Genome-Wide Association Study Identifies Genetic Polymorphisms Associated with Estimated Minimum Effective Concentration of Fentanyl in Patients Undergoing Laparoscopic-Assisted Colectomy.

Sensitivity to opioids varies widely among individuals. To identify potential candidate single-nucleotide polymorphisms (SNPs) that may significantly contribute to individual differences in the minimum effective concentration (MEC) of an opioid, fentanyl, we conducted a three-stage genome-wide association study (GWAS) using whole-genome genotyping arrays in 350 patients who underwent laparoscopic-assisted colectomy. To estimate the MEC of fentanyl, plasma and effect-site concentrations of fentanyl over the 24 h postoperative period were estimated with a pharmacokinetic simulation model based on initial bolus doses and subsequent patient-controlled analgesia doses of fentanyl. Plasma and effect-site MECs of fentanyl were indicated by fentanyl concentrations, estimated immediately before each patient-controlled analgesia dose. The GWAS revealed that an intergenic SNP, rs966775, that mapped to 5p13 had significant associations with the plasma MEC averaged over the 6 h postoperative period and the effect-site MEC averaged over the 12 h postoperative period. The minor G allele of rs966775 was associated with increases in these MECs of fentanyl. The nearest protein-coding gene around this SNP was DRD1, encoding the dopamine D1 receptor. In the gene-based analysis, the association was significant for the SERP2 gene in the dominant model. Our findings provide valuable information for personalized pain treatment after laparoscopic-assisted colectomy.

AK106-001616, a Potent and Selective Inhibitor of Cytosolic Phospholipase A2: In Vivo Efficacy for Inflammation, Neuropathic Pain, and Pulmonary Fibrosis.

3-[3-Amino-4-(indan-2-yloxy)-5-(1-methyl-1H-indazol-5-yl)-phenyl]-propionic acid (AK106-001616) is a novel, potent, and selective inhibitor of the cytosolic phospholipase A2 (cPLA2) enzyme. Unlike traditional nonsteroidal anti-inflammatory drugs and selective cyclooxygenase-2 inhibitors, AK106-001616 reduced prostaglandin E2 (PGE2) and leukotriene B4 (LTB4) production by stimulated cells. The suppression of PGE2 and LTB4 production was also confirmed using an air pouch model in rats administered a single oral dose of AK106-001616. AK106-001616 alleviated paw swelling in a rat adjuvant-induced arthritis (AIA) model. The maximum effect of the inhibitory effect of AK106-001616 was comparable with that of naproxen on paw swelling in a rat AIA model. Meanwhile, the inhibitory effect of AK106-001616 was more effective than that of naproxen in the mouse collagen antibody-induced arthritis model with leukotrienes contributing to the pathogenesis. AK106-001616 dose dependently reversed the decrease in paw withdrawal threshold not only in rat carrageenan-induced hyperalgesia, but also in a rat neuropathic pain model induced by sciatic nerve chronic constriction injury (CCI). However, naproxen and celecoxib did not reverse the decrease in the paw withdrawal threshold in the CCI model. Furthermore, AK106-001616 reduced the disease score of bleomycin-induced lung fibrosis in rats. In addition, AK106-001616 did not enhance aspirin-induced gastric damage in fasted rats, increase blood pressure, or increase the thromboxane A2/ prostaglandin I2 ratio that is thought to be an underlying mechanism of thrombotic cardiovascular events increased by selective cyclooxygenase-2 inhibitors. Taken together, these data demonstrate that oral AK106-001616 may provide valuable effects for wide indications without attendant gastrointestinal and cardiovascular risks.

[A Case of Unresectable Advanced Rectal Cancer with a Pancreatic Tumor That Was Successfully Treated with FOLFIRINOX].

