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The incidence, morbidity, and mortality of colorectal cancer are increasing, largely owing to an increasingly aging population. Additionally, along with the increasing age of cancer patients, the number of patients with various comorbidities such as membranous nephropathy is also rising, and problems associated with the administration of chemotherapy to elderly patients with these conditions are becoming more common. Herein, we describe a case involving an 80-year-old woman who presented with general malaise, edematous limbs, and pleural effusion. An abdominal CT revealed multiple, relatively large, metastatic lesions in a wide area of the liver and left pleural effusion, and she was accordingly diagnosed with membranous nephropathy secondary to ascending colon cancer and multiple liver metastases. Despite her advanced age and the presence of membranous nephropathy, her general condition was favorable and chemotherapy was hence administered. Taking the toxicity profiles and the patient's preference into consideration, S-1 and oxaliplatin (SOX) therapy was selected, which showed a good tolerability. An abdominal CT after 8 cycles of SOX therapy revealed a marked reduction in the metastatic lesions in the liver and a decrease in the left pleural effusion, and the levels of tumor markers also decreased (partial response). At the latest follow-up, after the completion of 16 cycles, the condition of the patient remained stable, without any apparent signs of progressive disease. Based on this case, we conclude that, even for elderly patients with systemic complications or comorbid diseases, standard treatments should be considered after their general conditions, and therapeutic regimens have been sufficiently examined.

Background It has been shown that lenvatinib is effective in patients with radioactive iodine- (RAI) refractory differentiated thyroid cancer; however, there are few reports of its use in clinical practice. Purpose We investigated the efficacy, toxicity, and optimal dose of lenvatinib that had been administered for differentiated thyroid cancer in our hospital. Method We examined dose reduction, dose-limiting toxicity (DLT), optimal dose, response rate (RR), and disease control rate (DCR) in 10 patients who had received lenvatinib for differentiated thyroid cancer from January 2016 to December 2018. Results The mean patient age was 70.5 (50-80) years; there were four men and three women, and all had papillary thyroid cancer. Eight patients had received RAI. In all cases, the starting dose of lenvatinib was 24 mg/day; all patients required interruption and dose reduction. DLT was related to arthralgia in one patient, hand-foot syndrome in one, hypertension in one, and proteinuria in seven. The mean optimal dose of lenvatinib was 10.4 mg/day; 14 mg/day in two patients, 10 mg/day in six, and 8 mg/day in two. The mean interval to optimal dose was 2.4 (1.4-4.7) months. The RR was 40% (partial response in four patients and stable disease in six), making the DCR 100%. Seven patients continued receiving lenvatinib therapy. Discussion In the SELECT study, 67.8% of participants receiving lenvatinib required dose reduction; the mean dose was 17.2 mg/day. However, in the present study, dose reduction was required in all 10 patients, the mean optimum dose being 10.4 mg/day. Conclusion We consider that revision of starting doses and guidelines for reducing the dose of lenvatinib for differentiated thyroid cancer may be necessary.

3548 Background: Elderly patients are often intolerable in combination of cytotoxic agents. Recently, Trifluridine/tipiracil plus bevacizumab has been shown as good candidate for the vulnerable patients. We aimed to assess the efficacy and safety of trifluridine/tipiracil plus bevacizumab in elderly patients with metastatic colorectal cancer. Methods: Patients aged 70 years and older with previously untreated, unresectable, metastatic colorectal cancer, who were not deemed to be candidates for oxaliplatin-based or irinotecan-based chemotherapy regimens, were included in this trial. Treatment consisted of trifluridine/tipiracil (35 mg/m2 orally a day on day 1-5 and day 8-12) with bevacizumab (5mg/kg intravenously on day 1 and day 15), given every 4 weeks until disease progression. The primary endpoint was progression-free survival (PFS). The secondary endpoints were response rate (ORR), Overall survival (OS) and adverse events (AEs). Results: Between 2017 January and 2018 March, 39 patients were enrolled in this study. The characteristics of patients were male/female : 17/22, median age : 77.5 (range: 70-88) and PS: 0/1 : 31/8. The ORR of 37 patients were assessed by the central review committee. The best response was 40.5(15/37) % (95% CI: 24.8-57.9), and the disease control rate was 86.5 (32/37) % (95% CI: 71.2–95.5). The AEs which were frequent as grade 3 or 4 were leucopenia (71.8 %), neutropenia (48.7 %), anorexia (12.8 %), febrile neutropenia (10.3 %) and fatigue (10.3 %). No treatment related death was reported. Conclusions: The combination of trifluridine/tipiracil plus bevacizumab is an effective and well-tolerated regimen for elderly patients with metastatic colorectal cancer. Hematological adverse events were need for caution. The primary endpoint of PFS will be presented in the end of this year. Clinical trial information: UMIN000025241.

A 69-year-old man underwent right hemicolectomy for ascending colon cancer with liver metastases. Postoperative systemic chemotherapy did not reduce the metastases, and therefore, hepatic arterial infusion chemotherapy (HAI) was administered. The metastases decreased in size after 26 rounds of therapy, and the patient underwent resection. He is recurrence-free 63 months after the primary operation. A 57-year-old man underwent Hartmann's operation for sigmoid colon cancer with liver metastases. He underwent hepatic left lobe resection after metastases reduction by systemic chemotherapy. However, multiple liver metastases were detected 2 months later. Because the disease progressed despite the administration of systemic chemotherapy, HAI was utilized instead. The metastases decreased in size remarkably, and resection was performed. The patient is surviving 52 months after the primary operation while being continuously treated with HAI, resection, and systemic chemotherapy for re-recurrence. HAI is a potential alternative treatment for patients with colorectal liver metastases resistant to systemic chemotherapy.

