[A Case of Long-Term Survival Achieved by Aggressive Surgical Treatment for Late Recurrence Following Initial Surgery for Breast Cancer].

We herein report a patient with postoperative late recurrence ofbreast cancer that was resistant to systemic therapy who achieved long-term survival after aggressive surgical treatment. A 53-year-old woman underwent modified muscle-preserving radical mastectomy for right breast cancer in May 1999. Adjuvant therapy with oral anticancer agents and an antiestrogen were initiated. Since the patient was recurrence free for 5 years postoperatively, only the administration of antiestrogen was continued. In November 2007, the administration oforal anticancer agents was resumed on the suspicion ofmetastasis to the right supraclavicular node. Although cyclophosphamide, epirubicin, and 5-fluorouracil(CEF)therapy plus an oral aromatase inhibitor was initiated in February 2008, lymph node enlargement was noted. As other forms of chemotherapy did not produce a favorable response, the patient underwent cervical lymphadenectomy in December 2009. As repeated recurrences were observed thereafter, surgical excisions of the right cervical mass were performed in January, March, and April 2010. In December 2013, right cervical lymphadenectomy was performed. Histological findings of all the excised specimens were consistent with breast cancer metastasis. Since then, the patient has been well without recurrence, although she continues to receive aromatase inhibitor treatment.

[Peritoneal Cancer Resected as a Greater Omentum Mass-Report of a Patient Surviving Long Term without Recurrence].

We present an interesting case in which a patient diagnosed with primary peritoneal cancer after the resection of a greater omentum mass achieved recurrence-free survival without postoperative systemic chemotherapy. The patient was a 78-yearold woman with no history ofmalignant disease. She underwent abdominal ultrasound at a local clinic, which revealed a mass shadow near the descending colon. She was referred to us in May 2014. Contrast-enhanced abdominal computed tomography showed a homogeneously enhanced soft-tissue mass measuring 94×80×34mm in size in the left lower abdomen, which did not connect to the gastrointestinal tract. In June 2014, a gastrointestinal stromal tumor was suspected, and laparotomy was performed. Laparotomy findings suggested a tumor originating from the greater omentum and no evidence of perifocal invasion. The tumor was resected with the surrounding greater omentum. Pathological examination revealed very poorly differentiated adenocarcinoma, also consistent with ovarian serous adenocarcinoma. No lesions were detected in any other organs by pre- and postoperative examinations, and the patient was diagnosed with primary peritoneal cancer. As the patient refused to receive postoperative systemic chemotherapy, we decided to continue with follow-up only. The patient was alive without recurrence as ofApril 2018.

[Complete Response Achieved with Oral Anticancer Monotherapy for Unresectable Lymph Node Metastasis after Cecal Cancer Surgery - A Case Report].

We herein report an interesting case in which a complete response was achieved with oral anticancer monotherapy for unresectable lymph node metastasis after surgery for cecal cancer. A 78-year-old woman was referred to our hospital to undergo a detailed examination for anemia. The examination led to a diagnosis of cecal cancer. She underwent open right hemicolectomy combined with adjacent abdominal wall resection and reconstruction of abdominal wall defects the next month. During follow-up without adjuvant therapy at her request, right iliac lymph node metastasis was detected 5 months later. A lymphadenectomy by laparotomy was attempted 6 months later but ended as only an exploratory laparotomy because the metastatic lymph node was difficult to detach from the vascular wall. Starting the next month, oral anticancer monothera- py(TS-1, 80mg/day for 2weeks followed by 1week of rest)was started at the patient's request. Abdominal ultrasonography performed in March 2011 revealed no evidence of lymphadenopathy, and subsequent imaging tests also confirmed the absence of lymphadenopathy. The anticancer monotherapy was discontinued after 4 years of medication. The patient remains alive, after 3 years and 5 months of medication to date, without recurrence.

[A case of liver and para-aortic lymph node metastasis of colorectal cancer responding to S-1].