A 72-year-old man was admitted to our hospital department in September 2014 because of a positive fecal occult blood test.Colonoscopy showed a type 2 tumor in half of the AV 15 cm rectosigmoid colon.Histology of the biopsy indicated a moderately differentiated adenocarcinoma, and the RAS gene test found wild type.On CT examination, there were multiple liver lung metastases and a 30mm diameter tumor with pancreatic duct extension to the pancreatic body.A PET-CT examination had a high SUVmax at the same site.Because of the location of the tumor EUS-FNA was not used.However, the possibility of pancreatic body cancer could not be denied after the CT examination.Treatment by radical resection was impossible because of the spread of the cancer so we selected chemotherapy.Undeniable pancreatic metastasis of rectal cancer, pancreatic cancer was used as a prognostic factor as double cancer of rectal cancer and pancreatic cancer, from that UGT1A1 test side effects appearance was a low-risk decision, was selected FOLFIRINOX in the treatment regimen.After 25 cycles, the pancreatic body tumor and liver metastases and also the primary tumor were reduced, the multiple lung metastases disappeared, and disease control was good.Side effects were diarrhea on the day of administration of irinotecan, but this was controllable by administering oral loperamide when starting the infusion.Grade 3 or more peripheral neuropathy has not developed, and this regimen is continuing.Pancreatic cancer is a solid cancer with a poor prognosis; if you do not reach the tissue diagnosis of metastatic pancreatic cancer, was a case in which no choice but to select a regimen to carcinoma of the prognostic.

[A Case of Resection of Para-Aortic Lymph Node Recurrence and Peritoneal Recurrence Following Sigmoid Colon Cancer Surgery].

In June 2010, a 73-year old man diagnosed with sigmoid colon cancer underwent laparoscopic sigmoidectomy. The histopathological diagnosis was tub2, pSS, n (-), stageⅡ.Vascular invasion was present; however, at the patient's request, no adjuvant chemotherapy was administered.Computed tomography (CT) performed at the outpatient follow-up 4 years and 6 months after the surgery revealed a para-aortic lymph node metastasis in the caudal aspect of the left renal artery branch point. No other definite mass shadows were detected. Positron emission (PET)-CT revealed high tracer accumulation (SUVmax) not only in the CT-identified lymph node, but also near the site of the anastomosis in the bowel. Considering that no tracer accumulation was detected at any other sites and the patient's compliance with medication and scheduled visits was poor, surgical resection rather than chemotherapy was adopted as the treatment strategy. No metastases other than at the sites identified by the diagnostic imaging were found during the surgery. Since the findings on palpation did not rule out the possibility that the nodule near the anastomotic site was present inside the intestinal tract, lymph node dissection, resection of the intestinal tract including the anastomotic site, and re-anastomosis were performed. The most likely diagnosis based on the histopathological findings was dissemination for both the adenocarcinoma and the nodule near the anastomotic site. At present, the patient is being treated with adjuvant chemotherapy. In the Japanese Society for Cancer of the Colon and Rectum (JSCCR) Guidelines for the Treatment of Colorectal Cancer, the recommended therapeutic intervention is surgical resection of hematogenous metastases; however, no treatment is specified for lymph node metastases. In general, chemotherapy is administered for distant metastases. However, we have found no reports of cases in which a complete remission has been achieved. There are reports of improvement of survival by surgical resection in cases with solitary lymph node metastasis or isolated dissemination of colorectal cancer. These observations suggest that surgical therapy may have contributed to the improved prognosis in the present case.

[A Case of Advanced Breast Cancer in Which Marked Improvement of Joint Pain Was Obtained with Stepwise Dose Reduction of Trastuzumab Emtansine (T-DM1)].

