Correlation between immune-related adverse events and prognosis in patients with various cancers treated with anti PD-1 antibody.

BACKGROUND: Immune checkpoint inhibitors (ICIs) targeting programmed cell death protein 1 (PD-1) are used for the treatment of various cancer types. However, immune-related adverse events (irAEs) occur in patients treated with ICIs. Several small-scale studies have reported the onset of irAEs and therapeutic effects of ICIs. Here we report a large-scale retrospective study covering a wide range of cancers. We evaluated irAEs and the therapeutic effects of ICIs and determined whether irAEs could be predicted. METHODS: This study included patients treated with the anti-PD-1 antibodies nivolumab or pembrolizumab at Fujita Health University Hospital between December 2015 and March 2019. We retrospectively reviewed the electronic medical records for age, cancer type, pre-treatment blood test data, presence or absence of irAE onset, type and severity of irAEs, outcome of irAE treatment, response rate, progression-free survival and overall survival. RESULTS: Two hundred-eighty patients received ICIs. The overall incidence of irAEs was 41.1% (115 patients), and the incidence of severe irAEs of grade 3 and higher was 2.8% (eight patients). The most common irAEs were skin disorders, thyroid disorders and interstitial pneumonitis. Patients with irAEs were significantly older than those without irAEs (69.7 versus 66.0 years, P = 0.02). The objective response rate (ORR) in patients with irAEs was 30.4%, which was significantly higher than in patients without irAEs (12.7%; P < 0.01). Both the median overall and progression-free survival were significantly longer in patients with irAEs (P < 0.01, p < 0.01). Based on the blood test data obtained before ICI therapy, hypothyroidism, thyroid-stimulating hormone levels and thyroglobulin antibody levels were associated with the onset of irAEs. In many patients with irAEs of Common Terminology Criteria for Adverse Events Grade 3 or higher, re-administration of ICIs was difficult, and their outcomes were poor. In contrast, many patients with irAEs of a lower grade were able to resume ICI therapy. CONCLUSION: Although the onset of irAEs was difficult to be predicted based on pre-treatment tests. It appeared that the continuation of ICI therapy, along with early detection and adequate control of irAEs, might contribute to the improved prognosis of patients.

Current State of and Problems Related to Cancer of the Intestinal Tract Associated with Crohn's Disease in Japan.

BACKGROUND/AIM: Cancer of the intestinal tract (small and large intestine) associated with Crohn's disease has a low incidence but can be fatal if it develops. Thus, the key question is how to deal with this type of cancer. The current study surveyed major medical facilities that treat inflammatory bowel disease (IBD) surgically in Japan in order to examine the clinical features of cancer of the intestinal tract associated with Crohn's disease and explore ways to deal with this cancer in the future. PATIENTS AND METHODS: Sixteen major medical facilities that treat IBD surgically were surveyed regarding cancer of the intestinal tract associated with Crohn's disease. The medical facilities had treated 3,454 patients with Crohn's disease, 122 of whom had developed intestinal cancer. The medical facilities were surveyed regarding those 122 patients. RESULTS: The incidence of intestinal cancer associated with Crohn's disease has increased yearly. Cancer most often developed in the left side of the colon and, particularly, in the rectum and anal canal. Seventy-six percent of cases were diagnosed preoperatively, 4% were diagnosed intraoperatively, while the remaining 20% were diagnosed pathologically after surgery. The most prevalent histological type of cancer was mucinous carcinoma (50%). Forty-two percent of cancers were differentiated, with 4% being poorly differentiated. The surgical procedure performed most often (67%) was abdominoperineal resection. The 5-year survival rate by stage was 88% for Stage I, 68% for Stage II, 71% for Stage IIIa, 25% for Stage IIIb and 0% for Stage IV. Overall, the 5-year survival rate was 52%. CONCLUSION: Gastrointestinal (GI) cancer associated with Crohn's disease had an incidence of 3.5%, but also involved a poor prognosis with a 5-year survival rate of 52%. Early detection through surveillance is crucial to improving the prognosis for patients. However, surveillance of the intestinal tract with endoscopy or contrast studies is technically and diagnostically hampered by Crohn's disease and intestinal strictures. A biopsy of the anal canal, a common site of cancer, can readily be performed and constitutes the first step in surveillance.

Factors affecting recurrence and prognosis after R0 resection for colorectal cancer with peritoneal metastasis.