A 78-year-old woman was diagnosed with liver and para-aortic lymph node metastasis of colorectal cancer via abdominal computed tomography (CT) during a post-operative follow-up. She and her family declined intensive chemotherapy. Therefore, reduced S-1 (80 mg/body/day) was administered for 2 weeks followed by a 2 week interval. After 5 courses, CT revealed a complete response for the liver metastasis and a partial response for the para-aorticlymph node metastasis. Twenty-four courses of chemotherapy were completed, and only a follow-up CT examination was performed. The paraaorticlymph node grew larger, but the liver metastasis did not reappear. Herein, we report a case that showed a good response to S-1.

[A case of HER2-positive advanced gastric cancer successfully treated via capecitabine, cisplatin, and trastuzumab combination chemotherapy].

We report a case of human epidermal growth factor receptor 2 (HER2) -positive advanced gastric cancer effectively treated via capecitabine, cisplatin, and trastuzumab (XPT) chemotherapy followed by curative gastrectomy. The patient was a 66- year-old man with type 2 gastric cancer in the greater curvature of the gastric angle. Biopsy revealed that the tumor was a well or moderately differentiated adenocarcinoma, and immunohistochemistry showed positive expression of HER2(3+). Chest and abdominal computed tomography(CT)showed a liver tumor 21×9 mm in size in the caudate lobe and swollen lymph nodes in the paragastric, para-aortic, and left supraclavicular regions. After 4 courses of XPT, a clinical complete response was obtained. The patient received additional 13 courses of trastuzumab and capecitabine and underwent Billroth I distal gastrectomy with D2 lymph node dissection and resection of the para-aortic and left supraclavicular lymph nodes. Liver metastasis was not detected. No residual cancer cells were found in the stomach or lymph nodes except for the left supraclavicular lymph nodes. Pathological classification according to the Japanese Classification of Gastric Carcinoma, 14 th edition, was ypT0, ypN0, ypM1(LYM), Grade 2, ypStage IV. The patient developed a post-operative anastomotic leakage that required drainage via laparotomy, but was discharged 76 days after surgery in good condition.

[Report of a successful case of multidisciplinary therapy for a patient with lung and liver metastasis from rectal adenocarcinoma].

A strategy of multidisciplinary therapy is considered necessary for the longer survival of a patient diagnosed with advanced colorectal cancer. We report a successful multi-disciplinary therapy case of a 70's-year-old male who received pulmonary resection for metastatic lung cancer twice after primary resection for rectal cancer. Solitary metastatic liver cancer with portal vein tumor thrombus (PVTT) was diagnosed 5 years and 4 months after primary surgery. Although systemic chemotherapy was started immediately, disease control was poor and local pulmonary recurrence appeared. Although intrahepatic metastasis was considered the most important prognostic factor, radiation therapy against PVTT (50 Gy) was initially performed to control disease. After verifying that no new recurrent lesions had arisen during radiation therapy, a third pulmonary resection (in the left upper remnant lobectomy)was performed. Hepatectomy(in the right lobectomy)was then performed for curative purposes. Pathological efficacy of radiation therapy to PVTT was revealed as GradeIb according to Evans' classification. In accordance with the patient's request, no adjuvant treatment was planned. Seven years after primary resection no sign of recurrence is evident. Radiation therapy is suggested to be most useful for disease control and patient selection.

[Long-term survival of a case of advanced cancer of the esophagogastric junction with complete response to low-dose 5-fluorouracil and cisplatin chemotherapy].

A 58-year-old man was admitted to the author's institution with complaints of dysphagia and tarry stool. An advanced squamous cell carcinoma of the esophagogastric junction was revealed by endoscopy. The clinical stage was GE, T4, N1, H0, M0, cStageIVa, according to the Japanese Classification of Esophageal Cancer. Low-dose FP chemotherapy(continuous 5-FU div of 500mg/day with intermittent CDDP div of 10mg/day)was used. The tumor size was remarkably reduced while the side effects were trivial. A clinically complete response was recognized with CT and with pathological findings from endoscopic biopsy. As a recurrence was diagnosed in the off-treatment period, the same regimen was resumed. Soon, a complete response was again. The patient is doing well with no reoccurrence after almost 10 years, with a low-dose FP chemotherapy.