S-1 plus cisplatin is the standard chemotherapy for recurrent gastric cancer. While depression and delirium are frequent in cancer patients, hypomania during chemotherapy is rare. We describe a rare case of hypomania during S-1 plus cisplatin treatment for recurrent gastric cancer. A 66-year-old woman, with no previous psychiatric disorder, received S-1 plus cisplatin for recurrent gastric cancer. She showed peculiar behavior. Physical examination, urine, blood and imaging findings were normal. There was no gastric cancer progression. During psychiatric consultation, she behaved inappropriately. However, she behaved normally while performing daily activities. She manifested a persistently elevated, expansive or irritable mood, clearly different from her usual non-depressed state, meeting hypomania diagnostic criteria. Her condition did not require chemotherapy discontinuation or additional medication. During the second and subsequent S-1 plus cisplatin cycles, symptoms were stable. Cancer patients often have adjustment disorders, depression and delirium, but rarely hypomania. Our patient showed no significant changes in blood biochemistry and brain and whole body imaging. While S-1 plus cisplatin-induced hypomania cannot be excluded, hypomanic symptoms did not improve during the chemotherapy rest period, nor was there deterioration during subsequent cycles, suggesting drug-induced mania to be unlikely. Possible onset mechanisms include manic defense phenomena, common with stressful life events. There are no reports of recurrent gastric cancer patients experiencing hypomania during S-1 or S-1 plus cisplatin therapy, i.e. our patient represents a rare course. Clinicians should recognize psychosis or mood disorders during gastric cancer treatment. Further accumulation of such rare cases might elucidate pathological mechanisms underlying hypomania in cancer patients.

Patients with cancer often receive chemotherapeutic agents concurrently with other medications to treat comorbidity. The practical effects of concomitant medications, especially polypharmacy, on adverse drug reactions related to irinotecan-based chemotherapy are not well documented. Associations of adverse drug reactions related to irinotecan monotherapy or a combination of irinotecan, 5-fluorouracil, and l-leucovorin (FOLFIRI) with concomitant medicines used to treat comorbidity were retrospectively investigated in Japanese patients with cancer. Of the 172 patients, 118 received concomitant medications. Twenty-one patients had grade 4 neutropenia and/or grade 3 or 4 diarrhea. Univariate and multivariate analyses revealed that concomitant medications were significantly associated with irinotecan-related severe neutropenia and/or diarrhea (P = 0.023 and 0.044). Multiple concomitant medications were significantly related to severe irinotecan-related toxicity in patients given monotherapy or FOLFIRI (P = 0.01). The incidence of severe irinotecan-related toxicities increased in parallel with the number of concomitant medications. We found that multiple concomitant medicines were significantly associated with severe irinotecan-related toxicity, indicating that polypharmacy must be effectively managed to decrease the risk of adverse drug reactions in patients with cancer who received irinotecan-based chemotherapy.

Reversible posterior leukoencephalopathy syndrome (RPLS) is a serious neurologic disease characterized by visual disturbance, seizures, headache, and altered mental status associated with white matter changes, particularly in the occipital lobes. RPLS has been attributed to chemotherapy, including modified FOLFOX6 regimens consisting of 5-fluorouracil, oxaliplatin, and leucovorin. Although the mechanism of development of RPLS remains unclear, impaired cerebral blood flow autoregulation and endothelial dysfunction seem to be involved. In particular, endothelial dysfunction has been implicated in the pathophysiology of RPLS associated with platinum agents. Platinum-based chemotherapy is thought to have a direct toxic effect on the vascular endothelium, leading to capillary leakage, disruption of the blood–brain barrier, and axonal swelling, triggering vasogenic edema. Much progress has been made in chemotherapy for colorectal cancer, and the increasing use of molecular-targeted agents is expected to further improve the outcome of therapy. RPLS has recently been associated with such molecular-targeted therapy, particularly in patients concurrently receiving platinum agents. This finding is consistent with previous reports suggesting that RPLS occurs more often in patients receiving platinum-based therapy than in those receiving molecular-targeted agents. Because platinum agents are the most widely used in cancer chemotherapy, clinicians should strongly suspect RPLS in patients receiving treatment with this class of drug.

This exploratory retrospective study examined the effects of polymorphisms in transporter genes related to irinotecan pharmacokinetics and those in genes related to irinotecan pharmacodynamics on the efficacy of first-line combination chemotherapy with irinotecan, 5-fluorouracil, and folinic acid (leucovorin) (FOLFIRI) in Japanese patients with advanced colorectal cancer. All patients harbored UDP-glucuronosyltransferase (UGT) 1A1*1/*1, *1/*6, or *1/*28 genotypes, which are associated with similar irinotecan pharmacokinetics and responses to FOLFIRI. Genetic polymorphisms were analyzed by direct sequencing. Overall response rate and median progression-free survival in a total of 61 patients were 43% and 7.5 months, respectively. The overall response rate was higher in patients with the CC genotype at -24 in ATP-binding cassette, subfamily C, and member 2 (ABCC2) than in the others (p = 0.0313). Median progression-free survival was the longest in patients with CC at -24 in ABCC2, followed by those with CT and TT (p = 0.00910). A clear gene-dose effect was seen between -24C>T and median progression-free survival. No other polymorphisms tested were related to the efficacy of FOLFIRI. We thus found that the -24C>T polymorphism in the ABCC2 gene was significantly associated with the efficacy of first-line FOLFIRI in Japanese patients with advanced colorectal cancer.

Objective: To evaluate the safety and efficacy of combination chemotherapy with 5-fluorouracil (5-FU), leucovorin, irinotecan and oxaliplatin (FOLFOXIRI) in Japanese patients with advanced colorectal cancer. Methods: This phase I dose-finding study was designed to determine the maximum tolerated dose (MTD), recommended dose (RD) or both of FOLFOXIRI. Patients with UDP-glucuronosyltransferase (UGT) 1A1*6/*6, *28/*28 and *6/*28 genotypes were excluded, because these UGT1A1 genotypes are linked to severe neutropenia in Japanese. Results: A total of 10 Japanese patients with advanced colorectal cancer were studied. The MTD of FOLFOXIRI in these Japanese patients was 165 mg/m2 irinotecan, 85 mg/m2 oxaliplatin and 2,400 mg/m2 5-FU. Accordingly, the RD of FOLFOXIRI was determined to be 150 mg/m2 irinotecan, 85 mg/m2 oxaliplatin and 2,400 mg/m2 5-FU. Toxic effects, evaluated until the completion of 4 cycles, were manageable. Grade 3–4 neutropenia occurred in 27% of cycles, but there was no febrile neutropenia. Among the 9 assessable patients, the objective response rate was 89%. Conclusions: We thus determined the RD of FOLFOXIRI in Japanese patients with advanced colorectal cancer who do not have UGT1A1*28/*28, *6/*6 or *6/*28 genotypes. Our results indicate that FOLFOXIRI is a well-tolerated regimen for these Japanese patients.

