A multicenter, prospective, phase II trial of second-line aflibercept plus FOLFIRI in patients with metastatic colorectal cancer refractory to an anti-EGFR antibody: HGCSG1801.

Aflibercept (AFL) plus FOLFIRI prolongs overall survival (OS) in patients with metastatic colorectal cancer (mCRC). However, there is limited evidence on the efficacy and safety of AFL plus FOLFIRI previously treated with anti-epidermal growth factor receptor (EGFR) agents. Therefore, we conducted a prospective open-label phase II trial evaluating the efficacy and safety of AFL plus FOLFIRI in Japanese patients with mCRC failing a prior oxaliplatin-based chemotherapy plus an anti-EGFR agent. AFL (4 mg/kg iv) followed by FOLFIRI (irinotecan 180 mg/m2, leucovorin 200 mg/m2 iv, bolus 5-fluorouracil [5-FU] 400 mg/m2, and infusional 5-FU 2400 mg/m2/46 h) was given every 2 weeks until progression or unacceptable toxicities. The primary endpoint was progression-free survival (PFS) rate at 6 months. Forty three patients were enrolled between November 2019 and October 2022. The primary endpoint was met: 6-month PFS rate was 58.8% (90% confidence interval [CI], 45.7%-72.0%). Median PFS and OS were 7.3 months (95% CI, 5.5-11.0 months) and 18.8 months (95% CI, 12.9-26.6 months), respectively. The overall response rate was 20.9% (95% CI, 10.0-36.0%) and disease control rate was 88.4% (95% CI, 74.9-96.1%). The main grade ≥3 adverse events included hypertension (62.8%), neutropenia (55.8%), leukopenia (25.6%), febrile neutropenia (11.6%), fatigue (9.3%), anorexia (9.3%), proteinuria (9.3%), and diarrhea (7.0%). No deaths and no new safety signals with a causal relation to the study treatment were observed. This study suggests that AFL plus FOLFIRI shows a high response rate and a manageable safety profile in Japanese patients with mCRC who failed prior oxaliplatin-based chemotherapy plus an anti-EGFR agent.

A DPC Database Study on the Safety of Atezolizumab/Bevacizumab/Carboplatin/Paclitaxel in Non-small Cell Lung Cancer in Japanese Patients.

INTRODUCTION: Atezolizumab, bevacizumab, carboplatin, and paclitaxel (ABCP) combination therapy is a standard of care for advanced non-squamous non-small cell lung cancer (NSQ-NSCLC); however, the lack of safety data limits its clinical application in Japan. METHODS: This study compared the safety of ABCP with that of bevacizumab, carboplatin, and paclitaxel (BCP) combination for the treatment of advanced NSQ-NSCLC in Japanese patients by evaluating the clinical background and incidence of adverse events (AEs) based on data extracted from the Diagnosis Procedure Combination (DPC) database. Incidence rates and restricted mean survival times (RMSTs) for up to 1 year were analyzed for 19 clinically important AEs. Covariates were adjusted using the inverse probability weighting method. RESULTS: A search conducted using the International Statistical Classification of Diseases and Related Health Problems 10th Revision codes identified 350,987 patients, of whom 202 were included in the ABCP cohort and 232 in the BCP cohort. Among the 19 AEs, the incidence of skin disorder and febrile neutropenia (FN) was significantly higher in the ABCP cohort versus the BCP cohort. The adjusted incidence rate ratios were 2.65 [95% confidence interval (CI) 1.43-4.91] for skin disorder and 1.70 (95% CI 1.01-2.85) for FN. The adjusted RMST differences were - 64.2 days (95% CI - 93.0 to - 35.4 days) and - 46.0 days (95% CI - 73.5 to - 18.5 days) for skin disorder and FN, respectively. These results were comparable to those of other pivotal clinical trials. CONCLUSIONS: The findings of this DPC database study highlight the safety of ABCP in Japanese clinical practice, and this methodology may facilitate more efficient research in real-world settings. TRIAL REGISTRATION: UMIN Clinical Trials Registry ID UMIN000041507.