Treatment for gastric carcinoma in the oldest old patients.

BACKGROUND: The strategy for treating extremely aged patients with gastric carcinoma is controversial. This study reviews the prognoses of patients aged 85 years and older who were diagnosed with gastric carcinoma. METHODS: One hundred seventeen patients aged 85 years and older were diagnosed as having gastric carcinoma after 1969 in our institution. After excluding those at stage IV, 36 cases underwent curative resection and 30 cases received best supportive care (BSC), which we reviewed retrospectively. RESULTS: Surgical methods included distal gastrectomy for 28 cases, total gastrectomy for five cases, and other procedures for three cases. Postoperatively, pneumonia developed in four cases, anastomotic leakage in two cases, and pancreatic fistula in one case. Two patients died of pneumonia within 1 month of surgery. Univariate analysis demonstrated that age, surgery, performance status, and sodium level were statistically significant prognostic factors. Multivariate analysis demonstrated that surgery was the only independent prognostic factor. When patients with a performance status of 4 were excluded, the clinical characteristics of the surgery group (n = 36) and BSC group (n = 20) were statistically identical, and the overall survival was significantly better in the surgery group (p = 0.0078). CONCLUSIONS: Postoperative outcomes were relatively acceptable. Surgery may be feasible and beneficial even for extremely aged patients 85 years and older, except for those with a performance status of 4.

[An autopsied case of giant small cell carcinoma of the pancreas].

A 58-year-old man who complained of an abdominal tumor was admitted to our hospital. Abdominal CT scan showed that a 15-cm tumor occupied the entire right upper abdomen and that there were ascites and liver metastases. A liver biopsy was performed. The liver biopsy showed a small cell carcinoma pattern, but no definitive origin of the tumor was determined. Considering the extensive peritoneal invasion and multiple liver metastases, he received 2 / courses of cisplatin/etoposide chemotherapy, but his tumor became larger with concomitant abdominal pain and nausea. The patient suddenly died due to multiple organ failure caused by tumor necrosis. The autopsy revealed a pathological diagnosis of primary small cell carcinoma of the pancreas.

[A case of stage IV advanced gastric cancer responding to TS-1/CDDP neoadjuvant chemotherapy which leads to a pathological complete response].

A 72-year-old male with advanced gastric cancer (cT3N2M0H0P0CY1, cStage IV) was treated with TS-1/CDDP as neoadjuvant chemotherapy. TS-1 (60 mg/m(2)/day) was orally administered for 3 weeks followed by 2 drug free weeks as a course, and CDDP (60 mg/m(2)) was administered by intravenous drip on day 8. After the fourth course,a significant tumor reduction was obtained. Total gastrectomy, splenectomy, and D 2 type nodal dissection were performed. The histological diagnosis revealed complete disappearance of cancer cells in the stomach and all of the lymph nodes, which is a so-called pathological complete response. The patient has now been in good health without a recurrence for 24 months after surgery. This case suggests that neoadjuvant chemotherapy with TS-1/CDDP is a potential regimen for advanced gastric cancer.

[A case of advanced gastric cancer with peritoneal dissemination responding to S-1/CDDP neoadjuvant chemotherapy].

The patient was a 72-year-old male diagnosed with type III poorly-differentiated adenocarcinoma in the lesser curvature by gastric fiberscopy. An abdominal computed tomography (CT) scan showed the thickness of the gastric wall and the enlarged lymph node around the stomach and laparoscopic examination revealed peritoneal dissemination. The patient received neoadjuvant combined chemotherapy with S-1 and CDDP. S-1 (100 mg/day) was orally administered for 3 weeks followed by 2 drug-free weeks as a course, and CDDP (100 mg/body) was administered by intravenous drip on day 8. After the third course, significant tumor reduction was obtained. Total gastrectomy, splenectomy and D2 nodal dissection were performed. Peritoneal dissemination disappeared, and the histological diagnosis revealed complete disappearance of cancer cells in the ascites and no metastasis in all lymph nodes. The patient has now been in good health with no recurrence for 22 months after surgery. The combined neoadjuvant chemotherapy with S-1 and CDDP can be an effective treatment of choice for advanced gastric carcinoma with peritoneal dissemination.