Differences in efficacy and toxicity between UDP-glucuronosyltransferase (UGT) 1A1*1/*1 and *1/*6 or *1/*28 genotypes remain unclear in Japanese patients. Patients with advanced colorectal cancer who received irinotecan combined with 5-fluorouracil plus l-leucovorin (FOLFIRI) as first-line therapy were divided into two groups: those with UGT1A1*1/*1 genotype and those with UGT1A1*1/*6 or *1/*28 genotype. Efficacy and toxicity were compared between these groups retrospectively. Forty-two patients (24 *1/*1 and 18 *1/*6 or *1/*28) were evaluated. The response rate was 48% in *1/*1 group and 56% in *1/*6 or *1/*28 group (P = 0.847). Median progression-free survival was 8.6 months in *1/*1 group and 8.5 months in *1/*6 or *1/*28 group (P = 0.888). No hematologic or non-hematologic toxic effects were clearly related to UGT1A1*1/*6 or *1/*28 during the first cycle or throughout the entire course of chemotherapy. There were no significant differences in the efficacy or toxicity of FOLFIRI between patients with UGT1A1*1/*1 genotype and those with UGT1A1*1/*6 or *1/*28 genotype. Our results suggest that patients with the latter genotypes can receive FOLFIRI at the same dose of irinotecan as those with the UGT1A1*1/*1 genotype receive.

319 Background: Gene mutations of SMAD4, TP53 and CDKN2A( p16) have been reported to be associated with poor prognosis and metastatic burden in advanced pancreatic cancer (PC). On the other hand, the association between these gene mutations and recurrence in PC is still unclear. The present study aimed to whether the 3 gene mutations were related to the recurrence and the prognosis in PC patients. Methods: Formalin-fixed paraffin-embedded tumor samples were gathered from patients with PC who underwent curative resection between January 2014 and December 2015. We retrospectively evaluated a relationship between the mutation status of SMAD4, TP53 and p16 and the recurrence and prognosis in patients with PC. Results: Totally, fifty-six samples of patients with PC (Stage I/ II/ III: 5/6/45 (UICC 7th)) were included in this analysis. Recurrence was seen in 32 patients (57.1%). Patients with PC both recurrence and advanced pathological stage showed poor prognosis. Each 3 gene mutation did not show a significant association with recurrence. TP53 and p16 single mutations did not show significant association with prognosis. However, the patients with PC who have SMAD4 mutation showed a significant poor prognosis (Overall survival: 18.6 vs. 34.5 months, p = 0.03). Multivariate analysis showed only recurrence was a significant prognostic factor (p = 0.01) Conclusions: The present study suggested that there was no association between SMAD4 and recurrence, whereas in case of recurrence, SMAD4 mutation may be associated with prognosis in PC patients.

A middle-aged man who underwent a thorough examination for epigastric pain was diagnosed with unresectable pancreatic cancer and referred to our department. A circumaortic left renal vein1 was incidentally detected on abdominal CT (figures 1 and 2). The ventral branch of the left renal vein (red arrow) ran between the aorta and the superior mesenteric artery, and …

A middle aged man underwent sigmoidectomy and hepatic metastasis resection for sigmoid cancer and hepatic metastases, respectively. Subsequently, hepatic arterial infusion therapy was performed for recurrence after the hepatic metastasis resection. However, no local control was obtained, and metastasis occurred at a site other than the liver, namely, the diaphragm. Therefore, the patient was referred to our department for systemic chemotherapy. Abdominal …

Pulmonary resection for colorectal metastases is well accepted. However, the main cause of death after pulmonary resection is recurrence in the lung. The aim of this study was to clarify whether a repeat pulmonary resection was warranted in patients with recurrent lung metastases. The records of 76 patients undergoing initial pulmonary resection, including 14 patients undergoing a repeat operation for lung metastases, were reviewed for survival, operative morbidity, and mortality. Overall, pulmonary resection was performed 96 times in this group of patients. The operative mortality was 0%, morbidity involved only one case of major postoperative hemorrhage associated with the first operation. The cumulative 5-year survival rate for the 76 patients was 32%. After the second pulmonary operation, recurrence was identified in 79% (11 of 14) of the patients. In 10 patients with isolated lung recurrence after a first pulmonary resection, who showed no extrapulmonary disease before or at the time of first thoracotomy, the 3-year, and 5-year-survival rate after the second pulmonary resection was 67%, and 33%, respectively, comparing favorably with the survival rate in those who underwent primary pulmonary resection. In contrast, all 4 patients with extrapulmonary disease before or at the time of thoracotomy had poor prognosis. Repeat pulmonary operation for isolated recurrent colorectal metastases to the lung yielded results comparable to those after the first pulmonary resection in terms of operative mortality and survival in the absence of hilar/mediastinal lymph node or extrathoracic involvement.

