Feasibility of Neoadjuvant FOLFOX Therapy Without Radiotherapy for Baseline Resectable Rectal Cancer.

BACKGROUND/AIM: The combination of oxaliplatin, leucovorin and fluorouracil (FOLFOX) has been established as postoperative adjuvant chemotherapy for stage III colon cancer. However, the safety and efficacy of neoadjuvant FOLFOX in patients with rectal cancer are still controversial. This prospective pilot study aimed to evaluate the feasibility of neoadjuvant FOLFOX therapy without radiation for baseline resectable rectal cancer (RC). PATIENTS AND METHODS: The study included 30 patients with clinical stage II/III RC between February 2012 and December 2015. The patients were treated with six cycles of FOLFOX followed by elective surgery. The primary endpoint was the R0 resection rate. The secondary endpoints were the scheduled treatment completion rate, adverse events, pathological response and the disease-free survival (DFS) rate. RESULTS: All the patients underwent elective R0 resection after neoadjuvant FOLFOX therapy. The completion rate of the 6-cycle regimen was 93.3% (28/30 patients). Grade 3-4 adverse events occurred in seven patients (23.3%). Pathological complete response was noted in two patients (6.7%). The 3-year DFS rate was 77.5% (95% confidence interval, 61.4%-93.7%). CONCLUSION: Neoadjuvant FOLFOX therapy without radiation is a feasible therapeutic strategy for baseline resectable RC.

Evaluation of the relationship between hepatocellular carcinoma location and transarterial chemoembolization efficacy.

AIM: To evaluate the relationship between the location of hepatocellular carcinoma (HCC) and the efficacy of transarterial chemoembolization (TACE). METHODS: We evaluated 115 patients (127 nodules), excluding recurrent nodules, treated with TACE between January 2011 and June 2014. TACE efficacy was evaluated according to mRECIST. The HCC location coefficient was calculated as the distance from the central portal portion to the HCC center (mm)/liver diameter (mm) on multiplanar reconstruction images rendered (MPR) to visualize bifurcation of the right and left branches of the portal vein and HCC center. The HCC location coefficient was compared between complete response (CR) and non-CR groups in Child-Pugh grade A and B patients. RESULTS: The median location coefficient of HCC among all nodules, the right lobe, and the medial segment was significantly higher in the CR group than in the non-CR group in the Child-Pugh grade A patients (0.82 vs 0.62, P < 0.001; 0.71 vs 0.59, P < 0.01; 0.81 vs 0.49, P < 0.05, respectively). However, there was no significant difference in the median location coefficient of the HCC in the lateral segment between in the CR and in the non-CR groups (0.67 vs 0.65, P > 0.05). On the other hand, in the Child-Pugh grade B patients, the HCC median location coefficient in each lobe and segment was not significantly different between in the CR and in the non-CR groups. CONCLUSION: Improved TACE efficacy may be obtained for HCC in the peripheral zone of the right lobe and the medial segment in Child-Pugh grade A patients.

Oxaliplatin-induced increase in splenic volume; irreversible change after adjuvant FOLFOX.

BACKGROUND AND OBJECTIVES: Oxaliplatin can cause hepatic sinusoidal obstruction syndrome (SOS). SOS can cause chemotherapy-related adverse effects or morbidity after liver resection. Conventionally, SOS is diagnosed using liver biopsy. Recently, it was reported that increased splenic volume (SV) can be used to detect SOS. In this study, we evaluated the changes in SV during adjuvant chemotherapy. METHODS: We enrolled 103 consecutive patients with stage III and high-risk stage II colorectal cancer treated with mFOLFOX6 (n = 37) or oral fluorouracil and leucovorin (n = 66) after curative surgery. SV was measured three times; pre-operatively, after chemotherapy, and 1 year after chemotherapy. RESULTS: SV was higher after mFOLFOX6 (median 135.89 mL) than pre-operatively (105.75 mL) (P < 0.001); SV at 1-year after finishing mFOLFOX6 (114.16 mL) returned to the same level as before surgery (P = 0.0015). SV increased in 28 patients (75.7%) treated with mFOLFOX6 (95%CI, 61.8-89.5), but had not recovered in 12 of these cases (42.9%) 1 year after finishing treatment (95%CI, 17.3-47.5). In contrast, oral fluorouracil and leucovorin did not change SV. CONCLUSIONS: SV increased after adjuvant mFOLFOX6, and had not recovered in almost half of cases 1-year after finishing chemotherapy. This increase may indicate continuous SOS, which can adversely affect treatment after recurrence.

