Management of Patients Receiving Antiplatelet Therapy During Gastroenterological Surgery: A Multicenter Prospective Cohort Study (GSATT).

OBJECTIVE: This study aimed to evaluate the effect of continuing preoperative aspirin monotherapy on surgical outcomes in patients receiving antiplatelet therapy (APT). SUMMARY BACKGROUND DATA: The effectiveness of continuing preoperative aspirin monotherapy in patients undergoing APT in preventing thromboembolic consequences is mostly unknown. METHODS: This prospective multicenter cohort study on the Safety and Feasibility of Gastroenterological Surgery in Patients Undergoing Antithrombotic Therapy (GSATT study) conducted at 14 clinical centers enrolled and screened patients between October 2019 and December 2021. The participants (n=1,170) were assigned to the continued APT group, discontinued APT group, or non-APT group, and the surgical outcomes of each group were compared. Propensity score matching was performed between the continued and discontinued APT groups to investigate the effect of continuing preoperative aspirin therapy on thromboembolic complications. RESULTS: The rate of thromboembolic complications in the continued APT group was substantially lower than that in the non-APT or discontinued APT groups (0.5% vs. 2.6% vs. 2.9%; P=0.027). Multivariate investigation of the entire cohort revealed that discontinuation of APT (P<0.001) and chronic anticoagulant use (P<0.001) were independent risk factors for postoperative thromboembolism. The post-matching evaluation demonstrated that the rates of thromboembolic complications were significantly different between the continued and discontinued APT groups (0.6% vs. 3.3%; P=0.012). CONCLUSIONS: APT discontinuation following elective gastroenterological surgery increases the risk of thromboembolic consequences, whereas continuing preoperative aspirin greatly reduces this risk. The continuation of preoperative aspirin therapy in APT-received patients is considered one of the best alternatives for preventing thromboembolism during elective gastroenterological surgery.

Conversion to complete resection with mFOLFOX6 with bevacizumab or cetuximab based on K-RAS status for unresectable colorectal liver metastasis (BECK study): Long-term results of survival.

BACKGROUND/PURPOSE: To investigate the long-term outcome and entire treatment course of patients with technically unresectable CRLM who underwent conversion hepatectomy and to examine factors associated with conversion to hepatectomy. METHODS: Recurrence and survival data with long-term follow-up were analyzed in the cohort of a multi-institutional phase II trial for technically unresectable colorectal liver metastases (the BECK study). RESULTS: A total of 22/12 patients with K-RAS wild-type/mutant tumors were treated with mFOLFOX6 + cetuximab/bevacizumab. The conversion R0/1 hepatectomy rate was significantly higher in left-sided primary tumors than in right-sided tumors (75.0% vs 30.0%, P = .022). The median follow-up was 72.6 months. The 5-year overall survival (OS) rate in the entire cohort was 48.1%. In patients who underwent R0/1 hepatectomy (n = 21), the 5-year RFS rate and OS rate were 19.1% and 66.3%, respectively. At the final follow-up, seven patients had no evidence of disease, five were alive with disease, and 20 had died from their original cancer. All 16 patients who achieved 5-year survival underwent conversion hepatectomy, and 11 of them underwent further resection for other recurrences (median: 2, range: 1-4). CONCLUSIONS: Conversion hepatectomy achieved a similar long-term survival to the results of previous studies in initially resectable patients, although many of them experienced several post-hepatectomy recurrences. Left-sided primary was found to be the predictor for conversion hepatectomy.

Conversion to complete resection with mFOLFOX6 with bevacizumab or cetuximab based on K-ras status for unresectable colorectal liver metastasis (BECK study).