横隔膜破裂は従来左側に多く, 右側例は稀であるとされている.しかし近年では右側受傷の報告が増加している.今回我々は2000年9月から2001年11月にかけ右側横隔膜破裂の4手術例を経験した.全例交通外傷にて久留米大学高度救命救急センターに搬入され, 肝臓の胸腔内への陥入を伴っていた.アプローチは開胸法が2例, 開腹法が1例, 開胸+開腹法が1例であった.受傷早期では腹腔内の臓器損傷を確認するため開腹法を選択し, 待機手術例では肺との癒着を想定し開胸術を選択した.受傷早期に手術を行ったのは2例で, 他の2例は循環動態の安定を待って手術を行った.いずれの症例も術後経過良好にて退院した.横隔膜損傷はそれ自体が予後に影響する可能性は少なく, 呼吸状態が保てれば循環動態が安定した慢性期に手術を行うことが安全であると思われた.

A giant bulla of the lung is suggested as a risk factor for lung cancer. Here we report a case with lung cancer in a giant bulla, which showed rapid progression. A 57-year-old man, who had a history of heavy smoking, was admitted to our hospital due to hemoptysis. A chest X-ray revealed a giant bulla with a ground glass shadow and a high fluid level in the right upper lung. Sputum cytology was negative for malignant cells. A chest X-ray a month later showed increases of the size of the radio-opaque shadow and of the air-fluid retention, suggesting pulmonary hemorrhage from the giant bulla. Limited resection or lobectomy was indicated, but pneumonectomy was performed due to the severe air-leak. Macroscopically, a multiple nodular tumor arose from the bulla wall, which might be related to blood flow and necrotic tissue. The postoperative pathological diagnosis was papillary adenocarcinoma. Unfortunately, the patient developed a recurrence of carcinoma in the pleuroperitoneal cavity and died at 2.5 months after the operation. Based on this report and review of other cases in the literature, we should keep in mind the rapid progression of lung cancer in association with an emphysematous bulla.

To investigate changes in atrial natriuretic peptide (ANP) and angiotensin II (AT-II) levels in a canine model of pulmonary embolism (PE), created by embolizing the left posterior pulmonary artery with gelatin powder. Pulmonary arterial pressure (PAP) was measured before, immediately after, and 1 day after pulmonary artery embolization. Plasma ANP and AT-II levels were measured by radioimmunoassay (RIA) before and 1, 3, 7, 14, 21, and 28 days after embolization. ANP and AT-II levels were also measured by RIA in both embolized and nonembolized lung tissue 28 days after embolization. No changes in plasma ANP or AT-II were seen within 28 days after embolization. Although the ANP level in the nonembolized lung tissue was significantly increased, the level in the embolized lung tissue was significantly decreased compared with that of sham-operated control lung tissue. The AT-II level in the nonembolized lung tissue was significantly decreased compared with that of the control lung tissue, but the level in the embolized lung tissue did not change. Both ANP and AT-II in the nonembolized lung tissue reacted to compensate for vasoconstriction caused by the PE in this model.

Objective: Optimal tracheobronchial stenosis treatment in esophageal cancer remains a clinical challenge.Methods: Subjects were 26 patients with tracheobronchial stenosis due to esophageal cancer treated by modalities such as expandable metallic stent emplacement, laser therapy, radiotherapy, and/or chemotherapy. We assessed patient outcome and modality efficacy, and determined prognostic factors for survival using multivariate analysis.Results: Of the 26, 16 (61%) had improved respiration after treatment. Average post-treatment survival was 140 days (10–1550 days). Multivariate analysis indicated that a Karnofsky performance score of ≥70% was the most significant prognostic factor, with chemotherapy and laser therapy also significant factors.Conclusions: Although individual modalities were effective in ameliorating respiratory symptoms, patients with good performance status survived the longest. After a tracheobronchial stenosis diagnosis in esophageal cancer patients, chemotherapy and laser therapy are recommended if the patient is in good general condition.

3549 Background: Neoadjuvant radiotherapy is the current standard of care for rectal cancer. However, radiation therapy is sometimes associated with short-term severe toxicity and long-term morbidity. Perioperative introduction of new chemotherapy agents without radiotherapy for locally advanced rectal cancer (LARC) may be a promising option. Several studies of combination chemotherapy with oxaliplatin plus S-1 (SOX) have reported promising efficacy and safety in patients with metastatic colorectal cancer, suggesting a potential replacement for mFOLFOX6. Methods: A randomized phase II trial was undertaken to compare the efficacy and safety of SOX and mFOLFOX6 as neoadjuvant chemotherapy for patients with LARC. Patients were randomly assigned to receive mFOLFOX6 (every 2 weeks; day 1: 400 mg/m2 bolus 5-fluorouracil [5-FU]; days 1 and 2: 2,400 mg/m2 continuous 5-FU; day1: 200mg/m2 l-LV; and day 1: 85 mg/m2 oxaliplatin) or SOX (every 3 weeks; days 1–14: 80 mg/m2 oral S-1; and day 1: 130 mg/m2oxaliplatin). The protocol period for neoadjuvant chemotherapy was 3 months. The primary endpoint was the 3-year disease-free survival rate (3y DFS), and the secondary endpoints included pathological effect, R0 resection rate, survival and safety. Results: Between September 2013 and October 2015, 110 patients were enrolled and randomized (56 received SOX and 54 received mFOLFOX6). Baseline characteristics were balanced between the two arms. The major adverse events were neutropenia, peripheral neuropathy, loss of appetite, and fatigue. The incidence of grade 3 or higher neutropenia based on the CTCAE Vers.4.0was 13.2% in the SOX group and 32.0% in the mFOLFOX6 group. The surgical completion rate was 100% for the SOX group and 96% for the mFOLFOX6 group. The incidence of grade II or more surgical site infection based on Clavien-Dindo classification (CD) was 11.3% and 4.2% for the SOX and mFOLFOX6 groups, respectively. The CD grade III anastomosis-related complications developed in 7 cases in total. Conclusions: The KSCC1301 study suggests that neoadjuvant chemotherapy without radiation is active and safe. The results of pathological response will be provided. Clinical trial information: UMIN000011486.

Silicone stents are widely used to treat benign or malignant airway stenosis. However, since straight silicone stents placed into the subglottic trachea to treat stenosis display a high risk of migration, novel approaches are required. The present report outlines our method of external fixation for silicone stents in the subglottic trachea. This technique utilizes a fixation apparatus, is readily performed, and may help to overcome the hesitation seen in placing silicone stents for subglottic tracheal stenosis.