BACKGROUND: Peritoneal metastases (PM) are a well-known poor prognostic factor. The aim of this study was to investigate the factors affecting recurrence and prognosis after R0 resection for colorectal cancer with synchronous peritoneal metastases. METHODS: We conducted a multi-institutional retrospective analysis of 72 patients without distant metastases who underwent R0 surgery between 1991 and 2007 for colorectal cancer with PM localized to the adjacent peritoneum. Clinicopathological variables were analyzed for their significance to recurrence and prognosis. RESULTS: Recurrence was found in 51 patients (70.8%) after R0 surgery. In logistic regression analyses, lymph node metastasis was shown to be an independent factor affecting recurrence. Non-intensive or no postoperative chemotherapy and eight or fewer dissected lymph nodes were identified as independent poor prognostic factors using the Cox proportional hazards model. Among patients who received postoperative chemotherapy, prognosis was significantly better in those who received intensive adjuvant chemotherapy using camptothecin-11 or oxaliplatin after R0 surgery than in those who received non-intensive chemotherapy. Among 47 patients whose recurrence date was known, 33 patients (70.2%) experienced recurrence within 18 months after R0 surgery for peritoneal metastases, and hematogenous recurrence was observed significantly more often than peritoneal recurrence. CONCLUSIONS: Harvesting of more than eight lymph nodes and administration of intense adjuvant chemotherapy after R0 surgery are recommended for greater prediction accuracy and improved prognosis. Intensive follow-up should be performed within 18 months after R0 surgery for colorectal cancer with synchronous peritoneal metastases.

Cascade utilization of water chestnut: recovery of phenolics, phosphorus, and sugars.

Overgrowth of aquatic plants, such as water chestnut, has been reported as a regional problem in various areas. We proposed cascade utilization of water chestnut through the recovery of phenolics, phosphorus, and sugars. Phenolics were extracted using 50 g (wet weight) of biomass with 300 mL of acetone, methanol, or hot water, and the yields of total phenolics were 80.2, 56.2, and 49.7 mg g(-1) dry weight of native biomass, respectively. The rate of eluted phosphorus in the phenolic extraction step was 8.6, 14.8, and 45.3 % of that in the native biomass, respectively, indicating that the use of polar organic solvents suppressed phosphorus elution at the phenolic extraction step. Extraction of phosphorus following the phenolic extraction was combined with alkaline pretreatment (1 % NaOH solution) of biomass for saccharification; 64.1 and 51.0 % of phosphorus in the native biomass were extracted using acetone and methanol for the phenolic extraction, respectively. Saccharification following the alkaline pretreatment showed that the glucose recovery rates were significantly increased (p<0.05) with the phenolic extraction step compared to alkaline pretreatment alone. This finding indicates that extraction of phenolics not only provides another useful material but also facilitates enzymatic saccharification.

Comparison of simultaneous and separate processes: saccharification and thermophilic L-lactate fermentation of catch crop and aquatic plant biomass.

Catch crop candidates (corn, guinea grass) for recovering nutrients from farm soil and aquatic plants (water caltrop, water hyacinth) were utilized to produce L-lactic acid. The efficiencies ofpre-treatment methods for enzymatic saccharification and L-lactate production of two fermentation processes, thermophilic simultaneous saccharification and fermentation (SSF), as well as separate saccharification and fermentation, were compared. Conditions were set at 55 degrees C and pH 5.5 for non-sterile fermentation. Alkaline/peroxide pre-treatment proved the most effective for saccharification in pre-treated corn, guinea grass, water caltrop and water hyacinth with glucose yields of 0.23, 0.20, 0.11 and 0.14 g/g-dry native biomass (24-hour incubation period), respectively. Examination of the two types of thermophilic L-lactate fermentation employed following alkaline/peroxide pre-treatment and saccharification demonstrated that the L-lactate yield obtained using SSF (0.15 g/g in the case of corn) was lower than that obtained using separate saccharification and fermentation (0.28 g/g in the case of corn). The lower yield obtained from SSF is likely to have resulted from the saccharification conditions used in the present study, as the possibility of cellulase deactivation during SSF by thermophilic L-lactate producing bacteria existed. A cellulase that retains high activity levels under non-sterile conditions and a L-lactate producer without cellulose hydrolysis activity would be required in order for SSF to serve as an effective method of L-lactate production.

Laparoscopic assisted synchronous gastrectomy and colectomy with lymphadenectomy for double cancer in our experience.

Laparoscopic gastrointestinal surgery with lymphadenectomy is rarely performed for multiple gastrointestinal cancers. We report four patients undergoing laparoscopic surgery for synchronous cancer of the stomach and colon. Resection of each organ with lymphadenectomy was performed by each specialist and the region of the lymphadenectomy was determined according to the lesion of cancer and its depth. The selection of gastric anastomosis, whether intracorporeal or extracorporeal, depended on the resecting areas of the large bowel to allow a small incision. All four cases were male with the median age of 69 (range 59-77) years. The median number of trocars used were 6 (range 5-8) and median length of incision was 4.5 cm (range 4-4.5 cm). The median operative time and blood loss were 495.5 minutes (range 390-605) and 88 g (range 36-245), respectively. In all four cases, laparoscopic surgery with a lymphadenectomy on each region was successfully accomplished according to the respective progression stage. Anastomosis was completed with a small incision by using techniques and devices to provide a variation of anastomosis methods and incision positions. Laparoscopic surgery with lymphadenectomy was also undertaken for a patient with gastric remnant cancer and colorectal cancer. The median length of the postoperative hospital stay was 14.5 days (range 12-29). No complications were observed after the surgery. There was no case of recurrence during a median follow-up of 84.3 months (range 54.9-111.5). Laparoscopic surgery was feasible for patients with double cancer of the stomach and colon.

