherapy with S-1 plus cisplatin to treat type 3 gastric cancer that was diagnosed as Stage IV tubular adenocarcinoma(T4a, N3, H0, P1, M1). For anemia and active bleeding from the tumor, TAE with gelatin sponge(Serescure®)was performed on the left and right gastric artery. Radiotherapy(31 Gy)with S-1 was performed because TAE was not effective for bleeding. After chemoradiotherapy, nab-PTX was administered. Case 3: An 74- year-old man underwent second-line chemotherapy with nab-PTX to treat type 4 advanced gastric cancer that was diagnosed as Stage IV tubular adenocarcinoma(T4a, N3, H1, P0, M1). For progression of anemia due to tumor bleeding, TAE with gelatin sponge(Serescure®)was performed on the left gastric artery. TAE was effective, and he was discharged from the hospital. In 2 of 3 cases, hemostasis was achieved by TAE. Therefore, TAE is effective to decrease bleeding from gastric cancer during chemotherapy.
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November 2016

[Examination of Patients with Malignant Obstruction Treated with Chemotherapy after Ileo/Coleostomy].

Gan To Kagaku Ryoho 2016 Nov;43(12):1452-1454

Dept. of Surgery, Sakai City Medical Center.

Management for obstructive cancer of the colon diverges into many ways. The aim of this study was to evaluate the treatment course of patients with malignant obstruction after ileo/coleostomy. Thirty-six patients with malignant obstruction who underwent ileo/coleostomy in our hospital from May 2012 to January 2016were enrolled in the study. Clinical outcomes were the period before treatment initiation, chemotherapy, radiotherapy, primary lesion resection, and death, and these were retrospectively analyzed. Although 9 stomal complications occurred, no case experienced a delayed treatment start. However, patients with perioperative complications, sepsis due to the tumor, pneumonia, cerebral infractions, and ileus needed a long recovery period before treatment initiation. Patients who need ileo/coleostomy must be considered for performance status and ways to decrease perioperative complications to prevent stomal complications from chemo/radiotherapy.
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November 2016