Sequential Treatment Strategy Using Fluoropyrimidine plus Bevacizumab Followed by Oxaliplatin for Metastatic Colorectal Cancer: A Phase II Study (OGSG 1107).

Introduction: Previous prospective studies suggest that the sequential use of cytotoxic agents, such as oxaliplatin, in patients with metastatic colorectal cancer (mCRC) has the potential to improve prognosis and maintain quality of life than combination chemotherapy. The purpose of this study was to investigate the feasibility and effectiveness of a sequential treatment strategy consisting of an initial therapy (capecitabine, S-1, or 5-fluorouracil with leucovorin [LV/5-FU] plus bevacizumab) and subsequent therapy (i.e., initial therapy plus oxaliplatin) for mCRC. Methods: The primary endpoint was second progression-free survival (2nd PFS) between the start of initial therapy and tumor progression after sequential therapy; secondary endpoints were PFS after initial treatment, overall survival (OS), objective response rate (ORR), and safety. Results: Sixty-six patients were planned to be recruited. However, owing to a slow accrual rate, recruitment was terminated when only 19 patients were enrolled between 2011 and 2015; 4, 10, and 5 patients were administered capecitabine plus bevacizumab, S-1 plus bevacizumab, and LV/5-FU plus bevacizumab, respectively. The proportions of those with a KRAS status (wild-type/mutant/unknown) were 26%, 21%, and 53%, respectively. The median 2nd PFS and OS were 19.1 months and not reached, respectively. The ORR was 45.5% in the initial therapy and 16.7% in the subsequent therapy. Grade 3/4 toxicities included neutropenia (5%), proteinuria (5%), and hypertension (47%). Conclusion: Although our data are limited and preliminary, the sequential treatment strategy may provide a survival benefit in patients with mCRC. Further investigation of this treatment approach is warranted.

The Management of Recurrence of Hepatocellular Carcinoma Occurring Within 6 Months After Hepatic Resection: A Comparative Study Using a Propensity Score Matching Analysis.

BACKGROUND: Hepatectomy is currently recommended as the most reliable treatment for hepatocellular carcinoma. However, the association between the choice of treatment for recurrence and the timing of recurrence remains controversial. METHODS: Three-hundred thirty-nine patients who underwent hepatectomy were retrospectively analyzed using a propensity score matching analysis for the risk factors and outcomes for early recurrences within 6 months. The remnant liver volumes and laboratory data were measured postoperatively using multidetector computed tomography on days 7 and months 1, 2, and 5 after surgery. The Student's t test and chi-square test, the likelihood-ratio test, Fisher's exact test, Mann-Whitney U test, or Wilcoxon signed-rank test were used in the statistical analyses. RESULTS: Early recurrence developed in 41/312 patients (13.1%). Vascular invasion and non-curative resection were independent risk factors for the occurrence of early recurrence (P < 0.001 and < 0.001, respectively). Patients with early recurrence had a poorer prognosis than patients who developed later recurrences (P < 0.001). Patients who underwent surgery or other local treatments had better outcomes (P < 0.001). The changes in remnant liver volumes and laboratory data after postoperative month 2 were not significantly different between the two groups. CONCLUSION: Patients with early recurrence within 6 months had a poorer prognosis than patients who developed a later recurrence. However, patients who underwent repeat hepatectomy for recurrences had a better prognosis than did those who underwent other treatments, with good prospects for long-term survival.

Pharmacokinetics of Dexamethasone when Administered with Fosaprepitant for Chemotherapy-Induced Nausea and Vomiting and Differences in Dose-Dependent Antiemetic Effects.