A DPC Database Study on the Safety of Atezolizumab/Carboplatin/Etoposide in Extensive-Disease Small Cell Lung Cancer in Japanese Patients.

INTRODUCTION: Atezolizumab, carboplatin, and etoposide (ACE) therapy is a standard of care for extensive-disease small cell lung cancer (SCLC); however, its safety data are scarce, limiting generalization to the Japanese population. METHODS: This study aimed to compare the safety of ACE versus carboplatin and etoposide (CE) therapies in Japanese patients using the Diagnosis Procedure Combination (DPC) database by comparing the incidence of adverse events (AEs). Retrospective data on clinical background and AEs were extracted from the DPC database. Incidence rates and restricted mean survival times (RMSTs) up to 6 months were analyzed for 19 clinically important AEs. Covariates were adjusted using the inverse probability weighting method. RESULTS: A total of 330,774 patients were identified using the International Statistical Classification of Diseases and Related Health Problems 10th Revision codes, of whom 277 were included in the ACE cohort and 478 in the CE cohort. Among the 19 AEs, the incidence of skin disorder and thyroid dysfunction was significantly higher in the ACE cohort compared with the CE cohort. The adjusted incidence rate ratios were 2.38 (95% confidence interval [CI] 1.04-5.43) for skin disorder and 6.92 (95% CI 2.00-23.89) for thyroid dysfunction. The adjusted RMST differences were - 8.2 days (95% CI - 16.0 to - 0.4 days) for skin disorder and - 8.8 days (95% CI - 15.7 to - 1.9 days) for thyroid dysfunction. CONCLUSIONS: This study provides evidence regarding the safety of ACE combination therapy in Japanese clinical practice using the DPC database, with results comparable to those reported in pivotal clinical trials. TRIAL REGISTRATION: UMIN Clinical Trials Registry ID UMIN000041508.

Study protocol for HGCSG1801: A multicenter, prospective, phase II trial of second-line FOLFIRI plus aflibercept in patients with metastatic colorectal cancer refractory to anti-EGFR antibodies.

Background: The first-line chemotherapy for patients with RAS and BRAF wild-type metastatic colorectal cancer (mCRC) commonly involves cytotoxic regimens, such as FOLFOX and FOLFIRI, combined with epidermal growth factor receptor (EGFR) antibodies. When progression occurs following anti-EGFR antibody-combined chemotherapy, anti-angiogenic inhibitors can be used as second-line treatment. Although randomized controlled trials have shown that anti-angiogenic inhibitors [bevacizumab, ramucirumab, and aflibercept (AFL)] carry survival benefit when combined with FOLFIRI as second-line chemotherapy, such trials did not provide data on patients with mCRC refractory to anti-EGFR antibody-combined chemotherapy. Therefore, our group planned a multicenter, nonrandomized, single-arm, prospective, phase II study to investigate the safety and efficacy of FOLFIRI plus AFL as a second-line chemotherapy for patients with mCRC refractory to oxaliplatin-based chemotherapy combined with anti-EGFR antibodies. Methods: FOLFIRI (irinotecan 180 mg/m2, l-leucovorin 200 mg/m2, bolus 5-FU 400 mg/m2, and infusional 5-FU 2400 mg/m2/46 h) and AFL (4 mg/kg) will be administered every 2 weeks until progression or unacceptable toxicities occur. The primary endpoint will be the 6-month progression-free survival (PFS) rate, whereas the secondary endpoints will include overall survival, PFS, response rate, disease control rate, adverse events, and relative dose intensity for each drug. A sample size of 41 participants will be required. This study will be sponsored by the Non-Profit Organization Hokkaido Gastrointestinal Cancer Study Group and will be supported by a grant from Sanofi. Discussion: There is only an observational study reporting data on FOLFIRI plus AFL for patients with mCRC who previously received anti-EGFR antibodies; therefore, a prospective clinical trial is needed. This study will prospectively evaluate the efficacy and safety of FOLFIRI plus AFL in patients with mCRC who are resistant to anti-EGFR antibodies and have limited data. Moreover, this study will reveal predictive biomarkers for AFL-based chemotherapy. Clinical trial registration: Japan Registry of Clinical Trials, jRCTs011190006. Registered 19 November, 2019, https://jrct.niph.go.jp/latest-detail/jRCTs011190006.