A 33-year-old woman being treated for rheumatoid arthritis was referred to our hospital for investigation of a mediastinal mass. A chest computed tomography scan showed an anterior mediastinal mass, 8.5 x 7.0 cm in size, with a cystic lesion and calcification. These findings were suggestive of either a noninvasive thymoma or a mature teratoma. Therefore, we performed tumor resection and thymectomy. Histologically, the tumor consisted of diffuse deposits of massive eosinophilic amorphous material. The tumor was stained red-orange by Congo red, and the staining disappeared following potassium permanganate digestion. Based on these findings, a diagnosis of reactive amyloidosis of the amyloid A-protein-derived type was made. Amyloidosis in the mediastinum has rarely been described.

Background: The number of patients with pancreatic cancer is rapidly growing, and the disease is the fifth leading cause of cancer-related death in Japan. At end stage of the disease, the patients are prone to suffer peritonitis carcinomatosa with chemorefractory ascites. It is known that cancer cells surviving in ascites show cancer stem cell (CSC)-like features (PLoS One 2012). The CSC-like cells robustly secrete extracellular vesicle called exosome, which plays important roles in tumorigenesis, tumor growth, metastasis, angiogenesis, pre-metastatic niche formation, immunosuppression, drug resistance, and epithelial-mesenchymal transition. The AIM of this prospective study was to assess whether exosomes taken from malignant ascites of patients with advanced pancreatic cancer included the CSC-associated proteins, that might be predictive markers for chemoresistance and prognosis. Methods: The malignant ascites was collected from the cancer patients who underwent abdominocentesis and/or cell-free and concentrated ascites reinfusion therapy (CART) in Kurume University Hospital. Ascites derived from patients with benign diseases, including decompensated liver cirrhosis (d-LC), was used as control. Informed consent was obtained from all of the patients. Exosomes in ascites were purified by using ExoQuick Exosome Precipitation Solution (System Biosciences) according to the manufacturer's protocol. Western blot analysis was performed to detect CSC-associated proteins, including CD133, CD44, CD44v9, xCT, CD24, and Dclk1. Results: Successful purification of exosomes from both the malignant ascites and the benign one was confirmed by monitoring exosome-specific proteins such as CD68, CD9, CD81, and HSP70. Among the CSC-associated proteins examined, CD133 was predominantly expressed in exosomes obtained from ascites of the pancreatic cancer patients compared with those obtained from ascites of the d-LC patients. Other molecules were faintly expressed or absent even in the malignant ascites. Conclusions: We first demonstrated abundant expression of CD133, a human pancreatic CSC marker, in exosomes derived from ascites of patients with the disease. The finding suggests that exosomal CD133 might be a potential biomarker for chemoresistance and prognosis of the patients. Citation Format: Takahiko Sakaue, Hironori Koga, Masaru Fukahori, Yasuko Imamura, Toru Nakamura, Yoshinobu Okabe, Yu Ikezono, Fumitaka Wada, Hideki Iwamoto, Atsutaka Masuda, Tomoyuki Ushijima, Keisuke Miwa, Tatsuyuki Kakuma, Osamu Tsuruta, Takuji Torimura. Expression of cancer stem cell-associated proteins in exosomes derived from ascites of patients with advanced pancreatic cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3955.

A 74-year-old woman who had undergone surgery for rectal cancer and also had lung metastases developed abdominal pain, diarrhoea and bloody stools 5 days after receiving her 22nd dose of S-1, oxaliplatin and bevacizumab therapy.1 She was admitted to the hospital with a suspected adverse reaction to chemotherapy and infectious enteritis. CT imaging …

BACKGROUND: The biological basis for cancer of unknown primary (CUP) at the molecular level remains largely unknown, with no evidence of whether a common biological entity exists. Here, we assessed the possibility of identifying a common diagnostic biomarker for CUP using a microarray gene expression analysis. METHODS: Tumor mRNA samples from 60 patients with CUP were analyzed using the Affymetrix U133A Plus 2.0 GeneChip and were normalized by asinh (hyperbolic arc sine) transformation to construct a mean gene-expression profile specific to CUP. A gene-expression profile specific to non-CUP group was constructed using publicly available raw microarray datasets. The t-tests were performed to compare the CUP with non-CUP groups and the top 59 CUP specific genes with the highest fold change were selected (p-value

We report here a case of reversible posterior leukoencephalopathy syndrome(RPLS)induced by modified FOLFOX6(mFOLFOX6). The patient was a 43-year-old woman who had sigmoid colon cancer with multiple liver metastases. Treatment with mFOLFOX6 was started. Early in the morning of day 11, the patient was transported by ambulance to the hospital due to nausea with headache, disturbed consciousness, and visual disturbance. The patient experienced sudden, severe nausea and subsequently presented generalized tonic-chronic seizures. The seizures subsided after treatment. On the evening of day 11, another episode of generalized tonic-chronic seizures occurred. Status epilepticus developed and tracheal intubation was performed for airway protection. Cranial MRI showed increased signal intensity in both occipital lobes, centered on the boundary between the gray and white matter on FLAIR images. Her condition stabilized with no seizure recurrence following intubation. Although hypertension was present on admission to the emergency room, blood pressure gradually fell to within the normal range without antihypertensive treatment. She was extubated on day 18. There were no neurologic sequelae. Cranial MRI on day 40 showed that the increased intensity in both occipital lobes had almost disappeared. Because the patient's condition was characterized by a reversible central nervous system disorder, RPLS was diagnosed.