[Case report of advanced breast cancer responding to capecitabine and trastuzumab combination therapy].

We conducted a concomitant administration of capecitabine (2,400 mg/day for 21 days followed by a 7-day interval) and trastuzumab (2 mg/kg weekly) to a 73-year-old female patient with impaired lower limb function diagnosed with bilateral breast cancer. The patient had a complete response (CR) to pulmonary metastases, and carcinoembryonic antigen (CEA) level had normalized from 46.4 ng/ml to 0.6 ng/ml. Left mastectomy was performed in order to control bleeding from tumors. No adverse events attributable to medication were observed. The concomitant administration of capecitabine and trastuzumab is a promising therapy with the potential to greatly improve patient quality of life (QOL).

[Combined chemotherapy with weekly Paclitaxel and doxifluridine for advanced and recurrent gastric cancers].

We conducted combined therapy of weekly paclitaxel and doxifluridine (5'-DFUR) for 23 cases of advanced and recurrent gastric carcinomas to investigate their efficacy and safety. Subjects included 7 unresectable cases, 5 noncurative resection cases, and 11 recurrent cases. Twenty of the 23 subjects had a history of prior treatment with another anticancer drug. The treatment regime consisted of one course comprising 70 mg/m(2)of paclitaxel weekly for three consecutive weeks followed by one week rest, combined with 800 mg/day of 5'-DFUR orally. Results revealed a response rate of 17.6% (3/17), with 2 cases of CR, 1 case of PR, 10 cases of NC, and 4 cases of PD. One of the CR cases was an unresectable case involving a primary tumor, liver metastasis, and abdominal lymph node metastasis, while the other was a recurrent case involving abdominal lymph node metastasis. The median survival period was 387 days. The one-and two-year survival rates were 52% and 24%, respectively. In terms of adverse effects, there were only single cases of grade 3 leukopenia and grade 3 neutropenia, with no cases of grade 4 hemotoxicity. Both patients could be treated as outpatients. Combination therapy of weekly paclitaxel and 5'-DFUR can be an effective and safe therapy for advanced and recurrent gastric carcinomas.

Local delivery of plasmid DNA into rat carotid artery using ultrasound.

BACKGROUND: Although viral vector systems are efficient to transfect foreign genes into blood vessels, safety issues remain in relation to human gene therapy. In this study, we examined the feasibility of a novel nonviral vector system by using high-frequency, low-intensity ultrasound irradiation for transfection into blood vessels. METHODS AND RESULTS: Luciferase plasmid mixed with or without echo contrast microbubble (Optison) was transfected into cultured human vascular smooth muscle cells (VSMC) and endothelial cells (EC) with the use of ultrasound. Interestingly, luciferase activity was markedly increased in both cell types treated with Optison. We then transfected luciferase plasmid mixed with Optison by means of therapeutic ultrasound into rat artery. Two days after transfection, luciferase activity was significantly higher in carotid artery transfected with luciferase gene with Optison and ultrasound than with plasmid alone. In addition, we transfected an anti-oncogene (p53) plasmid into carotid artery after balloon injury as a model of gene therapy for restenosis. Two weeks after transfection, the intimal-to-medial area ratio in rats transfected with wild-type p53 plasmid complexed with Optison by means of ultrasound was significantly decreased as compared with control, accompanied by a significant increase in p53 protein. No apparent toxicity such as inflammation could be detected in blood vessels transfected with plasmid DNA with ultrasound and Optison. CONCLUSIONS: Overall, we demonstrated that an ultrasound transfection method with Optison enhanced transfection efficiency of naked plasmid DNA into blood vessels without any apparent toxicity. Transfection of p53 plasmid with the use of this method should be useful for safe clinical gene therapy without a viral vector system.