A 51-year-old woman had previously received treatment for breast cancer at another hospital but had refused early and aggressive treatment. Therefore, she was treated with symptomatic therapy. As her disease progressed, the patient wished to receive palliative care, and was transferred to a palliative care hospital. However, based on her general condition, it was determined that aggressive treatment should not be abandoned, and she was referred to our hospital for treatment. During her initial visit, the patient was found to have left breast cancer with chest wall invasion, right breast metastasis, multiple liver and lung metastases, left pleural effusion accompanied by pleural dissemination, and left upper limb edema. There was no evidence of bone metastases. The patient's pain was managed with oral oxycodone sustained-release tablets (320 mg daily), using high-dose (80 mg) oral oxycodone hydrochloride hydrate as rescue medication. The results of immunohistochemical testing, confirmed by her previous hospital, were ER (-), PgR (-) and HER2/neu positive. First-line treatment was initiated with paclitaxel (PTX) plus trastuzumab (Tmab), and the response was rated as stable disease (SD). During the course of treatment, she developed drug-induced interstitial pneumonia, which was probably caused by the taxane. Therefore, the first-line treatment was discontinued and T-DM1 was initiated as second-line treatment. However, beginning with cycle 3 of the T-DM1 treatment, the patient began complaining of joint pain, mainly in the upper limbs. Therefore, the dose of oxycodone sustained-release tablets was increased to 600 mg per day. However, the patient's joint pain showed no improvement and it was considered unlikely that the pain was due to bone metastases. It was suspected that the pain was an adverse reaction to T-DM1, and the dose of T-DM1 was reduced by one step in cycle 7 of treatment. This resulted in a dramatic improvement of the patient's symptoms. Since oxycodone sustained-release tablets was being used at a high dose, sleepiness caused by the drug interfered with her activities of daily living. Consequently, as part of an opioid rotation scheme, topical fentanyl citrate was used concomitantly, and the initial daily oxycodone sustained-release tablets dose of 600 mg was reduced to 40 mg and administered in combination with fentanyl citrate (12mg). These findings suggest that uncontrollable joint pain can occur as an adverse reaction to T-DM1.

[Carcinoma of Unknown Primary Associated with a Sister Mary Joseph's Nodule--A Case Report].

A 72-year old woman visited our hospital complaining of an umbilical mass and a foul smell from the umbilical region. During the evaluation, a massive immobile tumor was palpated in the center of the lower abdomen in addition to an umbilical mass with necrosis. Computed tomography (CT) revealed a massive ovarian tumor accompanied by an umbilical tumor and cyst with peritoneal dissemination, metastases in the liver and spleen and a urachal tumor. There were no symptoms or imaging findings of gastrointestinal obstruction. While searching for the primary focus, it was determined that the ovarian tumor was not of ovarian origin. Under these circumstances, colonoscopy was the only remaining diagnostic modality. However, evaluation of the large intestine was impossible due to compression by the tumor, and diverticulosis of the sigmoid colon did not allow smooth insertion of the colonoscope. Therefore, an excisional biopsy of the umbilical tumor was performed. The most likely diagnoses based on the histopathological findings were colorectal cancer and urachal cancer. Therefore , mFOLFOX6 was selected for chemotherapy because it has been reported to be effective against both urachal and colorectal cancer. At the time of writing, good tumor control had been achieved in the lesions evaluated. Cases of Sister Mary Joseph's nodule have sporadically been reported. The most common primary foci for peritoneal metastases are the stomach, pancreas and ovary. However, in the present case, these sites were ruled out and the primary focus remained unidentified, making it difficult to select appropriate treatment. We present this case with a discussion of the literature.

[Resection of the Right External Iliac Artery and Vein after Local Recurrence of Cecal Cancer].

A 62-year-old woman was admitted with abdominal pain and distention in July 2013. Computed tomography (CT) revealed a small bowel obstruction caused by an ileocecal tumor, and colonoscopy revealed a type 3 cecal tumor. Because an ileus tube was not effective to relieve her symptoms, she was transferred to the Department of Surgery for an emergency operation. Open resection of the ileocecal tumor along with the right ureter and psoas was performed. Histological examination showed that cancer cells were present in the radial margin. The patient was treated with a post-operative course of chemotherapy (capecitabine and oxaliplatin), but the level of carcinoembryonic antigen was increasing; positron emission tomography (PET) revealed a local cancer recurrence. Although the right external iliac artery and reconstructed right ureter were encased by the tumor, there were no signs of lymph node metastasis or distant metastasis. Because the tumor was localized, we decided to perform a re-excision. Intraoperatively, the right external iliac vein was difficult to separate from the tumor. Therefore, we resected the right ureter, kidney, and right external iliac artery and vein en bloc. The right external iliac artery and vein were replaced with grafts. Histopathologically, the reconstructed right ureter was completely invaded by the tumor, and cancer cells had invaded the nearby adventitia of the artery, but the surgical margin was negative. Four months after the second operation, peritoneal dissemination was detected on PET. The patient was followed-up in an outpatient clinic without chemotherapy.

[Synchronous male bladder cancer and breast cancer - a case report].