Small cell carcinoma of the gastrointestinal tract is rare, and no effective strategy has yet been established. On the basis of regimens reportedly effective for small cell lung cancer, we performed chemotherapy with cisplatin plus etoposide in combination with radiotherapy to relieve obstruction, in a patient with small cell carcinoma of the gastro-oesophageal junction. Chemotherapy was switched to carboplatin plus etoposide due to renal toxicity. No distant metastases were detected and lesion spread was limited. A complete response, with no evidence of recurrence to date, was achieved. Curative resection was suggested but refused by the patient. He has been closely followed up in our outpatient clinic for more than a year and has shown no evidence of recurrence since the completion of treatment. Although cisplatin plus etoposide is a standard chemotherapy regimen for small cell carcinoma, carboplatin plus etoposide may be effective in cases in which cisplatin is contraindicated due to renal toxicity.

A 74-year-old man, who had been receiving S-1 plus cisplatin combination chemotherapy for gastric cancer and metastatic disease of the liver,1 developed disorientation, amnesia and anorexia on day 13 of the fourth cycle of the chemotherapy regime. On day 16, he was reviewed in the outpatients department and was admitted as an emergency. MRI of the brain obtained on his admission showed no metastatic …

To evaluate the safety and efficacy of combination chemotherapy with 5-fluorouracil (5-FU), leucovorin, irinotecan and oxaliplatin (FOLFOXIRI) in Japanese patients with advanced colorectal cancer.This phase I dose-finding study was designed to determine the maximum tolerated dose (MTD), recommended dose (RD) or both of FOLFOXIRI. Patients with UDP-glucuronosyltransferase (UGT) 1A1*6/*6, *28/*28 and *6/*28 genotypes were excluded, because these UGT1A1 genotypes are linked to severe neutropenia in Japanese.A total of 10 Japanese patients with advanced colorectal cancer were studied. The MTD of FOLFOXIRI in these Japanese patients was 165 mg/m(2) irinotecan, 85 mg/m(2) oxaliplatin and 2,400 mg/m(2) 5-FU. Accordingly, the RD of FOLFOXIRI was determined to be 150 mg/m(2) irinotecan, 85 mg/m(2) oxaliplatin and 2,400 mg/m(2) 5-FU. Toxic effects, evaluated until the completion of 4 cycles, were manageable. Grade 3-4 neutropenia occurred in 27% of cycles, but there was no febrile neutropenia. Among the 9 assessable patients, the objective response rate was 89%.We thus determined the RD of FOLFOXIRI in Japanese patients with advanced colorectal cancer who do not have UGT1A1*28/*28, *6/*6 or *6/*28 genotypes. Our results indicate that FOLFOXIRI is a well-tolerated regimen for these Japanese patients.

Objective: We examined the feasibility of regimen selection for first-line irinotecan, 5-fluorouracil and leucovorin or oxaliplatin, 5-fluorouracil and leucovorin in Japanese patients with advanced colorectal cancer based on UDP-glucuronosyltransferase 1A1 genotype as well as physical status of patients related to diarrhea. Methods: As first-line irinotecan, 5-fluorouracil and leucovorin is a little bit superior to oxaliplatin, 5-fluorouracil and leucovorin with respect to efficacy and toxicity, patients without risk factors of irinotecan-induced toxicity were first assigned to irinotecan, 5-fluorouracil and leucovorin. Patients with UDP-glucuronosyltransferase 1A1*28/*28, *6/*6, *28/*6 or *28/*27 and those with ascites, peritoneal dissemination or diarrhea first received oxaliplatin, 5-fluorouracil and leucovorin to avoid the irinotecan-induced neutropenia and diarrhea, respectively. We retrospectively evaluated the feasibility of this strategy by assessing toxicity and total progression-free survival in first- and subsequent second-line therapies in all patients studied. Results: In the first-line irinotecan, 5-fluorouracil and leucovorin (n ¼ 61), Grade 4 neutropenia, febrile neutropenia and Grade 3 diarrhea occurred in 8.2, 3.3 and 3.3% of patients, respectively. In the first-line oxaliplatin, 5-fluorouracil and leucovorin (n ¼ 26), Grade 4 neutropenia, febrile neutropenia, Grade 3 thrombocytopenia and Grade 3 neuropathy were observed in 11.5, 3.8, 3.8 and 7.7% of patients, respectively. In the second-line oxaliplatin, 5fluorouracil and leucovorin (n ¼ 38), Grade 3 diarrhea occurred in 2.6% of patients. In the second-line irinotecan monotherapy (n ¼ 11), Grade 4 or febrile neutropenia occurred in 18% of patients and Grade 3 diarrhea in 9.1% of patients. In second-line S-1 (n ¼ 9), Grade 3 anemia occurred in 2 patients. Median total progression-free survival in all 87 patients was 11.5 months. Conclusions: Present regimen selection strategy would be feasible, since it causes less toxicity and similar efficacy comparing to previous studies. Determination of appropriate reduced dose in the second-line irinotecan monotherapy or other standard second-line therapy for patients with high-risk to irinotecan-induced toxicity might make this strategy more effective.

We report here the case of a 64-year-old man with sternal osteomyelitis after pneumonectomy through a median sternotomy who was successfully treated using a pedicled omental flap. This is the first report in the literature to describe sternal osteomyelitis and mediastinitis after pneumonectomy. In this case, the visceral pleura of the remnant right lung was located just under the infected sternum. Careful management is recommended because empyema pleurae can be a fatal complication.

This prospective study is designed to examine the effects of severe renal failure on the pharmacokinetics of irinotecan. The pharmacokinetics of irinotecan, 7-ethyl-10-hydroxycamptothecin (SN-38), and SN-38 glucuronide (SN-38G) in three cancer patients with severe renal failure [creatinine clearance (Ccr) ≤ 20 ml/min] who were undergoing dialysis and received 100 mg/m(2) irinotecan as monotherapy were prospectively compared with those in five cancer patients with normal renal function (Ccr ≥ 60 ml/min). To ensure that the subjects had similar genetic backgrounds of UDP-glucuronosyltransferase (UGT) 1A1, patients with UGT1A1*1/*1, *1/*6, or *1/*28 were enrolled. The estimated terminal elimination rate constant of SN-38 in patients undergoing dialysis was approximately one tenth of that in patients with normal renal function (P = 0.025). Approximately 50% of SN-38 was dialyzed with a 2.1-m(2) dialysis membrane, whereas 27% was dialyzed with a 1.5-m(2) membrane. Our results showed that the elimination of SN-38 was significantly delayed in patients with severe renal failure compared with patients with normal renal function. We demonstrated that SN-38 was partly dialyzed.