Enhanced therapeutic angiogenesis by cotransfection of prostacyclin synthase gene or optimization of intramuscular injection of naked plasmid DNA.

BACKGROUND: Although clinical trials of therapeutic angiogenesis by angiogenic growth factors with intramuscular injection of naked plasmid DNA have been successful, there are still unresolved problems such as low transfection efficiency. From this viewpoint, we performed the following modifications: (1) combination with vasodilation using prostacyclin and (2) changing the agents or volume of naked plasmid DNA in vivo. METHODS AND RESULTS: First, we examined cotransfection of the VEGF gene with the prostacyclin synthase gene in a mouse hindlimb ischemia model. Cotransfection of the VEGF gene with the prostacyclin synthase gene resulted in a further increase in blood flow and capillary density compared with single VEGF gene. Similar results were obtained with other angiogenic growth factors, such as hepatocyte growth factor (HGF). Alternatively, we changed the injection volume of the solution of plasmid DNA. Luciferase activity was increased in a volume-dependent manner. An increase in injection volume at 1 site rather than separate injections at multiple sites resulted in high transfection efficiency, which suggests that transfection of naked plasmid DNA is mediated by pressure. Interestingly, treatment with hyperbaric oxygen increased the transfection efficiency. Finally, we also examined the effects of different solutions. Saline and PBS, but not water, achieved high transfection efficiency. In addition, sucrose solution but not glucose solution resulted in high luciferase activity. CONCLUSIONS: Overall, angiogenesis might be enhanced by cotransfection of prostacyclin synthase gene or an increase in injection volume and osmotic pressure. These data provide important information for the clinical application of therapeutic angiogenesis to treat peripheral arterial disease.

Increase in peripheral blood flow by intravenous administration of prostaglandin E1 in patients with peripheral arterial disease, accompanied by up-regulation of hepatocyte growth factor.

Since endothelial damage is a trigger for the progression of atherosclerosis, we evaluated the clinical utility of prostaglandin E1 (PGE1) in relation to peripheral blood flow and regulation of hepatocyte growth factor (HGF), an angiogenic growth factor, in patients with peripheral arterial disease (PAD). Fourteen male patients with PAD who showed the characteristic symptoms of arteriosclerosis obliterans (Fontaine I: n=2; Fontaine II: n=4; Fontaine III: n=2; Fontaine IV: n=6), confirmed by angiography, were enrolled in this study. Patients were administrated synthetic PGE1 at a dose of 120 microg per day for 14 consecutive days. Measurement of peripheral blood flow and serum HGF concentration was performed before PGE1 treatment and after 14 days of administration. Interestingly, intravenous administration of PGE1 for 2 weeks significantly increased the blood flow as assessed by a laser Doppler imager (p<0.01). In patients with Fontaine III and IV, serum HGF concentration was significantly higher than that in patients with Fontaine I or II and normal subjects. Of importance, administration of PGE1 further increased serum HGF concentration as compared to that before treatment (p<0.01). The increase in circulating HGF might work as a compensatory mechanism to decrease local HGF expression in patients with PAD, since HGF acts as an angiogenic growth factor with anti-apoptotic actions on endothelial cells. Moreover, to confirm the stimulatory effect of PGE1 on HGF in vessels, we employed an in vitro culture system. PGE1 increased HGF production and the growth of human cultured vascular endothelial cells. The stimulatory effect of PGE1 on HGF production might be due to an increase in cAMP, since forskolin and 8-bromo-cAMP induced HGF production. In conclusion, we demonstrated that administration of PGE1 stimulated peripheral blood flow, accompanied by an increase in systemic HGF concentration. Also, our in vitro data suggested that PGE1 augmented not only the systemic HGF level, but also local HGF production, probably through cAMP accumulation, resulting in improvement of endothelial function and blood flow.