The effect of Daikenchuto on postoperative intestinal motility in patients with right-side colon cancer.

PURPOSE: Daikenchuto (DKT) has a stimulant effect on intestinal motility and reportedly has a positive effect on postoperative intestinal motility in patients with sigmoid colon cancer. In this study, we investigated the effects of DKT in patients with right-side colon cancer. METHODS: This retrospective study included 88 patients with right-side colon cancer. We orally administered 7.5 g of DKT in the DKT group and did not administer any DKT to patients in the no-DKT group. All patients ingested radiopaque markers 2 h before surgery, which were used to assess intestinal motility. The postoperative intestinal motility was radiologically assessed by counting the numbers of residual markers in the large and small intestines. RESULTS: The DKT and no-DKT groups showed no marked differences in the total number of residual markers or number of residual markers in the small intestine. However, in the elderly subgroup, the total number of residual markers in the DKT group was significantly less than in the no-DKT group. CONCLUSION: Although DKT had some small effect on the postoperative intestinal motility for most patients, it may have positive effects in elderly patients.

Evaluation of hyperbaric oxygen therapy for chronic wounds.

BACKGROUND: Treating chronic wounds is challenging. Despite standard wound care, some chronic wounds fail to heal. Therefore, hyperbaric oxygen therapy (HBOT) was developed as an adjunct to standard wound care. OBJECTIVE: To evaluate the efficacy of HBOT for treating chronic wounds due to a variety of causes at our institution. METHODS: We reviewed the medical records of patients with chronic wounds treated with HBOT in addition to standard wound care at the Department of Dermatology, Nippon Medical School Hospital, from 2009 through 2012. Twenty-nine patients were reviewed (14 men and 15 women; mean age, 64.1±14.4 years). The cause of chronic wounds was diabetes mellitus (DM) in 13 patients, venous stasis in 10, polyarteritis nodosa cutanea in 2, and livedoid vasculopathy, pyoderma gangrenosum, chronic renal failure, and systemic sclerosis in 1 patient each. The patients underwent HBOT for 60 minutes with 100% oxygen delivered via a mask in a hyperbaric chamber pressurized to 2.8 atmospheres of absolute pressure. The response of the chronic wounds to HBOT was evaluated according to the following criteria: "excellent": more than 90% wound healing; "good": a greater than 30% reduction in wound size, and wound healing was confirmed on follow-up visits within 6 weeks; "fair": wound healing was achieved with a combination of further invasive interventions; and "poor": the wound showed a less than 30% reduction or worsened during HBOT, or wound healing had not been completed by follow-up visits within 6 weeks. RESULTS: The response to HBOT was "excellent" in 6 patients, "good" in 8, "fair" in 11, and "poor" in 4. All 4 patients with a "poor" response had DM and had undergone hemodialysis. CONCLUSIONS: HBOT is an effective treatment for patients with chronic wounds, due to a variety of causes, when used in combination with conventional standard therapy or further interventions. However, HBOT is less effective in patients with DM than in patients with venous stasis because hemodialysis, which is more common in patients with DM, has negative effects on wound healing.

Negative-balance isolated pelvic perfusion in patients with incurable symptomatic rectal cancer: results and drug dose correlation to adverse events.