BACKGROUND: Fosaprepitant, an NK1 receptor antagonist, inhibits and induces cytochrome P450 3A4 (CYP3A4) as its substrate. Contrarily dexamethasone is metabolized by CYP3A4. Therefore, in combination therapy wherein both agents interact with each other, it is recommended that the dexamethasone dose be reduced in the first two days. Thus far, there are only a few studies on the optimum dose of dexamethasone after day 3. Thus, we aimed to determine the pharmacokinetics of dexamethasone on day3 when administered together with fosaprepitant and investigate the dose-dependent differences in its antiemetic effect in patients with cancer. METHODS: Twelve patients with esophageal, stomach, or lung cancer received primary highly emetogenic chemotherapy (HEC). We intravenously administered 9.9 mg and 6.6 mg of dexamethasone on days 1 and 2, respectively, and 6.6 mg or 13.2 mg on day 3 together with the administration of 150 mg fosaprepitant and 0.75 mg palonosetron. We assessed the pharmacokinetics of dexamethasone on day 3 by dose and examined the dose-dependent antiemetic effect. RESULTS: No differences were observed in the time-to-maximum concentration and blood half-life of dexamethasone between patient groups that received dexamethasone at doses of 6.6 mg and 13.2 mg. In contrast, the area under the blood concentration-time curve and the maximum concentration of dexamethasone correlated with its dose. Moreover, the blood dexamethasone concentration on day 3 increased by twofold after the administration of a higher dose than after a lower dose. The severity of nausea in the delayed phase significantly decreased in a dose-dependent manner. CONCLUSION: Administration of a higher dexamethasone dose on day 3 improved the antiemetic effect of the combined regimen in patients with cancer who underwent HEC.
.

Retrospective Comparison of mFOLFOXIRI With XELOX/SOX as Neoadjuvant Chemotherapy for Locally Advanced Rectal Cancer.

BACKGROUND/AIM: Neoadjuvant chemotherapy without radiation (NAC) shows favorable outcomes for locally advanced rectal cancer (LARC), however, the optimal regimen has not been determined yet. This study aimed to compare the efficacy and safety of oxaliplatin, irinotecan, folinic acid, and 5-fluorouracil (mFOLFOXIRI) with capecitabine/S-1 and oxaliplatin (XELOX/SOX) in rectal cancer patients. PATIENTS AND METHODS: We retrospectively examined patients with LARC who received mFOLFOXIRI or XELOX/SOX as NAC. RESULTS: Between January 2015 and July 2019, 49 patients received mFOLFOXIRI and 37 patients received XELOX/SOX. The pathological response rates (over two-thirds affected tumor area) were 36.7% and 40.5% in the mFOLFOXIRI and XELOX/SOX groups, respectively. Grade 3/4 neutropenia was experienced by 45.0% of the patients in the mFOLFOXIRI group and 8.0% in the XEOX/SOX group. CONCLUSION: Although pathological responses were comparable between two groups, mFOLFOXIRI tended to be more toxic compared to XELOX/SOX as NAC for LARC.

Safety and Efficacy of Laparoscopic Liver Resection for Colorectal Liver Metastasis With Obesity.

INTRODUCTION: Laparoscopic liver resection (LLR) in obese patients has been reported to be particularly challenging owing to technical difficulties and various comorbidities. METHODS: The safety and efficacy outcomes in 314 patients who underwent laparoscopic or open nonanatomical liver resection for colorectal liver metastases (CRLM) were analyzed retrospectively with respect to the patients' body mass index (BMI) and visceral fat area (VFA). RESULTS: Two hundred and four patients underwent LLR, and 110 patients underwent open liver resection (OLR). The rate of conversion from LLR to OLR was 4.4%, with no significant difference between the BMI and VFA groups (P = .647 and .136, respectively). In addition, there were no significant differences in terms of operative time and estimated blood loss in LLR (P = .226 and .368; .772 and .489, respectively). The incidence of Clavien-Dindo grade IIIa or higher complications was not significantly different between the BMI and VFA groups of LLR (P = .877 and .726, respectively). In obese patients, the operative time and estimated blood loss were significantly shorter and lower, respectively, in LLR than in OLR (P = .003 and < .001; < .001 and < .001, respectively). There was a significant difference in the incidence of postoperative complications, organ/space surgical site infections, and postoperative bile leakage between the LLR and OLR groups (P = .017, < .001, and < .001, respectively). CONCLUSION: LLR for obese patients with CRLM can be performed safely using various surgical devices with no major difference in outcomes compared to those in nonobese patients. Moreover, LLR has better safety outcomes than OLR in obese patients.

