Preoperative FOLFOX in resectable locally advanced rectal cancer can be a safe and promising strategy: the R-NAC-01 study.

PURPOSE: The aim of this study was to assess the safety of rectal surgery after 5-fluorouracil-leucovorin-oxaliplatin chemotherapy (FOLFOX6). METHODS: This was a prospective, multicenter study in 11 Japanese hospitals. We included patients with rectal cancer who received 4 courses of modified FOLFOX6 (mFOLFOX6) before rectal surgery and examined the postoperative complication rate, the clinicopathological response, and the rate of chemotherapy-related adverse events (UMIN 000012559). RESULTS: The study population included 36 men and 5 women. The average age of the patients was 60.8 years and the average body mass index was 23.1 kg/m2. After 4 courses of chemotherapy, grade 2 peripheral nerve disorder and other grade 3 adverse events were seen in 3 patients each (7.3%). Twenty-eight (73.7%) and 8 (21.1%) patients underwent low anterior resection and abdominoperineal resection, respectively. The pelvic nerves were preserved in 35 patients. Surgical morbidity (grade ≥ 3) occurred in 4 patients (10.5%). Anastomotic leakage occurred after surgery in 2 patients (7.1%). No patients achieved pathologically complete remission. However, downstaging of the clinical stage and N stage was seen in 17 (41.5%) and 22 (53.7%) patients, respectively. CONCLUSIONS: Surgery after four courses of mFOLFOX6 chemotherapy can be a safe and promising strategy for patients with locally advanced rectal cancer.

Efficacy of DHMEQ, a NF-κB inhibitor, in islet transplantation: I. HMGB1 suppression by DHMEQ prevents early islet graft damage.

BACKGROUND: Pancreatic islet transplantation (PITx) is an attractive treatment option for restoring appropriate glucose homeostasis in type 1 diabetes patients. Although islet grafts can successfully engraft after PITx, large numbers of islet grafts are required mainly because immune reactions, including inflammation, destroy islet grafts. In these processes, nuclear factor (NF)-κB plays a central role. We hypothesized that the inhibition of NF-κB activation would ameliorate inflammatory responses after PITx and aid successful engraftment. METHODS: To test this hypothesis, a newly developed NF-κB inhibitor, dehydroxymethylepoxyquinomicin (DHMEQ), was used on a syngeneic mouse PITx model. One hundred seventy-five islets from C57BL/6 (B6) mice were transplanted into streptozotocin-induced diabetic B6 mice. The recipient mice were administered DHMEQ for 1, 2, or 3 days after PITx. The underlying mechanisms of DHMEQ on islet graft protection were investigated in an in vitro coculture model of pancreatic islets and macrophages. RESULTS: With a vehicle treatment, only 11.1% of the islet-recipients achieved normoglycemia after PITx. In sharp contrast, DHMEQ treatment markedly improved the normoglycemic rate, which was associated with the suppression of serum high mobility group complex-1 (HMGB1) and proinflammatory cytokines, including tumor necrosis factor-α, monocyte chemoattractant protein-1, macrophage inflammatory protein-1ß, interleukin-1ß, and interleukin-6, after PITx. In a murine macrophage-like cell line, DHMEQ inhibited HMGB1-driven activation and proinflammatory cytokine secretion and further prevented death isolated islets after coculture with these activated macrophages. CONCLUSIONS: Inhibition of NF-κB activation by DHMEQ after PITx reduces the HMGB1-triggered proinflammatory responses and results in engraftment of transplanted islets even with fewer islet grafts.

Efficacy of DHMEQ, a NF-κB inhibitor, in islet transplantation: II. Induction DHMEQ treatment ameliorates subsequent alloimmune responses and permits long-term islet allograft acceptance.