A Chemical Strategy toward Novel Brain-Penetrant EZH2 Inhibitors.

Aberrant gene-silencing through dysregulation of polycomb protein activity has emerged as an important oncogenic mechanism in cancer, implicating polycomb proteins as important therapeutic targets. Recently, an inhibitor targeting EZH2, the methyltransferase component of PRC2, received U.S. Food and Drug Administration approval following promising clinical responses in cancer patients. However, the current array of EZH2 inhibitors have poor brain penetrance, limiting their use in patients with central nervous system malignancies, a number of which have been shown to be sensitive to EZH2 inhibition. To address this need, we have identified a chemical strategy, based on computational modeling of pyridone-containing EZH2 inhibitor scaffolds, to minimize P-glycoprotein activity, and here we report the first brain-penetrant EZH2 inhibitor, TDI-6118 (compound 5). Additionally, in the course of our attempts to optimize this compound, we discovered TDI-11904 (compound 21), a novel, highly potent, and peripherally active EZH2 inhibitor based on a 7 member ring structure.

Selective PPARα Modulator Pemafibrate and Sodium-Glucose Cotransporter 2 Inhibitor Tofogliflozin Combination Treatment Improved Histopathology in Experimental Mice Model of Non-Alcoholic Steatohepatitis.

Ballooning degeneration of hepatocytes is a major distinguishing histological feature of non-alcoholic steatosis (NASH) progression that can lead to cirrhosis and hepatocellular carcinoma (HCC). In this study, we evaluated the effect of the selective PPARα modulator (SPPARMα) pemafibrate (Pema) and sodium-glucose cotransporter 2 (SGLT2) inhibitor tofogliflozin (Tofo) combination treatment on pathological progression in the liver of a mouse model of NASH (STAM) at two time points (onset of NASH progression and HCC survival). At both time points, the Pema and Tofo combination treatment significantly alleviated hyperglycemia and hypertriglyceridemia. The combination treatment significantly reduced ballooning degeneration of hepatocytes. RNA-seq analysis suggested that Pema and Tofo combination treatment resulted in an increase in glyceroneogenesis, triglyceride (TG) uptake, lipolysis and liberated fatty acids re-esterification into TG, lipid droplet (LD) formation, and Cidea/Cidec ratio along with an increased number and reduced size and area of LDs. In addition, combination treatment reduced expression levels of endoplasmic reticulum stress-related genes (Ire1a, Grp78, Xbp1, and Phlda3). Pema and Tofo treatment significantly improved survival rates and reduced the number of tumors in the liver compared to the NASH control group. These results suggest that SPPARMα and SGLT2 inhibitor combination therapy has therapeutic potential to prevent NASH-HCC progression.

Multisession CyberKnife Radiosurgery for Orbital Cavernous Hemangiomas.

Orbital cavernous hemangioma is a rare benign tumor that causes protrusion of the eye-ball and lowers visual acuity. Surgical resection is the first choice of treatment, however, it is challenging due to the anatomical structure of the orbit. Stereotactic radiosurgery (SRS) has become an established alternative treatment for any challenging microsurgery in the skull. Five cases of orbital cavernous hemangioma were successfully treated with multisession CyberKnife (Accuray, Sunnyvale, CA, USA) stereotactic radiotherapy. The tumor volume ranged from 0.2 cc to 11.9 cc, all of which decreased in size after treatment. The radiation prescription dose ranged from 24 Gy to 26.1 Gy with fractions of 5 or 6. Visual acuity was preserved in all cases. Thus, multisession CyberKnife radiotherapy for orbital cavernous hemangioma might be a safe and effective treatment option.

Hemostasis through Extended Transsphenoidal Route for Subarachnoid Hemorrhage after Conventional Transsphenoidal Surgery for a Pituitary Adenoma.