A 74-year-old man complained of blood in his urine over a 1-week period beginning in early October 2013, and was examined in the urology department of our hospital. A thorough examination revealed bladder cancer, and surgery was planned after two cycles of preoperative gemcitabine plus cisplatin chemotherapy. A chest computed tomography (CT) performed to evaluate the response to chemotherapy revealed a mass in the right breast. The patient had previously complained about the same site, and mammography and ultrasonography had suggested the possibility of a malignant mammary gland tumor. The results of aspiration cytology were Class V, and based on that finding, a diagnosis of cancer of the right breast was made. In February 2014, we performed a mastectomy, while preserving the pectoral muscles, along with sentinel node biopsy, total cystectomy, urethrectomy, pelvic lymph node dissection, and ureteroileal anastomosis. The histopathological diagnosis of the right breast tumor was invasive ductal carcinoma[scirrhous carcinoma, ly (+), v (-), g (+), f (+), s (+), nuclear grade 1=atypia 2+mitosis 1, EIC (-), ICT (-), NCAT (-)]. A micrometastatic tumor measuring approximately 1mm was observed in the sentinel lymph node. The breast disease was classified as pT1N1mi(sn)M0, Stage IIA, and the tumor was ER (+), PgR (+), HER2/neu (2+), and FISH (-). The bladder cancer was diagnosed as urothelial carcinoma, non-papillary, invasive G2>G3, pT2a; no pelvic lymph node metastases were detected, and it was classified as pT2aN0M0, Stage II. Synchronous male breast cancer and bladder cancer is a very rare condition, and we report the case with a review of the literature.

[Carcinosarcoma of the esophagus - a case report].

The patient was a 79-year-old male complaining of fever, loss of appetite, cough, and a feeling of obstruction when swallowing. He was diagnosed with pneumonia and admitted as an emergency case the same day. Because an esophagus space-occupying lesion was observed on chest computed tomography(CT), in addition to evidence of pneumonia, an upper gastrointestinal endoscopy was performed. A tumor, protruding into the lumen of the esophagus, was seen in the midesophagus, 25-30 cm from the incisors. Because of the narrow lumen, only a fine caliber fiber could be passed. Biopsy results indicated only necrotic tissue, and a repeat biopsy was performed, with similar histological findings. No esophagobronchial fistulas were observed during bronchoscopy. We therefore diagnosed the patient with aspiration pneumonia, secondary to esophageal narrowing by a tumor. A preoperative diagnosis of cancer could not be made, and no distant organ metastasis was detected, but surgery was indicated because of the narrowing of the esophagus, regardless of the possibility of cancer. After the pneumonia improved, total thoracic esophagectomy was performed through a right thoracolaparotomy, plus a 3- region cervico-thoraco-abdominal lymph node dissection. Pathological examination of the surgical specimen revealed autolysis of the superficial layer with progression to necrosis and associated inflammation. The majority of the tumor was composed of spindle-shaped atypical cells, but because a very small transitional area between squamous cell carcinoma and sarcoma was noted, a diagnosis of carcinosarcoma was made. Depth of invasion was sm3, and no regional lymph node metastasis was detected. The patient's disease was classified as pT1b(sm3)N0M0, StageI. No definite diagnosis was made preoperatively. Although carcinosarcoma of the esophagus is rare, the endoscopic findings are characteristic. We report this case with a review of the literature.

[A case of remnant gastric cancer seven years after initial diagnosis].

A 79-year-old woman was admitted with cholangitis caused by a common bile duct stone (CBDS), and the CBDS was removed by endoscopic sphincterotomy (EST). The patient had undergone distal gastrectomy for gastric cancer located in the lower body of the stomach in 2006. A flat, elevated lesion of the cardiac region was noted in the preoperative examination; however, this lesion was not treated because there was no clear evidence of malignancy upon histopathological examination of the biopsy specimen. Following esophagogastroduodenoscopy in 2013, the macroscopic findings had changed to infiltrative cancer. The lesion was considered to be a submucosal(sm)cancer, and the patient underwent simultaneous cholecystectomy and remnant gastrectomy. The histopathological examination of the surgical specimens revealed a well differentiated tubular adenocarcinoma, type 0-IIb+0-IIa, tub1>tub2, pT1b1, ly0, v0, n0.