BACKGROUND: Drug leakage and lack of a drug-removal system have prevented clinical application of isolated pelvic perfusion (IPP). These barriers were overcome with negative-balance IPP (NIPP) in experimental pig models. Here, a phase 1 clinical study of NIPP was performed in patients with incurable symptomatic rectal cancer. PURPOSE: To establish a safe regimen of high-dose regional chemotherapy with NIPP using cisplatin in patients with incurable rectal cancer. MATERIAL AND METHODS: Between June 2004 and January 2007, NIPP therapy was performed for 23 patients (11 women, 12 men; mean age, 58 years). NIPP was routinely performed twice over a 4-week interval. Dose-limiting toxicities (DLTs) were defined using a 5 + 3 design, and cisplatin doses were escalated from 170 mg/m(2), with a fixed 5-fluorouracil dose of 1000 mg/m(2). The grade of adverse events (AEs) at the first and second sessions of NIPP therapy, pharmacokinetics, and antitumor response were evaluated. RESULTS: No DLTs were observed during the first session of NIPP. However, at the second session, two patients experienced the DLT of neuropathy after administration of 200 mg/m(2) cisplatin. Therefore, 190 mg/m(2) cisplatin was indicated as the maximum tolerated dose (MTD). The plasma pelvic-to-systemic exposure ratio was 18.4 based on the maximum concentration and 19.0 based on the concentration-time curve. Solid tumor responses included complete response in two patients, partial response in five patients, stable disease in 15 patients, and progressive disease in one patient. CONCLUSION: NIPP may offer the safe delivery of high-dose regional chemotherapy (MTD of 190 mg/m(2) cisplatin) with negligible AEs and effective control of tumor growth in patients with incurable rectal cancer.

Long-term outcomes after Frey's procedure for chronic pancreatitis with an inflammatory mass of the pancreatic head, with special reference to locoregional complications.

BACKGROUND: Frey's procedure might be a good alternative to pylorus-preserving pancreaticoduodenectomy (PPPD) for patients with an inflammatory mass of the head of the pancreas, because it is technically easy and associated with low morbidity and good pain relief. PURPOSE: To analyze the short-term and long-term outcomes of Frey's procedure in comparison with PPPD and to evaluate the efficacy of Frey's procedure against preoperative locoregional complications. PATIENTS AND METHODS: From August 1997 through December 2007, 6 patients underwent Frey's procedure (as described by Frey and Smith), and 10 patients underwent PPPD. The mean follow-up times were 70.8 months (Frey's procedure) and 119.8 months (PPPD). Preoperative biliary stricture and duodenal stenosis were observed in 4 and 3 patients, respectively, of patients undergoing Frey's procedure. Pain intensity was assessed with a pain scoring system. Quality of life (QOL) was assessed with the European Organization for Research and Treatment of Cancer Quality of-Life Questionnaire-Core 30. Exocrine and endocrine pancreatic function was measured during follow-up. RESULTS: Significant reductions in total pain scores and all QOL scale scores were observed immediately after surgery in all patients (P<0.05). Frey's procedure was superior to PPPD with regard to physical status 7 years after surgery (P<0.05). One patient in the Frey group had a grade B pancreatic fistula, and 2 patients in the PPPD group had intra-abdominal bleeding and delayed gastric emptying. There were no re-operations or surgery-related deaths in either group. Diabetes developed postoperatively in 2 patients in the PPPD group. No patients with preoperative duodenal or biliary stricture or both had a relapse. Three patients in the PPPD group died during follow-up of diseases unrelated to chronic pancreatitis. CONCLUSION: Frey's procedure is safe and effective with regard to pain relief, preservation of pancreatic function, and improvement of QOL over the long term. Moreover, this procedure can also be used to treat preoperative biliary stricture and duodenal stenosis associated with an inflammatory mass of the pancreatic head.

[Reduction in oxaliplatin-related neurotoxicity by the administration of Keishikajutsubuto(TJ-18)and powdered processed aconite root].