Safety and efficacy of cell-free and concentrated ascites reinfusion therapy (CART) in gastrointestinal cancer patients with massive ascites treated with systemic chemotherapy.

PURPOSE: Gastrointestinal cancer is frequently associated with malignant ascites, resulting in poor prognosis. While cell-free and concentrated ascites reinfusion therapy (CART) improves ascites-related symptoms, its clinical impact in combination with systemic chemotherapy is unclear. The purpose of this study was to evaluate the safety and efficacy of CART in gastrointestinal cancer patients with massive ascites treated with chemotherapy. METHODS: We retrospectively reviewed the medical records of gastrointestinal cancer patients with massive ascites who received CART and chemotherapy at our hospital between July 2015 and September 2017. RESULTS: A total of 30 patients received CART and chemotherapy: gastric cancer (n = 21) and colorectal cancer (n = 9). The initial CART improved performance status in 20% of the patients, and the mean serum albumin and creatinine was significantly improved. Median time to treatment failure and overall survival of chemotherapy following CART were 2.1 and 3.5 months in gastric cancer patients and 5.8 and 5.8 months in colorectal cancer patients, respectively. The frequency of paracentesis was decreased after introduction of CART followed by chemotherapy in 83% of gastric cancer and in all colorectal cancer patients who had received paracentesis before the initial CART. There were no grade 3/4 adverse events during the CART procedure. Grade 3/4 hematotoxic and non-hematotoxic adverse events of chemotherapy following CART were 30% and less than 10%, respectively. CONCLUSIONS: The combination of CART followed by chemotherapy is safe and could be a treatment option for gastrointestinal cancer patients with massive ascites.

IL33 Is a Key Driver of Treatment Resistance of Cancer.

Recurrence and treatment resistance are major causes of cancer-associated death. There has been a growing interest in better understanding epithelial-mesenchymal transition, stemness of cancer cells, and exhaustion and dysfunction of the immune system for which numerous genomic, proteomic, microenvironmental, and immunologic mechanisms have been demonstrated. However, practical treatments for such patients have not yet been established. Here we identified IL33 as a key driver of polyploidy, followed by rapid proliferation after treatment. IL33 induction transformed tumor cells into polyploid giant cells, showing abnormal cell cycle without cell division accompanied by Snail deregulation and p53 inactivation; small progeny cells were generated in response to treatment stress. Simultaneously, soluble IL33 was released from tumor cells, leading to expansion of receptor ST2-expressing cells including IL17RB+GATA3+ cells, which promoted tumor progression and metastasis directly and indirectly via induction of immune exhaustion and dysfunction. Blocking IL33 with a specific mAb in murine IL33+ metastatic tumor models abrogated negative consequences and successfully elicited antitumor efficacy induced by other combined treatments. Ex vivo assays using tumor tissues and peripheral blood mononuclear cells of patients with cancer validated the clinical relevancy of these findings. Together, these data suggest that targeting the IL33-ST2 axis is a promising strategy for diagnosis and treatment of patients likely to be resistant to treatments in the clinical settings. SIGNIFICANCE: These findings indicate that the functional role of IL33 in cancer polyploidy contributes to intrinsic and extrinsic mechanisms underlying treatment failure.

Correlation between immune-related adverse events and prognosis in patients with gastric cancer treated with nivolumab.