[Recurrent rectal cancer with multiple liver and lung metastases treated effectively with oxaliplatin and capecitabine plus bevacizumab chemotherapy-a case report].

A 60-year-old woman receiving treatment for diabetes underwent laparoscopic-assisted low anterior resection and was diagnosed as having rectosigmoid cancer in January 2010( pSS, n2[ +], sM0 fStage IIIb, mutant-type K-ras). She refused adjuvant chemotherapy. In July, after surgery, chest-abdominal-pelvic computed tomography( CT) scans showed bilateral lobe multiple liver metastases and right lobe lung metastases. We recommended oxaliplatin and capecitabine (CapeOX) plus bevacizumab( BV) chemotherapy or surgery. The CapeOX plus BV regimen was initiated at the patient's request. After 8 cycles of chemotherapy, a partial response was observed in the metastatic liver tumors and stable disease was observed in the lung metastases. As hypertension appeared after 16 cycles of chemotherapy, we switched the treatment to CapeOX. After 10 cycles of CapeOX, the chemotherapy was changed to capecitabine at the patient's request owing to the development of grade 2 chronic peripheral neuropathy. Chest-abdominal-pelvic CT scans after 32 cycles of this regimen revealed shrinkage of the multiple liver metastases. The patient has been receiving treatment as an outpatient. Surgical resection should be considered for patients with initially unresectable colon cancer with liver and/or lung metastases if systemic chemotherapy is effective.

[A case of pancreatic metastasis from renal cell carcinoma 27 years after nephrectomy].

A 78-year-old man was admitted to Ogikubo Hospital for pancreatic tumors detected by computed tomography (CT). The patient had undergone right nephrectomy for renal cell carcinoma (RCC) 27 years previously. Dynamic CT revealed a hypervascular mass in the pancreatic head and a cystic mass in the pancreatic body that were approximately 35 mm and 20 mm in size, respectively. Total pancreatectomy and splenectomy were performed. Histological examination of the resected specimens revealed metastatic tumors from RCC and they were diagnosed as clear cell type. Metastatic carcinoma of the pancreas is uncommon. Pancreatic metastasis from RCC is rare; however, it could occur many years after the initial diagnosis and treatment of the primary tumor. A long and careful follow-up that includes examination of the pancreas is mandatory after nephrectomy for RCC. In this paper, we discuss a case of RCC metastasis to the pancreas and report it in the literature.

[Short-term outcomes of reduced port laparoscopy-assisted total gastrectomy].

PURPOSE: Several technological advances have been made in laparoscopic surgery, and the use of reduced port surgery (RPS)has gradually become widespread. To assess the safety and usefulness of RPS, we compared the short -term outcomes of conventional laparoscopy-assisted total gastrectomy(LATG)and LATG with the RPS approach. PATIENTS AND METHODS: From April 2009 to February 2012, 16 cases with gastric cancer underwent conventional LATG with 5 ports as well as minilaparotomy for anastomosis(Conventional group). From February 2012 to November 2012, 12 cases underwent RPS LATG(RPS group). In the RPS group, a multi-instrument port at the umbilicus was used during surgery. This port held 3 trocars and 2 5-mm trocars that were inserted under the right lumbocostal arch. RESULTS: The mean operation time was 333 minutes in the Conventional group, and 370 minutes in the RPS group. The mean postoperative hospital stay was 23 days in the Conventional group, and 17 days in the RPS group. Postoperative mortality was 0% in both groups. Anastomotic leakage occurred in 2 cases in the Conventional group, whereas pancreatic fistula occurred in 2 cases in the RPS group. Due to postoperative bleeding, 1 case in the RPS group underwent redo laparoscopic operation. Anastomotic stenosis was noted in 4 cases in each group. The patients with stenosis required endoscopic balloon dilation several times and the symptom eventually resolved in all cases. CONCLUSION: By comparing the short-term outcomes for conventional LATG and RPS LATG, we noted that reduced port laparoscopy-assisted total gastrectomy is a feasible procedure.

[A case of effective trastuzumab plus gemcitabine therapy for human epidermal growth factor receptor 2-positive breast cancer].