This report describes a 49-year-old male patient who presented with a pituitary adenoma extending to the suprasellar region. Subarachnoid hemorrhage (SAH) occurred after conventional transnasal transsphenoidal surgery for a non-functioning pituitary adenoma despite no suprasellar arachnoid membrane breakdown. Through extended transsphenoidal route, the suprasellar hematoma was removed and bleeding from a small vessel thought to be the branch of left superior hypophyseal artery was successfully controlled. Indeed, several case reports regarding this rare complication have been published, but the mechanism of SAH has never been identified and the prognosis was poor in most cases. This report illustrates the origin and mechanism of the bleeding clearly using the intraoperative video. This case suggests that immediate therapeutic intervention is necessary and extended transnasal transsphenoidal repeat surgery is useful for an appropriate hemostasis and removal of hematoma located in the suprasellar region.

CyberKnife Radiotherapy for Skull Base Petroclival Metastases Including Dorello's Canal: Report of 10 Cases.

Skull base petroclival metastases cause diplopia due to abducens nerve palsy. Diplopia is visually disabling, and skull base metastasis is extremely difficult to treat even with microscopic surgery. However, stereotactic radiotherapy with CyberKnife (Accuray Incorporated, Sunnyvale, California) has been very successful in 10 cases. As the abducens nerve runs through Dorello's canal in the skull base, the radiation dose and fraction were adjusted to avoid damage to the nerve. Since these metastases are not located inside the brain but in the skull base, contrast magnetic resonance imaging (MRI) combined with fluorodeoxyglucose-positron emission tomography (FDG-PET) was essential to detect the cancers.

Long-range intramolecular allostery and regulation in the dynein-like AAA protein Mdn1.

Mdn1 is an essential mechanoenzyme that uses the energy from ATP hydrolysis to physically reshape and remodel, and thus mature, the 60S subunit of the ribosome. This massive (>500 kDa) protein has an N-terminal AAA (ATPase associated with diverse cellular activities) ring, which, like dynein, has six ATPase sites. The AAA ring is followed by large (>2,000 aa) linking domains that include an ∼500-aa disordered (D/E-rich) region, and a C-terminal substrate-binding MIDAS domain. Recent models suggest that intramolecular docking of the MIDAS domain onto the AAA ring is required for Mdn1 to transmit force to its ribosomal substrates, but it is not currently understood what role the linking domains play, or why tethering the MIDAS domain to the AAA ring is required for protein function. Here, we use chemical probes, single-particle electron microscopy, and native mass spectrometry to study the AAA and MIDAS domains separately or in combination. We find that Mdn1 lacking the D/E-rich and MIDAS domains retains ATP and chemical probe binding activities. Free MIDAS domain can bind to the AAA ring of this construct in a stereo-specific bimolecular interaction, and, interestingly, this binding reduces ATPase activity. Whereas intramolecular MIDAS docking appears to require a treatment with a chemical inhibitor or preribosome binding, bimolecular MIDAS docking does not. Hence, tethering the MIDAS domain to the AAA ring serves to prevent, rather than promote, MIDAS docking in the absence of inducing signals.

Pemafibrate, a selective PPARα modulator, prevents non-alcoholic steatohepatitis development without reducing the hepatic triglyceride content.

Non-alcoholic steatohepatitis (NASH) is characterized by macrovesicular steatosis with ballooning degeneration of hepatocytes, diffused lobular inflammation, and fibrosis. PPAR ligands are promising therapeutic agents in NASH; accordingly, we evaluated the effects of the first clinically available selective PPARα modulator, pemafibrate. We found that pemafibrate improves F4/80-positive macrophage accumulation, ballooning degeneration of hepatocytes, and the non-alcoholic fatty liver disease (NAFLD) activity score without affecting triglyceride (TG) accumulation in the liver of a mouse model of NASH (STAM). A global gene expression analysis indicated that pemafibrate enhances TG hydrolysis and fatty acid ß-oxidation as well as re-esterification from dihydroxyacetone 3-phosphate and monoacylglycerol to TG. These changes are accompanied by the induction of genes involved in lipolysis and lipid droplet formation, along with an increased number and reduced size of lipid droplets in pemafibrate-treated livers. Pemafibrate reduced the expression of the cell adhesion molecule Vcam-1, myeloid cell markers, and inflammation- and fibrosis-related genes in STAM mice. Furthermore, pemafibrate significantly reduced VCAM-1 expression induced by high glucose in cultured human umbilical vein endothelial cells. These results suggest that pemafibrate prevents NASH development by reducing myeloid cell recruitment via interactions with liver sinusoidal endothelial cells, without altering hepatic TG accumulation.