BACKGROUND: Recent studies have shown that immune-related adverse events (irAEs) caused by immune checkpoint inhibitors were associated with clinical benefit in patients with melanoma or lung cancer. In advanced gastric cancer (AGC) patients, there have been few reports about the correlation between irAEs and efficacy of immune checkpoint inhibitors. In this study, we retrospectively investigated the correlation between irAEs and efficacy in AGC patients treated with nivolumab. METHODS: The subjects of this study were AGC patients received nivolumab monotherapy between January 2015 and August 2018. IrAEs were defined as those AEs having a potential immunological basis that required close follow-up, or immunosuppressive therapy and/or endocrine therapy. We divided the patients who received nivolumab into two groups based on occurrence of irAEs; those with irAEs (irAE group) or those without (non-irAE group). We assessed the efficacy in both groups. RESULTS: Of the 65 AGC patients that received nivolumab monotherapy, 14 developed irAEs. The median time to onset of irAEs was 30.5 days (range 3-407 days). Median follow-up period for survivors was 32 months (95% CI, 10.8 to 34.5). The median progression-free survival was 7.5 months (95% CI, 3.6 to 11.5) in the irAE group and 1.4 months (95% CI, 1.2 to 1.6) in the non-irAE group (HR = 0.11, p < 0.001). The median overall survival was 16.8 months (95% CI, 4.4 to not reached) in the irAE group and 3.2 months (95% CI, 2.2 to 4.1) in the non-irAE group (HR = 0.17, p < 0.001). Multivariate analysis demonstrated that number of metastatic sites ≥2 (HR = 2.15; 95% CI, 1.02 to 4.54), high ALP level (HR = 2.50; 95% CI, 1.27 to 4.54), and absence of irAEs (HR = 9.54, 95% CI, 3.34 to 27.30 for yes vs. no) were associated with a poor prognosis. The most frequent irAEs was diarrhea/colitis (n = 5). Grade 3 adverse events were observed in 6 patients; hyperglycemia (n = 2), diarrhea/colitis (n = 1), adrenal insufficiency (n = 1), aspartate aminotransferase increased (n = 1), peripheral motor neuropathy (n = 1). There were no grade 4 or 5 adverse events related to nivolumab. CONCLUSIONS: Development of irAEs was associated with clinical benefit for AGC patients receiving nivolumab monotherapy.

Chemoradiotherapy for Local Recurrence of Rectal Cancer: A Single Center Study of 18 Patients.

BACKGROUND/AIM: When possible, surgical resection is recommended for local recurrence after resection of colorectal cancer. In unresectable cases, chemotherapy is usually indicated, although the success of chemoradiotherapy (CRT) in this setting is unclear. PATIENTS AND METHODS: We retrospectively reviewed the treatment outcomes of 18 patients who received CRT for unresectable local recurrence after radical colorectal cancer surgery at our hospital between January 2000 and May 2016. RESULTS: Of these 18 patients, three experienced complete response and four experienced partial response, resulting in a 39% overall response. With a median follow-up time of 42 months, the 5-year progression-free survival and overall survival were 34.8% and 54.4%, respectively; associated with a median local failure-free survival time of 40.9 months. Two of the three patients that underwent CRT remained local failure free for 5 years. CONCLUSION: CRT for local recurrence of rectal cancer without distant metastasis produces similar overall survival rates and local control as conventional surgical resection.

Hyperprogressive disease during nivolumab or irinotecan treatment in patients with advanced gastric cancer.