A 71-year-old postmenopausal woman was undergoing treatment for depression. She visited the hospital with a chief complaint of fibrosclerosis of the entire left breast 8 years previously. She was diagnosed as having stage IV( T3N1M1b) left breast cancer (papillotubular>scirrhous carcinoma, g+, f+, estrogen receptor [ER]-negative, progesterone receptor [PgR]-negative, and human epidermal growth factor receptor 2[ HER2/neu]-positive[ 3+]). Synchronous bone metastases were detected in the left tenth rib, the eleventh dorsal vertebra, and in the area spanning the lower lumbar to sacral vertebrae. First-line treatment was systemic therapy with 4 cycles of Adriamycin and cyclophosphamide (AC) followed by 4 cycles of trastuzumab and paclitaxel. The breast mass initially observed on clinical imaging disappeared and only calcifications were observed. Bone metastases were detected only in the left tenth rib. As an additional therapy, 3-dimensional radiotherapy( 50 Gy/25 fractions), which irradiated the left mammary gland, axilla, and supraclavicular fossa, was administered. The tumor was well controlled for approximately 3 years. However, a gradual increase in the level of carcinoembryonic antigen( CEA) was accompanied by an increase in the left breast mass and enlargement of left axillary lymph nodes. Modified radical mastectomy (Bt+Ax [level I]) was performed for this condition 3 years ago. Papillotubular-type invasive ductal carcinoma (INF ß, ly3, v0, g+, f+, s+, nuclear grade 3 [atypia 3+mitosis 3]) was diagnosed histopathologically. Lymph node metastases were also detected. As histopathological examination of the bone metastatic lesion showed no progression, administration of lapatinib and capecitabine was initiated. After 15 cycles of treatment, enlarged right axillary lymph nodes were observed and local excision was performed. Histopathological examination revealed recurrence of the breast cancer. The patient was diagnosed as having grade 3( atypia 3, mitosis 2) breast cancer( ER-negative, PgR-negative, HER2/neu positive[ 3+], and MIB-1 index 50%). The response to treatment with lapatinib and capecitabine was progressive disease( PD), and therefore, trastuzumab and gemcitabine therapy was selected. Currently, the patient has undergone 30 cycles of this regimen and the tumor is well controlled. This regimen was considered effective for the treatment of patients with HER2-positive metastatic breast cancer.

[Treatment of early rectal carcinoma by transanal resection-a case report].

A 55-year-old female was admitted to Ogikubo Hospital for severe anemia and prolapse of a tumor from the anus, which had developed over 2 years. Rectal examination revealed a giant soft tumor. Endoscopic study revealed a lobulated giant tumor with a granular surface. Gastrografin-enema study showed a giant tumor, which was full of the rectum. Pathological examination showed a well differentiated carcinoma. No other prominent metastatic lesions were demonstrated. The transanal diagnostic resection of rectal cancer was performed in October 2010. This correct diagnosis showed both well differentiated adenocarcinoma and intramucosal carcinoma. We therefore recommend that a tumor of the lower rectum should undergo a diagnostic excision by means of either a local excision, ESD or TEM.

[A case of advanced gastric cancer resistant to S-1 successfully treated with weekly administration of paclitaxel].

A 62-year-old female was diagnosed with type 2 advanced gastric cancer in May 2003. Pathological examination showed a poorly differentiated carcinoma. Computed tomography (CT) revealed paraaortic lymph node metastasis, duodenal metastasis and ascites due to peritoneal dissemination. Chemotherapy with CDDP+S-1 was started and continued. After the chemotherapy, there were progressive diseases. Therefore, paclitaxel (PTX) was administered at a dose of 80 mg/m2/day for 3 weeks followed by a week rest. Clinical symptoms were relieved, and CT scan revealed metastatic lymph nodes were reduced after 4 cycles. After 13 cycles, MRI revealed a solitary brain mass was detected. She was resected for a right temporal-occipital brain metastatic tumor, and local cerebral irradiation was performed. After this operation, she was diagnosed with brain metastasis from advanced gastric cancer. The procedure was interrupted for about 6 months. After rehabilitation, PTX treatment was restarted as 14th cycle. She has survived without recurrence more than 30 cycles after the resection. A weekly administration of PTX may be a promising regimen as second-line chemotherapy for S-1 resistant recurrent gastric cancer.