Recently, significant progress in treatment of metastatic colorectal cancer has been achieved. Either FOLFIRI (fluorouracil, leucovorin and irinotecan) or modified FOLFOX6 (fluorouracil, leucovorin and oxaliplatin, oxaliplatin dose 85 mg/m(2)) is selected as first-line therapy in clinical practice in Japan. However, economic burden of colorectal cancer is considerable.Analysis was made for all patients who were treated with FOLFIRI or modified FOLFOX6 for metastatic colorectal cancer. Regimen of FOLFIRI was compared with modified FOLFOX6 under consideration from clinical and economic standpoints. Progression free survival, response, toxicity and cancer care cost in patients with metastatic colorectal cancer was analyzed. Direct costs based on the fee schedule of the Japanese national health insurance were calculated.Median progression free survival was 7.7 months for FOLFIRI versus 8.4 months for modified FOLFOX6 (P = 0.48). Overall cost for first four cycles was yen756 284 for FOLFIRI and yen1 081 162 for modified FOLFOX6 (P0.0001). All grade alopecia was significantly more frequent with FOLFIRI than with modified FOLFOX6 (P = 0.04). All grade neuropathy was more observed with modified FOLFOX6 than FOLFIRI (P = 0.0002).FOLFIRI is inexpensive in the initial stage of treatment which a number of patients can receive chemotherapy than modified FOLFOX6 as first-line therapy for metastatic colorectal cancer in Japanese national insurance system.

We developed a population pharmacokinetic (PPK) model of S-1 including the cytochrome P450 (CYP) 2A6 genotype and then used this PPK model to assess the influence of the CYP2A6 genotype on PK parameters of S-1 and the relationship between toxicity and the individual maximum concentrations (Cmax) or the area under the concentration-time curve (AUC) of 5-fluorouracil (5-FU) in Japanese patients with advanced cancer. Fifty-eight patients with advanced cancer were assessed. A dose of 80 mg/m(2)/day of S-1 was given orally. On the basis of the CYP2A6 genotypes (*1, *4, *7 and *9), all patients were classified as having the wild-type, 1 variant allele or 2 variant alleles. The PPK model was established with plasma concentration data for tegafur (FT), 5-chloro-2,4-performed dihydroxypyridine (CDHP) and 5-FU. In patients with 2 variant alleles of CYP2A6, the clearance of FT was 58% less than in patients with the wild-type or 1 variant allele. The AUC of 5-FU correlated with the AUC of CDHP, but not with the AUC of FT. Therefore, the CYP2A6 genotype did not affect the AUC of 5-FU. The individual AUC or Cmax of 5-FU did not differ significantly between patients with grade 3 or 4 toxicities and patients with grade 0-2 toxicities. In conclusion, the CYP2A6 genotype did not affect the AUC of 5-FU, although the clearance of FT was lower in patients with 2 variant alleles of CYP2A6 than in patients with the wild-type or 1 variant allele.

S-1 is an oral anticancer agent that combines tegafur, a prodrug of 5-fluorouracil (5-FU), and 5-chloro-2,4-dihydroxypyridine (CDHP), an inhibitor of dihydropyrimidine dehydrogenase. We examined the effects of aging on the pharmacokinetics of the components of S-1. The median area under the concentration-time curve (AUC) of active 5-FU did not significantly differ between 10 patients 75 years or older and 53 patients younger than 75 years (P = 0.598, Mann-Whitney U test). It is interesting to note that the median oral clearance of tegafur in patients 75 years or older was significantly lower than that in patients younger than 75 years (P = 0.011). Furthermore, the median AUC of CDHP was significantly higher in patients 75 years or older than in those younger than 75 years (P = 0.004). This effect was caused by reduced renal function in the elderly, because CDHP is excreted in the urine by glomerular filtration. The opposing effects of aging on the oral clearance of tegafur and the AUC of CDHP may offset each other, leading to unchanged systemic exposure of 5-FU.

BACKGROUND S-1 is an oral anticancer agent that combines tegafur (FT) with 5-chloro-2,4-dihydroxypyridine (CDHP) and potassium oxonate. The recommended initial dose of S-1 is 120 mg/day for patients with a body surface area (BSA) of > or =1.5 m(2) in Japan. METHODS We examined the effects of using this fixed dose on the pharmacokinetics of FT, CDHP, and active 5-fluorouracil (5-FU) on the basis of actual BSA. The pharmacokinetics was compared between patients with a BSA of 1.5-1.75 m(2) and those with a BSA of > or =1.75 m(2). RESULTS The median areas under the time-concentration curves (AUCs) of 5-FU and CDHP were significantly lower in patients with a BSA of > or =1.75 m(2) than in those with a BSA of 1.5-1.75 m(2) (P = 0.005 and 0.006, respectively; Mann-Whitney U-test). There was no difference between the groups in the median AUC of FT. CONCLUSION Systemic exposure to 5-FU is significantly lower in Japanese cancer patients with a large BSA of >1.75 m(2) who received the recommended fixed dose of S-1.