BACKGROUND: Nivolumab showed a survival benefit for advanced gastric cancer (AGC). However, an acceleration of tumour growth during immunotherapy, (hyperprogressive disease, HPD) has been reported in various cancers. This study reviewed the HPD in patients with AGC treated with nivolumab or irinotecan. METHODS: The subjects of this retrospective study were patients with AGC with measurable lesions, and their tumour growth rates (TGR) during nivolumab or irinotecan were compared with those during prior therapy. HPD was defined as an increase in TGR more than twofold. RESULTS: 34 and 66 patients received nivolumab and irinotecan in third or later line between June 2009 and September 2018 at our hospital; 22 patients receiving nivolumab had prior treatment with irinotecan, and one patient received irinotecan after nivolumab. Nivolumab and irinotecan showed no differences in disease control rates (38.2% and 34.8%) and in progression-free survival (PFS) (HR 1.1, 95% CI 0.7 to 1.6, p=0.802). The incidence of HPD was slightly higher after nivolumab (29.4%) than after irinotecan (13.5%) (p=0.0656), showing no differences in background between the patients with and without HPD. Compared between HPD and PD other than HPD after nivolumab, the HRs for PFS and overall survival (OS) were 1.1 (95% CI 0.5 to 2.7; p=0.756), and 2.1 (95% CI 0.7 to 5.8; p=0.168), but such clear difference in OS was not observed after irinotecan. CONCLUSIONS: HPD was observed more frequently after nivolumab compared with irinotecan, which was associated with a poor prognosis after nivolumab but not so clearly after irinotecan.

Efficacy of Prophylactic G-CSF in Patients Receiving FOLFIRINOX: A Preliminary Retrospective Study.

OBJECTIVE: Recent guidelines have adopted an incidence of febrile neutropenia (FN) threshold of 20% for the use of prophylactic granulocyte colony-stimulating factor (G-CSF). In a Japanese phase II study of a combination chemotherapy regimen consisting of oxaliplatin, irinotecan, fluorouracil and leucovorin (FOLFIRINOX) for Japanese patients with advanced pancreatic cancer, the incidence of FN and severe neutropenia were 24.7% and 77.8%, respectively, without G-CSF prophylaxis. The aim of this retrospective study was to investigate the incidence of FN or severe neutropenia induced by full-dose FOLFIRINOX administration with G-CSF prophylaxis during the first cycle of treatment. METHODS: Patients with advanced pancreatic cancer who received FOLFIRINOX with G-CSF prophylaxis during the first cycle of treatment from January 2014 to August 2014 were investigated and the frequency of adverse events during the first cycle was measured. RESULTS: Among seven patients who received FOLFIRINOX, six patients met the eligibility criteria. The patient characteristics were as follows: median age (range), 57 (50-66); men/women, 3/3; performance status 0/1, 2/4. Grade 3/4 hematological adverse events were as follows: leukopenia in 33% of the patients, neutropenia in 33% of the patients, thrombocytopenia in 33% of the patients and FN in 17% of the patients. One patient was heterozygous for the UGT1A1*6 and UGT1A1*28 polymorphisms and experienced FN. Grade3/4 non-hematological adverse events were as follows: anorexia in 33% of the cases and nausea in 50% of the cases. CONCLUSION: Although the present study was retrospective and small, the simultaneous administration of G-CSF might be effective for the prevention of severe neutropenia and FN in patients treated with FOLFIRINOX.

[A Case of Esophageal Neuroendocrine Carcinoma for Which Irinotecan and Cisplatin Combination Therapy Was Effective].

A 72-year-old previously healthy man visited our hospital with complaints of hoarseness and dysphagia. Computed tomography showed wall thickening of the thoracic esophagus; invasion to the left main bronchus, aorta, and right supraclavicular lymph nodes (LNs); right recurrent nerve LNs; and cardiac LN swelling. Esophagogastroduodenoscopy revealed an elevated tumor in the middle thoracic esophagus, which was similar to a submucosal tumor and had a longitudinal ulcer at its center. Pathologicexamination showed a tumor with a high N/C ratio, and immunohistochemical staining showed the tumor was CD56 and NSE positive, with a Ki-67 index >80%. We diagnosed esophageal neuroendocrine carcinoma (NEC), cT4N3M0, Stage IVa. We started chemotherapy with irinotecan and cisplatin (IP therapy) according to a regimen for small-cell lung cancer. After 3 courses of chemotherapy, the primary lesion and the LN swelling had almost disappeared. Esophageal NEC is relatively rare disease, so there are no standard established treatments. We report a case of esophageal NEC for which IP therapy was effective with the relevant literature cited.