BACKGROUND: Patients with colorectal liver metastasis (CRLM) might be down-staged by chemotherapy from an initially unresectable stage to a resectable stage. Because the tumor response to preoperative chemotherapy has been correlated with resection rate, the improved efficacy from the concept that only the patients without K-ras mutations receive an anti-EGFR antibody might be expected to increase the conversion rate. The purpose of this study is to evaluate the conversion rate from unresectable CRLM to complete resection. METHODS: We conducted a multi-institutional phase II trial for unresectable CRLM. Patients received mFOLFOX6 with either bevacizumab (bev) or cetuximab (cet) based on K-ras status (UMIN000004310). Planned treatment was for six cycles during which tumors were assessed for resectability every three cycles. Patients whose disease was unresectable after six cycles switched their chemotherapy regimen from mFOLFOX6 to FOLFIRI. The primary endpoint was R0 resection rate. RESULTS: Thirty-five patients with unresectable CRLM were enrolled. A total of 22/12 patients with K-ras wild-type/mutant (wt/mt) were treated with mFOLFOX6 plus cet/bev, respectively. The overall response rate was 64.7% (wt/mt; 77.3%/41.7%, P = 0.04). In 20 patients (58.8%), hepatectomy was performed according to protocol treatment, and the conversion rate was 72.7%/33.3% in wt/mt patients, respectively (P = 0.03). Finally, 23 patients (67.6%) underwent hepatectomy, and the conversion rate was 77.2%/50.0% in wt/mt patients (P = 0.09). The overall R0 resection rate was 47.1% (wt/mt; 50.0%/41.7%, P = 0.36). CONCLUSIONS: This prospective study showed that combined chemotherapy based on K-ras status can facilitate conversion to resection in patients with unresectable CRLM.

[Long-Term Survival of a Patient with Rectal Neuroendocrine Carcinoma after Treatment with Curative Resection and Adjuvant Chemotherapy with Capecitabine].

A 63-year-old man who complained of hematochezia underwent colonoscopy, and a type 2 tumor was detected at the Rs portion. The tumor was initially diagnosed as a poorly differentiated adenocarcinoma by biopsy. Laparoscopy-assisted anterior resection with regional lymphadenectomy was performed, and pathological examination showed the tumor was a neuroendocrine carcinoma (NEC) with muscular invasion and lymph node metastasis. The Ki-67 index of the tumor was more than 70%. This patient underwent adjuvant chemotherapy with capecitabine for 6 months and is now alive without recurrence, more than 40 months after surgery. Although the prognosis of NEC is generally poor, capecitabine might be effective as an adjuvant chemotherapy regimen after curative resection.

Solitary metastatic gallbladder malignant melanoma originated from the nasal cavity: A case report.

INTRODUCTION: Solitary gallbladder metastasis of malignant melanoma is rare and generally originates from skin melanoma. We report a case of gallbladder metastasis from a malignant melanoma of the nasal mucosa that was surgically treated. PRESENTATION OF CASE: A 77-year-old Japanese woman diagnosed with malignant melanoma of the left sinonasal cavity three years ago underwent follow-up PET-CT and FDG uptake was detected only at the gallbladder. The nasal melanoma had been stable for the last 1.5 years after chemoradiation and her general condition was good. Cholecystectomy was performed with partial liver resection. Lymphadenectomy of the hepatoduodenal ligament was also performed. The tumor was soft and whitish, and was microscopically diagnosed as a poorly differentiated malignant melanoma that was not similar to the nasal cavity melanoma. No further metastasis is observed for more than 13 months after surgery. DISCUSSION: In the literature, cutaneous melanoma is described as the origin of most metastatic gallbladder melanomas; however, no skin lesion was evident in this case. We believe that the poorly differentiated compartment of the nasal melanoma had metastasized to the gallbladder. CONCLUSION: For patients with melanomas and gallbladder tumors, the possibility that metastasis could occur should be considered when selecting optimal treatment. Even when original melanoma is present, surgical treatment for gallbladder metastasis may be useful depending on the patient's conditions.

Solitary metastasis to the intercostal muscle from hepatocellular carcinoma: A case report.