BACKGROUND: Long-term graft deterioration remains a major obstacle in the success of pancreatic islet transplantation (PITx). Antigen-independent inflammatory and innate immune responses strengthen subsequent antigen-dependent immunity; further, activation of nuclear factor (NF)-κB plays a key role during these responses. In this study, we tested our hypothesis that, by the inhibition of NF-κB activation, the suppression of these early responses after PITx could facilitate graft acceptance. METHODS: Full major histocompatibility complex (MHC)-mismatched BALB/c (H-2) mice islets were transplanted into streptozotocin-induced diabetic C57BL/6 (B6: H-2) mice. The NF-κB inhibitor dehydroxymethylepoxyquinomicin (DHMEQ) was administered for either 3 or 14 days after PITx. To some PITx recipients, tacrolimus was also administered. Islet allograft survival, alloimmune responses, and in vitro effects of DHMEQ on dendritic cells (DCs) were assessed. RESULTS: With a vehicle treatment, 600 islet allografts were promptly rejected after PITx. In contrast, 3-day treatment with DHMEQ, followed by 2-week treatment with tacrolimus, allowed permanent acceptance of islet allografts. The endogenous danger-signaling molecule high mobility group complex 1 (HMGB1) was elevated in sera shortly after PITx, whereas DHMEQ administration abolished this elevation. DHMEQ suppressed HMGB1-driven cellular activation and proinflammatory cytokine secretion in mouse bone marrow-derived DCs and significantly reduced the capacity of DCs to prime allogeneic T-cell proliferation in vitro. Finally, the DHMEQ plus tacrolimus regimen reverted the diabetic state with only 300 islet allografts. CONCLUSIONS: Inhibition of NF-κB activation by DHMEQ shortly after PITx suppresses HMGB1, which activates DCs and strengthens the magnitude of alloimmune responses; this permits long-term islet allograft acceptance, even in case of fewer islet allografts.

[A case of drug-induced pulmonary injury showing organizing pneumonia pattern due to S-1].

Reported here is the case of a 76-year-old male with gastric cancer. Distal gastrectomy was performed after his admission to our hospital. Histopathologically, the cancer was determined to be in the advanced stage. Combination chemotherapy with CDDP and S-1 was administered for 6 courses, after which S-1 was used alone. Chest X-ray and CT showed multiple dispersed lesions in the lung. Further examination by bronchoscope was performed. Histopathological examination of a biopsy specimen revealed the lesion to be organizing pneumonia. A drug-induced lymphocyte stimulation test (DLST) for S-1 proved to be positive. Discontinuation of S-1 administration led to natural improvement of the pneumonia. These results suggest that S-1 had induced the organizing pneumonia.

Induction of insulin-dependent diabetes mellitus by total pancreatectomy for pancreatic islet transplantation in cynomolgus monkeys.

BACKGROUND/PURPOSE: In order to perform a preclinical trial of pancreatic islet transplantation (PIT) in nonhuman primates, insulin-dependent diabetes mellitus (IDDM) must be induced. Methods for IDDM induction are administration of streptozotocin (STZ) or total pancreatectomy (TP). While STZ-induced IDDM is not always reliable, TP is appropriate for IDDM induction. However, TP is very difficult because of the complex surgical procedure required, necessary confirmation of IDDM, and difficulty in postoperative management. In this study, we tried to establish a reliable IDDM model for PIT in cynomolgus monkeys. METHODS: TP was performed in 5 male cynomolgus monkeys (Macaca fascicularis). This was followed by scheduled measurements of blood glucose, C-peptide levels, insulin levels, oral intake, and insulin requirements. IDDM induction was confirmed by serum C-peptide levels and intravenous glucose tolerance test (IVGTT). Allogeneic PIT was performed 14 days later with immunosuppressive therapy. RESULTS: TP successfully induced IDDM in all animals, confirmed by reduction of fasting serum C-peptide levels. Negative responses of serum C-peptide levels and insulin in IVGTT provided further confirmation of IDDM induction. No mortality or morbidity was encountered in any of the animals. CONCLUSIONS: TP successfully induced IDDM for PIT in cynomolgus monkeys.

[An example of metastasis to the iliopsoas muscle from sigmoid colon cancer].