Acute pericarditis as the first manifestation of familial Mediterranean fever: a possible relationship with idiopathic recurrent pericarditis.

A 56-year-old man was admitted to our hospital due to periodic episodes of acute pericarditis. These episodes occurred monthly along with a high fever and elevation of the C-reactive protein (CRP) level. The patient became afebrile and his CRP level decreased following the administration of a non-steroidal anti-inflammatory drug. A mutation analysis revealed the heterozygote of the familial Mediterranean fever (FMF) gene (E84K, G304R). This finding confirmed our diagnosis, and we treated the patient with colchicine. He responded to treatment and has been visiting our hospital without disease recurrence. FMF should be included in the differential diagnosis of repeated episodes of pericarditis.

Retrospective study as first-line chemotherapy combined anti-VEGF antibody with fluoropyrimidine for frail patients with unresectable or metastatic colorectal cancer.

BACKGROUND/AIM: Combination chemotherapies of oxaliplatin or irinotecan with fluoropyrimidine and molecular target drug were reported to be active in several clinical studies and so regarded as a first-line standard therapy for unresectable or metastatic colorectal cancer. However, the incidence of adverse events is not so low. We investigated the efficacy and safety of chemotherapy combined bevacizumab with fluoropyrimidine as a first-line treatment for frail patients. METHODS: Twenty-six patients with unresectable or metastatic colorectal cancer who were treated with first-line chemotherapy combined bevacizumab with S-1 or 5FU/LV (modified Roswell Park Memorial Institute regimen) at our hospital between October 2007 and December 2010 were retrospectively investigated. RESULTS: The median age was 72 years (range 66-84). Performance status was 0, 1 and 2 in 8, 17 and 1 patient, respectively. The primary lesion was located in the colon in 14 patients and in the rectum in 12. Twenty patients were with resection of the primary lesion and 6 were without, 8 were with postoperative adjuvant chemotherapy and 18 were without. The number of metastasized organs was 1, 2 and 3 in 17, 9 and 0 patients, respectively. The liver, lung, lymph node and peritoneum were metastasized in 9, 9, 11 and 5 patients, respectively. The KRAS gene was wild in 11, mutated in 7 and unknown in 8 patients. Bevacizumab with S-1 was used in 17 patients and bevacizumab with 5FU/LV was used in 9. Response and disease control rates were 50 and 100%, respectively. The median duration of progression-free survival was 9.1 months and the median time to treatment failure was 9.0 months. The incidences of all grades of neutropenia and hypertension were 31%, those of grade 3 or severer were 12%, and those of other adverse events were low. Grade 3 cerebral hemorrhage, grade 4 pulmonary embolism and grade 5 febrile neutropenia each occurred in 1 patient. CONCLUSION: The first-line chemotherapy combined bevacizumab with fluoropyrimidine for frail patients with unresectable or metastatic colorectal cancer in Japan was comparable to the safety and efficacy of combination therapy reported previously in Western countries.

Crystallographic study of wild-type carbonic anhydrase alpha CA1 from Chlamydomonas reinhardtii.

Carbonic anhydrases (CAs) are ubiquitously distributed and are grouped into three structurally independent classes (alphaCA, betaCA and gammaCA). Most alphaCA enzymes are monomeric, but alphaCA1 from Chlamydomonas reinhardtii is a dimer that is uniquely stabilized by disulfide bonds. In addition, during maturation an internal peptide of 35 residues is removed and three asparagine residues are glycosylated. In order to obtain insight into the effects of these structural features on CA function, wild-type C. reinhardtii alphaCA1 has been crystallized in space group P6(5), with unit-cell parameters a=b=134.3, c=120.2 A. The crystal diffracted to 1.88 A resolution and a preliminary solution of its crystal structure has been obtained by the MAD method.