Protein-bound polysaccharide K augments IL-2 production from murine mesenteric lymph node CD4+ T cells by modulating T cell receptor signaling.

The protein-bound polysaccharide isolated from basidiomycetes (PSK), a biological response modifier, has been used as immunotherapeutic agent for the treatment of cancers. It has been demonstrated previously that PSK activates various types of immune cells in vitro, and orally administrated PSK activates anti-tumor CD4+ T cell response in mesenteric lymph nodes (MLNs). The detailed mechanism of action of PSK, however, has not been elucidated yet. The objective of the present study was to clarify the molecular mechanism of immunopotentiating effects of PSK using primary culture of the MLN CD4+ T cells. T cell receptor (TCR) stimulation-induced interleukin-2 production from MLN CD4+ T cells was significantly augmented by PSK in a concentration-dependent manner, and the augmentation was reflected at mRNA level. Furthermore, PSK augmented transcriptional activities of nuclear factor of activated T cells and activator protein 1, and phosphorylation of extracellular signal-regulated kinase 1/2 and linker for activation of T cells induced by TCR stimulation, whereas PSK had no influences without TCR stimulation. Collectively, the results indicate that PSK augments activation of MLN CD4+ T cells, probably by modulating the TCR signaling, and provide important knowledge for the elucidation of the true target molecule(s) of PSK.

[Five cases of locally advanced rectal cancer or local recurrence performed intra-arterial infusion chemotherapy via the internal iliac artery].

Intra-arterial infusion chemotherapy via the internal iliac artery was performed in 5 patients with locally advanced rectal cancer or recurrent rectal cancer. Arterial infusion chemotherapy was conducted into the internal iliac artery via bilateral femoral artery following a blood flow change with a coil. 5 FU 500 mg and l-leucovorin 125 mg/m2 were injected weekly. An average time of injections or its duration was 40 (17-74) times or 12.8 (5-23) months, respectively. Disappearance or improvement of symptoms was observed in 4 cases. A decrease of tumor size observed by CT was in 2 cases and a decrease of blood CEA level was in 3 cases. As for the complication of arterial infusion chemotherapy, dermatopathy was found in all of the cases, and sensory disturbance of lower extremities was in 3 cases, infection was in 2 cases and catheter obstruction was in 2 cases. A decrease of dosage or abundance of continuation was done during the course due to complications. Two patients with primary cancer died 1-3 years after the treatment, and 2 patients with recurrence died 7 months to 1 year after the treatment. One patient with primary cancer is continuing the treatment for the last 2 years though multiple metastatic diseases have been confirmed.

[Variation of cytokines with administration of chemotherapeutic and immuno-therapeutic drugs for colorectal cancer].

Systemic and local immunological responses were studied in patients with or without preoperative administration of chemotherapeutic and/or immunotherapeutic drugs for colorectal cancer. The plasma TGFbeta and other cytokines such as IL-2, IL-4, IL-6, IL-10, IL-12, IFN-gamma in the supernatant fluid of culture of peripheral blood mononuclear cell (PBMC) and regional lymph node were measured by the ELISA method. A systemic response of cytokines was as follows: the production of plasma TGFbeta increased in many cases by chemotherapeutic drugs with a significant elevation of the mean production. Productions of IFN-gamma, IL-2, IL-12 in the supernatant fluid of culture of PBMC increased in many cases by immunotherapeutic drugs, and that of IL-4, IL-6 increased in many cases by chemotherapeutic drugs. A local response of cytokines was as follows: the production of IL-2 by immunotherapeutic drugs was greater than that without immunotherapeutic drugs whereas the production of IL-10 by immunotherapeutic drugs was smaller than that without immunotherapeutic drugs.

[A case of locally extended rectal cancer responding to intra-arterial infusion therapy via the internal iliac artery].

Chemotherapy with combined administration of 5-FU and l-Leucovorin has been reported to be effective for advanced rectal cancer. A 61-year-old woman with a huge, locally extended advanced rectal cancer was treated with intra-arterial infusion therapy via internal iliac artery. Catheters were inserted from the bilateral femoral arteries to the opposite internal iliac arteries and the bilateral upper and lower gluteal arteries and lateral sacral artery were embolized with a metallic coil. The port was positioned under the skin of her lower abdominal wall. The chemotherapy regimen was 5-FU (500 mg/body) and l-Leucovorin (250 mg/m2), administered over 5 hours once weekly to bilateral reservoirs through an infuser pump. After 5 sessions of the chemotherapy, the perineal pain decreased and the patient no longer needed morphine. Following 34 administrations (at 10 months) of this regimen, reductions of tumor size on pelvic CT and CEA level were confirmed. Side effects of the intra-arterial infusion chemotherapy were pygal dermatitis, leg desensitization, infection of circumferential reservoir and obstruction of the catheter due to flection were observed. Local intra-arterial infusion chemotherapy via the internal iliac artery appears to be effective for local advanced rectal cancer.