INTRODUCTION: Skeletal muscle metastases from carcinomas, especially to intercostal muscles, are rare. Most metastatic chest wall tumors from hepatocellular carcinoma (HCC) result from disseminations through needle tracts of intrahepatic HCC treatments. PRESENTATION OF CASE: We report the case of a 65-year-old man with chronic viral hepatitis B whose intrahepatic lesions were stabilized by repeated radiofrequency ablations and transcatheter arterial chemoembolization. Follow-up computed tomography demonstrated a well-enhanced mass in the right chest wall. Because α-fetoprotein and des-γ-carboxy prothrombin levels were elevated and no other tumors were detected, we diagnosed the mass as an extrahepatic metastasis from the HCC and resected it along with the surrounding ribs. There was no involvement of the bone, pleura, and lung. DISCUSSION: The tumor was microscopically diagnosed as an intercostal muscle tumor metastasized from HCC, which has not been documented previously. The resection rate of extrahepatic tumors of HCC is low in literature. No other apparent extrahepatic recurrence has been observed for more than 20 months after the surgery. CONCLUSION: We report the case of HCC patient who underwent surgical resection of an intercostal muscle tumor that had metastasized from HCC. Pathological examination of the tumor revealed the tumor cells in the blood vessels, and we speculate it hematogeneous metastasis.

[Improved QOL in a case of remnant gastric cancer with common bile duct obstruction treated with weekly paclitaxel therapy and cholecystojejunostomy].

We report a patient with unresectable remnant gastric cancer with common bile duct stricture, whose quality of life(QOL) was improved by switching to cholecystojejunostomy from percutaneous transhepatic gallbladder drainage(PTGBD). He was a 69-year-old man who underwent distal gastrectomy(Billroth I reconstruction)3 years previously, and he vomited many times due to cancer at the anastomosis. It could not be resected because of its involvement with the hepatoduodenal ligament, and therefore, gastrojejunostomy was performed. Four days later, abdominal pain occurred and gallbladder swelling was observed, resulting from common bile duct obstruction. PTGBD relieved the pain, and four courses of S-1/cisplatin (CDDP)treatment were performed. The bile duct stenosis was still so severe that the chemotherapy regimen was changed to weekly paclitaxel(PTX). The bile amount of PTGBD decreased after its four courses and the tube, which was a great burden for the patient, was removed. Because abdominal pain recurred in 2 weeks, the tube needed to be reinserted. An endoscopic stent was not inserted successfully. We performed cholecystojejunostomy and he was finally free from the PTGBD tube. The spread of cancer to the cystic duct was controlled by continuing the PTX for more than 20 courses. Thus, this case highlights PTX's contribution toward improving the patient's QOL.

[Three cases effectively treated with S-1 therapy for liver metastasis of breast cancer in long term].

We experienced 3 cases of anti-cancer drug-resistant recurrent breast cancer with liver metastasis showing significant improvement by S-1. Almost all patients maintained the full dose through the whole course of treatment, and the drug showed good tolerability. Furthermore, long-term therapeutic efficacy(more than 2 years)and QOL have been maintained for all patients. We concluded that S-1 is not only effective as a therapeutic agent, but is safe and maintains QOL.

Gastric carcinoid with hypergastrinemia: report of three cases.

We report 3 cases of gastric carcinoids with hypergastrinemia. Case 1: A 60-year-old man had a 2 cm carcinoid of the stomach and underwent partial resection. Involvement of the muscularis propria and lymph nodes metastasis were observed microscopically. Follow-up gastroscopy revealed another carcinoid lesion and total gastrectomy was performed. Case 2: A 67-year-old woman with multiple carcinoids of the entire stomach underwent antrectomy. No growth of residual tumors has been detected so far. Case 3: A 61-year-old man had a tumor near the esophagogastric junction and underwent total gastrectomy. Carcinoid component was diffusely intermingled with adenocarcinoma in the tumor and invaded into the subserosa. In all 3 cases, the serum gastrin level was high and atrophic gastritis was microscopically observed. Carcinoid tumor in Case 3 was different from those in Cases 1 and 2 and interestingly, gastric carcinoid with hypergastrinemia showed various types of appearance.

[A case of advanced ascending colon cancer, curatively resected after complete response in left supraclavicular and paraaortic lymph nodes and liver metastases to FOLFOX4 therapy].