Oxaliplatin (L-OHP)is an important chemotherapeutic drug for the treatment of colorectal cancer. Peripheral neuropathy was observed in 90% of patients who received L-OHP.Neuropathy often results in the discontinuation of treatment or a decrease the quality of life(QOL). The most effective method for reducing neuropathy is the discontinuation of L-OHP. To reduce neuropathy, we administered Keishikajutsubutou(TJ-18)with powdered processed aconite root(TJ-3023), and we report the effect of these compounds. The subjects comprised 11 patients with metastatic colorectal cancer. L-OHP(85mg/m2)was administered as part of the FOLFOX6(10 patients)or FOLFOX7(1 patient)regimen. All patients had experienced neuropathy. We administered TJ-18(7.5 g)and T-3023(1 g). After 2 weeks, the TJ-3023 dose was increased to 2 g for nonresponders. The response was evaluated according to the Neurotoxicity Criteria of DEBIOPHARM. Reduction in neuropathy was observed in 5 cases(45.5% ). Among 6 patients whose feet and hands felt warm, reduction in neuropathy was observed in 5(83.3% ).

Surgical resection of late solitary locoregional gastric cancer recurrence in stomach bed.

BACKGROUND: Late-onset and solitary recurrence of gastric signet ring cell (SRC) carcinoma is rare. We report a successful surgical resection of late solitary locoregional recurrence after curative gastrectomy for gastric SRC carcinoma. CASE REPORT: The patient underwent total gastrectomy for advanced gastric carcinoma at age 52. Seven years after the primary operation, he visited us again with sudden onset of abdominal pain and vomiting. We finally decided to perform an operation, based on a diagnosis of colon obstruction due to the recurrence of gastric cancer by clinical findings and instrumental examinations. The laparotomic intra-abdominal findings showed that the recurrent tumor existed in the region surrounded by the left diaphragm, colon of splenic flexure, and pancreas tail. There was no evidence of peritoneal dissemination, and peritoneal lavage fluid cytology was negative. We performed complete resection of the recurrent tumor with partial colectomy, distal pancreatectomy, and partial diaphragmectomy. Histological examination of the resected specimen revealed SRC carcinoma, identical in appearance to the previously resected gastric cancer. We confirmed that the intra-abdominal tumor was a locoregional gastric cancer recurrence in the stomach bed. The patient showed a long-term survival of 27 months after the second operation. CONCLUSIONS: In the absence of effective alternative treatment for recurrent gastric carcinoma, surgical options should be pursued, especially for late and solitary recurrence.

Chemosensitivity test for 5-fluorouracil and 5-chloro-2, 4-dihydroxypyridine predicts outcome of gastric cancer patients receiving S-1 postoperatively.

BACKGROUND: Chemosensitivity tests have long been discussed but remain a topic of research. In this study, we investigated the correlation between the results of a chemosensitivity test for 5-fluorouracil and 5-chloro-2, 4-dihydroxypyridine and the clinical outcomes of gastric cancer patients treated with S-1, an oral fluoropyrimidine, as adjuvant chemotherapy. METHODS: For gastric cancer patients, we performed surgical treatment and a lymph node dissection of D2 or more. Afterwards, a chemosensitivity test for 5-fluorouracil and 5-chloro-2, 4-dihydroxypyridine was performed, using the collagen gel droplet embedded culture drug-sensitivity test (CD-DST), in surgical specimens. All the patients received postoperative adjuvant chemotherapy with S-1 for 1 year, and the overall survival (OS), relapse-free survival (RFS), and adverse events were investigated. RESULTS: The chemosensitivity test was performed for 27 patients. The growth inhibition rate (IR) was 50% or more (high-sensitivity group) in 59.3% (16 cases) and it was under 50% (low-sensitivity group) in 40.7% (11 cases). The 3-year OS rate was 100% in the high-sensitivity group and 62.34% in the low-sensitivity group. The 3-year RFS rate was 83.33% in the high-sensitivity group and 24.24% in the low-sensitivity group. Thus, the 3-year OS rate and the 3-year RFS rate were higher in the high-sensitivity group than in the low-sensitivity group. No adverse events of grade 3 or greater severity were observed. CONCLUSIONS: The results of the chemosensitivity test were correlated with the patient outcome. Therefore, such results might be useful for individualizing cancer chemotherapy and for determining future indications for postoperative adjuvant chemotherapy.