Even though skeletal muscle, making up about 40% of body weight, is the largest organ in the human body, metastasis from malignant lesions is rare. Among reports of metastasis, those involving the iliopsoas muscle are numerous but few reports involve resection. Reported here is one example we experienced where metastasis developed in the iliopsoas muscle following colectomy, resection was then made possible by radiotherapy and chemotherapy. The case involved a 71-year- old male in which a Hartmann procedure was performed for sigmoid colon cancer. The pathology was Type 3 (8 × 7 cm, adenocarcinoma( mod), ss or more, ly1, v1, n0, ow(-), aw or ew(+), stage II). Upon additional sampling, thermal degredation of neoplastic cells was shown and outpatient oral UFT was performed. Five years following surgery, lymphoadenopathy was noted in the area of the left iliac artery upon US and CT. PET showed a probable metastasis to the left iliopsoas muscle. Early esophageal and stomach cancer were diagnosed by GFT. The esophageal cancer was located 30-32 cm from the incisors, unstained, Borrmann type 1, penetrating deeper than the muscularis propria. Biopsy revealed a diagnosis of tubular adenocarcinoma. ESD was performed for the esophageal cancer and one month later, a total gastrectomy D1+ß was performed. During surgery, the iliopsoas muscle tumor was determined to be large and impossible to resect. Radiotherapy of 10MV X-ray, 8 fields, 65-70 Gy/26 times for 6 . 5 weeks was performed for residual tumor but had no effect on tumor size. Fifteen courses of FOLFOX+bevacizumab were then performed. The tumor was markedly reduced in size, unidentifiable upon CT but showed slight uptake on PET and resection of the suspected residual tumor was performed. Histologically, atypical cells were shown in scarred muscle and connective tissue, however, degradation by chemotherapy was high. Residual tumor at resection margins was found, findings consistent with metastasis form sigmoid colon cancer. Taking into account the age and condition of the patient following surgery, chemotherapy was changed to S-1. Currently, 5 months after resection, there has been no recurrence.

[Preoperative S-1/CDDP combination chemotherapy was effective in a case of local advanced gastric cancer].

INTRODUCTION: The prognosis of type 4 advanced gastric cancer is extremely poor, even the use of multidisciplinary treatment cannot provide satisfactory results. Presented here is a case of highly advanced gastric cancer in which preoperative chemotherapy was effective and resection possible. CASE: A 64-year-old female complained of epigastric distress. Current medical history included: hypertension, hyperlipemia, diabetes, chronic heart disease and development of epigastric distress. Endoscopy was performed upon examination in the Gastroenterology Department. Visual inspection showed a lesion extending from the greater curvature of the fundus to the antrum. Type 4 advanced gastric cancer was strongly suspected. Biopsy samples taken from the antral lesser curvature and from the ulcer border on the upper anterior wall of the body were diagnosed as Group V, adenocarcinoma. Abdominal CT revealed no hepatic mass, but overall thickening of the gastric wall was noticeable and the lymph nodes in the area of the lesser curvature of the stomach and celiac artery were identified. Abdominal ultrasound showed an overall thickening of the gastric wall, and invasion into a portion of the left hepatic lobe and pancreas was suspected. Swelling of the lymph nodes surrounding the stomach was suspected. TREATMENT: Because of gastric cancer with suspected invasion of the left hepatic lobe and pancreas, it was decided to perform preoperative chemotherapy (S-1 + CDDP) and then perform a total gastrectomy. Four courses were performed. RESULTS: Endoscopy revealed no change in the lesion within the stomach. Only scarring in the body and antrum was found, the enlargement was greatly reduced and visual inspection revealed no esophageal infiltration. Biopsy samples were taken from 2 sites, the body center on the lesser curvature side and the greater curvature of the antrum. Scar-like fibrosis was significant and it was not possible to distinguish an increase in poorly differentiated adenocarcinoma. Abdominal CT showed a reduction in gastric wall thickening. These findings showed preoperative chemotherapy to be effective. Following the chemotherapy, a total gastrectomy in addition to splenectomy and cholecystectomy were performed. Histopathological findings showed MLU, type 5, approx. 8.5 × 13 cm, poorly differentiated adenocarcinoma (por 2), INF γ, sci, pT2 (SS), ly2, v0, pN2 (#1: 2/8, #6: 1/6, #11p: 2/5), pPM (-), pDM (-), Stage IIIA. Along with the formation of fibrous scar tissue, an invasive growth of por 2 poorly differentiated adenocarcinoma was found from the submucosal layer to just beneath the serosal layer. Therapeutic effect of the chemotherapy was Grade 2. Post operative S-1 + CDDP was begun but nausea developed and S-1 was reduced. Because of a decrease of neutrophils and nausea, the therapy was changed to UFT. It is currently 6 months after surgery and there are no signs of recurrence. CONCLUSION: Preoperative chemotherapy (S-1 + CDDP) is a therapy which shows promise in reducing tumor size even in highly advanced gastric cancer.