We report a resected case of ascending colon cancer with left supraclavicular and paraaortic lymph nodes and liver metastases which completely responded in terms of metastases but not the primary tumor to FOLFOX4 therapy. A 62-year-old woman with epigastric discomfort was initially diagnosed as malignant lymphoma by FDG-PET with abnormal accumulation at left supraclavicular and paraaortic lesions. Pathological examination of the supraclavicular lymph nodes showed undifferentiated adenocarcinoma, and ascending colon cancer was detected by colonoscopy which was a mixture of various types of differentiation. FOLFOX4 therapy was effective for metastatic lesions but colon tumor did not regress and was accompanied by abdominal pain. Macroscopically, a curative right hemicolectomy was performed, and microscopic examination revealed that the tumor had become a mass of undifferentiated cancer cells. Thus, the present case demonstrates the dedifferentiation of colon cancer during chemotherapy.

Systemic antitumor effect of intratumoral injection of dendritic cells in combination with local photodynamic therapy.

PURPOSE: Photodynamic therapy (PDT), which is used clinically for the palliative treatment of cancer, induces local tumor cell death but has no effect on tumors in untreated sites. The purpose of this study was to determine if local PDT followed by intratumoral injection of naïve dendritic cells (IT-DC) induces systemic antitumor immunity that can inhibit the growth of untreated as well as PDT + IT-DC-treated tumors. EXPERIMENTAL DESIGN: BALB/c or C57Bl/6 mice were injected s.c. with CT26 colorectal carcinoma cells and B16 melanoma cells, respectively, and following 10 to 12 days of tumor growth, the tumors were treated with PDT alone or PDT followed by IT-DC or IT-PBS. In other studies, tumors were established simultaneously in both lower flanks or in one flank and in the lungs, but only one flank was treated. RESULTS: Whereas neither PDT nor IT-DC alone was effective, PDT + IT-DC eradicated both CT26 and B16 tumors in a significant proportion of animals and prolonged the survival of mice of which the tumors were not cured. The spleens of mice treated with PDT + IT-DC contained tumor-specific cytotoxic and IFN-gamma-secreting T cells whereas the spleens of control groups did not. Moreover, adoptive transfer of splenocytes from successfully treated CT26 tumor-free mice protected naïve animals from a subsequent challenge with CT26, and this was mediated mainly by CD8 T cells. Most importantly, PDT plus IT-DC administered to one tumor site led to tumor regression at distant sites, including multiple lung metastases. CONCLUSIONS: PDT + IT-DC induces potent systemic antitumor immunity in mice and should be evaluated in the treatment of human cancer.

In vivo manipulation of dendritic cells overcomes tolerance to unmodified tumor-associated self antigens and induces potent antitumor immunity.

Most tumor-associated Ags are self proteins that fail to elicit a T cell response as a consequence of immune tolerance. Dendritic cells (DCs) generated ex vivo have been used to break tolerance against such self Ags; however, in vitro manipulation of DCs is cumbersome and difficult to control, resulting in vaccines of variable potency. To address this problem we developed a method for loading and activating DCs, in situ, by first directing sufficient numbers of DCs to peripheral tissues using Flt3 ligand and then delivering a tumor-associated Ag and oligonucleotide containing unmethylated CG motifs to these tissues. In this study, we show in three different tumor models that this method can overcome tolerance and induce effective antitumor immunity. Vaccination resulted in the generation of CD8(+) T and NK cell effectors that mediated durable tumor responses without attacking normal tissues. These findings demonstrate that unmodified tumor-associated self Ags can be targeted to DCs in vivo to induce potent systemic antitumor immunity.

Induction of potent antitumor immunity by in situ targeting of intratumoral DCs.