[A successful resected case of far-advanced cancer at the esophagogastric junction by chemoradiotherapy with docetaxel, nedaplatin and 5-fluorouracil].

The patient, a 73-year-old male, was admitted to our hospital because of dysphagia. A far-advanced cancer was diagnosed at the esophagogastric junction by upper gastrointestinal endoscopic examination. Pathological biopsy examinations revealed poorly-differentiated adenocarcinoma. Computed tomography (CT) of the chest and abdomen showed invasion to the diaphragm. Clinical Stage was IV in an unresectable far-advanced tumor. He received radiation therapy (40 Gy/total, 2 Gy/day×20 times) in combination with chemotherapy using docetaxel (40 mg/m², day 1), nedaplatin (10mg/body, days 1-5) and 5-fluorouracil (500 mg/body, days 1-5). After this combination chemoradiation therapy (CRT), macroscopic examinations showed significant reductions in the size of tumor, leading a partial response according to the RECIST guidelines. He underwent total gastrectomy, partial resection of the lower esophagus via left thoracotomy, and Roux-en Y reconstruction with jejunostomy. Pathological examination of the resected specimens revealed Stage IV (T3N2P1CY0). The postoperative course was uneventful. He was treated on an outpatient basis without adjuvant therapy, and died 6 months after the operation by liver, spleen and lymph node metastases.

Left paraduodenal hernia incidentally diagnosed during operation for transverse colon cancer.

We report the case of a patient with paraduodenal hernia diagnosed incidentally during an operation for transverse colon cancer. The patient was a 77-year-old woman who complained of dizziness. Laboratory data revealed no abnormal findings except slight anemia. Barium enema and colonoscopic examination revealed an irregular surfaced mass, about 5.0 cm in size, located near the flexure of the spleen of the transverse colon. A biopsy of the mass was performed, and a moderately differentiated adenocarcinoma was diagnosed. In April 2009, following the diagnosis of transverse colon cancer, laparotomy was performed, which revealed that a few loops of the jejunum were herniated through the orifice into the space posterior to the transverse mesocolon. Moreover, the jejunal loops were located right between a shifted left branch of the middle colic artery and ascending left colic artery. There were no ischemic changes in the jejunum. These findings were consistent with a left paraduodenal hernia associated with transverse colon cancer. The scheduled left hemicolectomy was performed in addition to a radical operation of the left paraduodenal hernia. The abdominal computed tomography (CT) images were reviewed postoperatively. The scan projection radiogram obtained by CT revealed a packing of jejunal loops in the middle of the abdomen. Abdominal CT revealed ascending left colic artery at the left edge of a packing of jejunal loops. The patient was discharged from our hospital 14 days after the surgery without any complications. Left paraduodenal hernias are rare and constitute less than 0.4% of all intestinal obstructions. Retrospectively reviewed, the preoperative CT is suggestive. In addition to the packing of jejunal loops in the middle of the abdomen, ascending left colic artery was clearly observed at the left edge of the packing of jejunal loops, which indicates left paraduodenal hernia.

Dose determination of cinacalcet hydrochloride in Japanese hemodialysis patients with secondary hyperparathyroidism.