S-1 is an oral anticancer agent composed of tegafur (FT), 5-chloro-2,4-dihydroxypyridine (CDHP), and potassium oxonate. CDHP is added to prevent degradation of 5-fluorouracil (5-FU) by inhibiting dihydropyrimidine dehydrogenase. CYP2A6 is involved in the biotransformation of FT to 5-FU. Thus, we prospectively analyzed the effects of the CYP2A6 genotype, plasma level of CDHP, and patient characteristics on the pharmacokinetic (PK) variability of FT and 5-FU. Fifty-four Japanese patients with metastatic or recurrent cancers who received S-1 were enrolled. The CYP2A6 polymorphisms (*4A, *7, and *9) with deficient or reduced activity were analyzed. All subjects were classified into three groups according to their CYP2A6 genotype: wild type (*1/*1), one-variant allele (*1/any), or two-variant alleles (combination other than *1). The PK of FT, 5-FU, and CDHP were measured on day 1 of treatment. Multivariate regression analysis revealed that oral clearance of FT was associated with the CYP2A6 genotype (analysis of variance [ANOVA], P = 0.000838). The oral clearance of FT seen in patients with the two-variant alleles was significantly lower than those in wild type and the one-variant allele (95% confidence intervals 0.75-2.41 and 0.41-1.82, respectively; Tukey-Kramer test). The area under the time-concentration curve (AUC) of 5-FU was significantly correlated with the AUC of CDHP (ANOVA, P = 0.00126). The AUC of 5-FU and CDHP were inversely correlated with creatinine clearance (ANOVA, P = 0.0164 and P = 0.000762, respectively). Although the CYP2A6 variants are the cause of the PK variability of FT, the AUC of CDHP affected by renal function is the key determinant of the variability in the PK of 5-FU.

We report two patients with refractory recurrent breast cancer (HER2/neu: +) postoperatively, who had failed response to the available conventional chemotherapy of CAF (cyclophosphamide, adriamycin, 5-fluorouracil) and docetaxel, etc. They markedly responded to the combination immunotherapy using intraperitumoral injections of autologous tumor cell-stimulated T lymphocyte (AuTL) and trastuzumab (Herceptin), an anti-HER2 monoclonal antibody.AuTLs were administrated directly into the recurrent tumor by intraperitumoral injections biweekly and trastuzumab was infused systemically every week. The treatments were repeated for 6 and 11 injections in the patients, respectively. The total administered T cells had reached to 3.8 x 10(9) and 6.4 x 10(9), respectively. The dosage of trastuzumab was 2 mg/kg in each patient.The carcinomatous pleural effusion had disappeared and was well controlled in patient 1 and a marked regression in injected fields in comparison to the size of the recurrent tumor before treatment was observed in patient 2. The tumor marker proteins (CEA, CA15-3, TPA) had also decreased significantly. The adverse effects of the immunotherapy were tolerable with grades 1-2 infusion reaction of fever, tachycardia and hypotension, but no cardiac dysfunction was observed.Clinical responses of recurrent breast cancer were observed in two patients after receiving the intra-peritumoral AuTL injection plus trastuzumab immunotherapy. These results showed that refractory recurrent breast cancer may be controlled effectively and safely by repeating the cellular immunotherapy combined with trastuzumab and suggested utility of combining these agents in clinical trial.

Antineoplastons such as A10 include naturally occurring peptides and amino acid derivatives that control the neoplastic growth of cells. The mechanism underlying this antitumor effect was investigated using the breast cancer cell line, SKRB-3. Cells treated with A10 were monitored for any changes in cell cycle, expression of protein kinase C (PKC), or intracellular signal transduction, particularly phos-phorylation of mitogen-activated protein kinase (MAPK). The A10 markedly inhibited SKBR-3 proliferation due to arrest in the G(1) phase. A10 down-regulated the expression of PKCalpha protein, resulting in inhibition of extracellular signal-regulated kinase (ERK) MAPK phosphorylation. This increased the expression of p16 and p21 protein, with resultant inhibition of Rb phosphorylation, leading to G(1) arrest. This study has defined a pathway in which A10 arrested SKBR-3 cells in the G(1) phase via PKCalpha and MAPK. Our findings indicate that the antineoplaston A10 antitumor effect could be utilized as an effective therapy for breast cancer patients.

We present a case of a 78-year-old man with a synchronous double cancer of the lung and Vater's papilla. A pancreaticoduodenectomy was performed for Vater's papilla cancer and a partial lung resection for lung cancer. The pathological diagnosis of the tumors was a well differentiated tubular adenocarcinoma and well differentiated bronchioloalveolar carcinoma, respectively. Although most cases of synchronous double cancers involve lung and gastric cancers, a combination of lung and Vater's papilla is extremely rare. This patient is still alive with no recurrence for 5 years after the last operation.

A 65-year-old man was admitted to our hospital for treatment of a squamous cell carcinoma in his right lung. Respiratory function testing showed an extremely reduced forced expiratory volume in 1 second (FEV1) of 1.0 l (29.9% of predicted), and a reduced FEV1/FVC ratio of 24.1%. Arterial blood gases on room air showed a pH of 7.41, a PaCO(2) of 36.7 mmHg, and a PaO(2) of 79.3 mmHg. To assess the predictive postoperative cardiopulmonary function, unilateral pulmonary artery occlusion (UPAO) testing was performed. In the condition of right main PA occlusion, the mean pulmonary artery pressure (mPAP), cardiac index (CI) and total pulmonary vessel resistance index (TPVRI) was 18 mmHg, 3.2 l/min/m(2) and 443.37 dyne.sec.cm(-5)/m(2), respectively. He underwent a middle lobectomy with combined partial resection of both the upper and lower lobes. He also underwent simultaneous resection of a giant bulla arising from the right upper lobe as lung volume reduction surgery. At 80 days after the operation, his FEV1 rose to 1.88 l, and the PaO(2) on room air was improved to 88.9 mmHg. UPAO testing was suggested to be more useful than routine pulmonary function test to determine the accurate predictive postoperative cardiopulmonary function and to decide indication for a radical operation.

We present the case of a 55-year-old man with advanced esophageal cancer who was successfully treated using a self-expandable metallic stent (S-EMS) for 6 months and subsequently was treated for an esophagobronchial fistula as a complication of the initial S-EMS using a silicone airway stent for an additional 4 months. This is the first report in the literature concerning penetration into the airway of an S-EMS implanted in the esophagus. The present case suggests that airway stenting using a silicone stent as treatment for an esophagobronchial fistula may represent a useful modality.