Multiorgan Systems Study Reveals Igfbp7 as a Suppressor of Gluconeogenesis after Gastric Bypass Surgery.

Roux-en-Y gastric bypass (RYGB) surgery reduces weight in obese patients. A marked decrease in blood glucose levels occurs before weight loss; however, key molecules that improve the glycemic profile remain largely unknown. Using a murine RYGB surgery model, we performed multiorgan proteomics and bioinformatics to monitor the proteins and molecular pathways that change in this early glycemic response. Multiplexed proteomic kinetics data analysis revealed that the Roux limb, biliopancreatic limb, liver, and pancreas each exhibited unique temporal and molecular responses to the RYGB surgery. In addition, protein-protein network analysis indicated that the changes to the microbial environment in the intestine may play a crucial role in the beneficial effects of RYGB surgery. Furthermore, insulin-like growth factor binding protein 7 (Igfbp7) was identified as an early induced protein in the Roux limb. Known secretory properties of Igfbp7 prompted us to further investigate its role as a remote organ regulator of glucose metabolism. Igfbp7 overexpression decreased blood glucose levels in diet-induced obese mice and attenuated gluconeogenic gene expression in the liver. Secreted Igfbp7 appeared to mediate these beneficial effects. These results demonstrate that organs responded differentially to RYGB surgery and indicate that Igfbp7 may play an important role in improving blood glucose levels.

Promotion of the Warburg effect is associated with poor benefit from adjuvant chemotherapy in colorectal cancer.

Metabolic reprogramming, including the Warburg effect, is a hallmark of cancer. Indeed, the diversity of cancer metabolism leads to cancer heterogeneity, but accurate assessment of metabolic properties in tumors has not yet been undertaken. Here, we performed absolute quantification of the expression levels of 113 proteins related to carbohydrate metabolism and antioxidant pathways, in stage III colorectal cancer surgical specimens from 70 patients. The Warburg effect appeared in absolute protein levels between tumor and normal mucosa specimens demonstrated. Notably, the levels of proteins associated with the tricarboxylic citric acid cycle were remarkably reduced in the malignant tumors which had relapsed after surgery and treatment with 5-fluorouracil-based adjuvant therapy. In addition, the efficacy of 5-fluorouracil also decreased in the cultured cancer cell lines with promotion of the Warburg effect. We further identified nine and eight important proteins, which are closely related to the Warburg effect, for relapse risk and 5-fluorouracil benefit, respectively, using a biomarker exploration procedure. These results provide us a clue for bridging between metabolic protein expression profiles and benefit from 5-fluorouracil adjuvant chemotherapy.

T2 ∗ Relaxation Time Obtained from Magnetic Resonance Imaging of the Liver Is a Useful Parameter for Use in the Construction of a Murine Model of Iron Overload.

Aim: Iron overload is a life-threatening disorder that can increase the risks of cancer, cardiovascular disease, and liver cirrhosis. There is also a risk of iron overload in patients with chronic kidney disease. In patients with renal failure, iron storage is increased due to inadequate iron utilization associated with decreased erythropoiesis and also to the inflammatory status. To evade the risk of iron overload, an accurate and versatile indicator of body iron storage in patients with iron overload is needed. In this study, we aimed to find useful iron-related parameters that could accurately reflect body iron storage in mice in order to construct a murine model of iron overload. Methods: To select an appropriate indicator of body iron status, a variety of parameters involved in iron metabolism were evaluated. Noninvasively measured parameters were R1, R2, and R2 ∗ derived from magnetic resonance imaging (MRI). Invasively measured parameters included serum hepcidin levels, serum ferritin levels, and liver iron contents. Histopathological analysis was also conducted. Results/Conclusion: Among the several parameters evaluated, the MRI T2 ∗ relaxation time was able to detect iron storage in the liver as sensitively as serum ferritin levels. Moreover, it is expected that using an MRI parameter will allow accurate evaluation of body iron storage in mice over time.