Cinacalcet hydrochloride is a calcimimetic agent that activates the calcium-sensing receptor on the surface of parathyroid cells and inhibits parathyroid hormone (PTH) secretion. To manage secondary hyperparathyroidism, cinacalcet, which lowers PTH levels without increasing serum calcium, phosphorus and calcium-phosphorus product (Ca x P) levels, may provide a new potential therapy. To identify the optimal starting dose of cinacalcet for Japanese hemodialysis patients with secondary hyperparathyroidism, this double-blind, placebo-controlled, parallel, dose-finding study was conducted. One hundred and twenty Japanese hemodialysis patients with intact PTH levels greater than or equal to 300 pg/mL were randomized into four groups: placebo, and 12.5, 25 and 50 mg of cinacalcet. The treatment period was three weeks followed by a two-week follow-up observation period. Cinacalcet decreased serum intact PTH levels in a dose-dependent manner, and also decreased serum calcium, phosphorus, Ca x P, tartrate-resistant acid phosphatase and osteocalcin levels. The treatment with cinacalcet was generally well tolerated in this study. However, the incidence of treatment-related adverse events, such as gastrointestinal disorders and hypocalcemia, and the rate of withdrawal from the study due to treatment-related adverse events were higher in the 50 mg dose group than in the other groups. On the basis of both efficacy and safety results, 25 mg has been identified as the optimal starting dose of cinacalcet for Japanese hemodialysis patients with secondary hyperparathyroidism.

Cinacalcet (KRN1493) effectively decreases the serum intact PTH level with favorable control of the serum phosphorus and calcium levels in Japanese dialysis patients.

BACKGROUND: Cinacalcet hydrochloride (KRN1493) acts on the parathyroid calcium receptors to suppress parathyroid hormone (PTH) secretion, and is already in wide use in the United States and the European countries. In this study, we examined the efficacy and safety of cinacalcet in Japanese patients on maintenance haemodialysis. METHODS: One hundred forty-four patients with serum intact PTH (iPTH) levels >or=300 pg/ml were enrolled and randomly allocated to two groups assigned to receive either cinacalcet or placebo for 14 weeks. Cinacalcet was started at the dose of 25 mg/day and titrated up to 100 mg/day to achieve the target iPTH level of <250 pg/ml. RESULTS: Cinacalcet significantly decreased the median iPTH level from 606.5 pg/ml to 241.0 pg/ml, despite the mean dialysis vintage being 2.4 times longer (14.3+/-7.1 years) and the proportion of patients receiving vitamin D sterols being higher, than in the phase 3 studies conducted in the US/EU. The target iPTH level was achieved in 51.4% of the patients in the cinacalcet group, in sharp contrast to only 2.8% in the placebo group. Furthermore, the percentage of patients with both the serum calcium and phosphorus levels within the target range in the K/DOQI guidelines increased from 4.2% to 26.4% by cinacalcet. CONCLUSIONS: These results suggest that lower dose levels of cinacalcet, as compared to those in US/EU studies, may be sufficient effectively suppress the serum iPTH levels and allow favourable management of the serum calcium and phosphorus levels in Japanese patients, having a longer average dialysis vintage.

Evaluation of the clinical pathway for laparoscopic cholecystectomy and simulation of short-term hospitalization.

The effectiveness of the clinical pathway for laparoscopic cholecystectomy was evaluated, and the efficiency of medical care was analyzed. The duration of hospitalization and the number of National Health Insurance (NHI) points for medical service fees were compared between 86 patients treated after introduction of the clinical pathway (pathway group) and 56 patients treated before introduction of the clinical pathway (pre-pathway group). In the pathway group, variance from the pathway occurred in 24 patients (27.9%) due to postponement of discharge in 7 patients, to earlier discharge in 5 patients, and to insertion of a bile duct catheter in 5 patients. Total and postoperative hospitalization times were significantly shorter in the pathway group than in the pre-pathway group (8.0 +/- 1.6 vs 13.7 +/- 9.0 days, p<0.0001, 5.4 +/- 1.1 vs 6.5 +/- 2.2 days, p<0.0001, respectively). In the pathway group, the total number of NHI points was lower and the number of points per day was higher. By simulation, the total number of NHI points for the 5-day pathway (discharge on postoperative day 3 or earlier) was significantly lower than that for the current 7-day pathway. Moreover, the weekly profit per bed with the 3-day pathway (discharge on postoperative day 1) was more than twice that with the current pathway. The results suggest that the clinical pathway for laparoscopic cholecystectomy is beneficial for patients and useful for the introduction of diagnosis procedure combination in our hospital.