Recent reports of tumor regression following delivery of autologous tumor antigen-pulsed DCs suggest that defective antigen presentation may play a key role in tumor escape. Here we show in two different murine tumor models, CT26 (colon adenocarcinoma) and B16 (melanoma), that the number and activation state of intratumoral DCs are critical factors in the host response to tumors. We used CCL20/macrophage inflammatory protein-3alpha (MIP-3alpha) chemokine to increase the number of tumoral DCs and intratumoral injections of CG-rich motifs (CpGs) to activate such cells. Expression of CCL20 in the tumor site attracted large numbers of circulating DCs into the tumor mass and, in the case of CT26 tumors, led to complete tumor regression. Intratumoral CpG injections, in addition to CCL20, were required to induce therapeutic immunity against B16 tumors. In this model CpG overcame tumor-mediated inhibition of DC activation and enabled tumoral DCs to cross-present tumor antigens to naive CD8 T cells. CpG activation of tumoral DCs alone was not sufficient to induce tumor regression in either tumor model, nor was systemic delivery of the DC growth factor, Flt3 ligand, which dramatically increased the number of circulating DCs but not the number of tumoral DCs. These results indicate that the number of tumoral DCs as well as the tumor milieu determines the ability of tumor-bearing hosts to mount an effective antitumor immune response. Our results also suggest that DCs can be manipulated in vivo without delivery of defined tumor antigens to induce a specific T cell-mediated antitumor response and provide the basis for the use of chemokines in DC-targeted clinical strategies.

Dendritic cells coinjected with tumor cells treated with an anticancer drug to induce tumor rejection.

PURPOSE: We examined whether bone marrow-derived dendritic cells (DCs) could induce antitumor immunity when a chemotherapeutic drug was added. METHODS: CT26 (a murine colon cancer cell line syngeneic with BALB/c) and CT26-bearing mice were treated with mitomycin C (MMC) intraperitoneally (i.p.). Next, mice immunized with a coinjection of DCs and MMC-treated CT26 (i.p.) were given an intradermal inoculation of CT26. Finally, CT26-bearing mice were treated with MMC (i.p.) with or without DCs, given peritumorally. RESULTS: Although the inoculated tumor was not rejected in the control mice, CT26 was rejected in 50% of the mice injected with MMC alone. Apoptosis was observed in the MMC-treated CT26 cells in vitro and in vivo. Immunization with DCs and apoptotic CT26 cells, but not with apoptotic CT26 alone, gave protection against tumor challenge in 7 of 13 mice. A significantly higher level of cytotoxic T-cell activity and interferon-gamma production was seen in the protected mice. When MMC (i.p.) treatment was followed by peritumoral DC injection in the CT26-bearing mice, remarkable therapeutic effects were observed. CONCLUSION: DCs can collaborate with chemotherapy-induced apoptotic tumor cells and elicit improved antitumor immunity, probably through the acquisition of tumor-associated antigens from apoptotic tumor cells.

Interleukin-12-gene transduction makes DCs from tumor-bearing mice an effective inducer of tumor-specific immunity in a peritoneal dissemination model.

Dendritic cells (DCs) from cancer patients, as well as tumor-infiltrating DCs, are reported to have suppressed immunostimulatory capacity. One of the major problems in the clinical use of DCs for treating tumors is that the DCs must be autologous ones obtained from patients. Compared with normal DCs (nDCs), flow-cytometric analysis and allogeneic mixed lymphocyte reaction (MLR) have revealed lower expression of the costimulatory molecules and suppressed T-cell-stimulatory activity in DCs derived from tumor-bearing mice (tDCs) despite of culture. We reported previously that the interleukin-12 (IL-12)-gene-transduced nDCs inhibited tumor growth due to induced tumor-specific Th1 and cytotoxic T cells (CTLs) in a murine established subcutaneous tumor model. In the present study, we examined whether tDCs could induce immune responses against tumors after IL-12-gene transduction in an established peritoneal dissemination model. The intraperitoneal injection of IL-12-gene-transduced tDCs resulted in prolonged survival of some treated mice (log-rank test; P=0.001) and tumor-specific Th1 and CTL activity. The injection of IL-12-gene-transduced nDCs prolonged the survival of all treated mice (P<0.0001) and elicited tumor-specific immunity, which were better than those of IL-12-gene-transduced tDCs. Taken together, DC modification of IL-12-gene transduction is an effective and promising approach for cancer therapy even when immunosuppressive tDCs are employed.