Rad51 siRNA delivered by HVJ envelope vector enhances the anti-cancer effect of cisplatin.

BACKGROUND: Every cancer therapy appears to be transiently effective for cancer regression, but cancers gradually transform to be resistant to the therapy. Cancers also develop machineries to resist chemotherapy. Short interfering RNA (siRNA) has been evaluated as an attractive and effective tool for suppressing a target protein by specifically digesting its mRNA. Suppression of the machineries using siRNA may enhance the sensitivity to chemotherapy in cancers when combined with an effective delivery system. METHODS: To enhance the anti-cancer effect of chemotherapy, we transferred siRNA against Rad51 into various human cancer cells using the HVJ (hemagglutinating virus of Japan, Sendai virus) envelope vector in the presence or absence of cis-diamminedichloroplatinum(II) (CDDP, cisplatin). The inhibition of cell growth was assessed by a modified MTT assay, counting cell number, or fluorescence-activated cell sorting (FACS) analysis after Annexin V labeling. The synthetic Rad51 siRNA was also introduced into subcutaneous tumor masses of HeLa cells in SCID mice with or without intraperitoneal injection of CDDP, and tumor growth was monitored. RESULTS: When synthetic Rad51 siRNA was delivered into HeLa cells using the HVJ envelope vector, no Rad51 transcripts were detected on day 2, and Rad51 protein completely disappeared for 4 days after siRNA transfer. When HeLa cells were incubated with 0.02 microg/ml CDDP for 3 h after siRNA transfer, the number of colonies decreased to approximately 10% of that with scrambled siRNA. The sensitivity to CDDP was enhanced in various human cancer cells, but not in normal human fibroblasts. When Rad51 siRNA was delivered into tumors using the HVJ envelope vector, the Rad51 transcript level was reduced to approximately 25%. Rad51 siRNA combined with CDDP significantly inhibited tumor growth when compared to siRNA or CDDP alone. CONCLUSIONS: Rad51 siRNA could enhance the sensitivity to CDDP in cancer cells both in vitro and in vivo. Our results suggest that the combination of CDDP and Rad51 siRNA will be an effective anti-cancer protocol.

Enhanced tumor-specific long-term immunity of hemagglutinating [correction of hemaggluttinating] virus of Japan-mediated dendritic cell-tumor fused cell vaccination by coadministration with CpG oligodeoxynucleotides.

Immunization with dendritic cells (DCs) using various Ag-loading approaches has shown promising results in tumor-specific immunotherapy and immunoprevention. Fused cells (FCs) that are generated from DCs and tumor cells are one of effective cancer vaccines because both known and unknown tumor Ags are presented on the FCs and recognized by T cells. In this study, we attempted to augment antitumor immunity by the combination of DC-tumor FC vaccination with immunostimulatory oligodeoxynucleotides containing CpG motif (CpG ODN). Murine DCs were fused with syngeneic tumor cells ex vivo using inactivated hemagglutinating virus of Japan (Sendai virus). Mice were intradermally (i.d.) immunized with FCs and/or CpG ODN. Coadministration of CpG ODN enhanced the phenotypical maturation of FCs and unfused DCs, and the production of Th1 cytokines, such as IFN-gamma and IL-12, leading to the induction of tumor-specific CTLs without falling into T cell anergy. In addition, immunization with FCs + CpG ODN provided significant protection against lethal s.c. tumor challenge and spontaneous lung metastasis compared with that with either FCs or CpG ODN alone. Furthermore, among mice that rejected tumor challenge, the mice immunized with FCs + CpG ODN, but not the mice immunized with FCs or CpG ODN alone, completely rejected tumor rechallenge, indicating that CpG ODN provided long-term maintenance of tumor-specific immunity induced by FCs. Thus, the combination of DC-tumor FCs and CpG ODN is an effective and feasible cancer vaccine to prevent the generation and recurrence of cancers.