One-lung ventilation in a patient with Fontan circulation undergoing diaphragmatic plication surgery: a case report.

BACKGROUND: Surgeries requiring one-lung ventilation (OLV) in patients with Fontan circulation pose great challenges. However, little information is available regarding the safety of OLV in Fontan patients when hemidiaphragmatic paralysis is present. CASE PRESENTATION: A 41-year-old woman who underwent repeated Fontan procedures was re-admitted to our hospital because of worsening shortness of breath. As left hemidiaphragmatic paralysis was considered to be contributing to her symptom, an open thoracic left diaphragmatic plication surgery was scheduled. A preoperative pulmonary artery angiogram revealed a remarkably reduced blood flow to the left lung. The surgeon requested OLV during the surgery. Despite our concern regarding the impact of OLV on the Fontan circulation, OLV did not result in major hemodynamic changes. CONCLUSION: OLV can be safely implemented in patients with hemidiaphragmatic paralysis with preserved Fontan circulation. Preoperative pulmonary artery angiography may provide useful information for estimating the impact of OLV on the Fontan circulation.

Iron attenuates erythropoietin production by decreasing hypoxia-inducible transcription factor 2α concentrations in renal interstitial fibroblasts.

Iron is an essential mineral for oxygen delivery and for a variety of enzymatic activities, but excessive iron results in oxidative cytotoxicity. Because iron is primarily used in red blood cells, defective erythropoiesis caused by loss of the erythroid growth factor erythropoietin (Epo) elevates iron storage levels in serum and tissues. Here, we investigated the effects of iron in a mouse model of Epo-deficiency anemia, in which serum iron concentration was significantly elevated. We found that intraperitoneal injection of iron-dextran caused severe iron deposition in renal interstitial fibroblasts, the site of Epo production. Iron overload induced by either intraperitoneal injection or feeding decreased activity of endogenous Epo gene expression by reducing levels of hypoxia-inducible transcription factor 2α (HIF2α), the major transcriptional activator of the Epo gene. Administration of an iron-deficient diet to the anemic mice reduced serum iron to normal concentration and enhanced the ability of renal Epo production. These results demonstrate that iron overload due to Epo deficiency attenuates endogenous Epo gene expression in the kidneys. Thus, iron suppresses Epo production by reducing HIF2α concentration in renal interstitial fibroblasts.

Overexpression of p54nrb/NONO induces differential EPHA6 splicing and contributes to castration-resistant prostate cancer growth.

The non-POU domain-containing octamer binding protein p54nrb/NONO is a multifunctional nuclear protein involved in RNA splicing, processing, and transcriptional regulation of nuclear hormone receptors. Through chromosome copy number analysis via whole-exome sequencing, we revealed amplification of the chromosome Xq11.22-q21.33 locus containing the androgen receptor (AR) and NONO genes in androgen-independent, castration-resistant prostate cancer (CRPC)-like LNCaP-SF cells. Moreover, NONO was frequently amplified and overexpressed in patients with CRPC. RNA sequencing data revealed that a truncated ephrin type-A receptor 6 (EPHA6) splice variant (EPHA6-001) was overexpressed in LNCaP-SF cells, and knockdown of NONO or EPHA6-001 prevented EPHA6-001 expression and reduced proliferation and invasion by LNCaP-SF cells grown under androgen deprivation conditions. Growth inhibition and differential splicing of EPHA6 mRNA by p54nrb/NONO were confirmed in gene silencing experiments in 22Rv1 PCa cells. Importantly, NONO knockdown in LNCaP-SF cells led to reduced tumor growth in castrated mice. These findings indicate that p54nrb/NONO is amplified and overexpressed in CRPC cells and clinical samples, and facilitates CRPC growth by mediating aberrant EPHA6 splicing. We therefore propose that p54nrb/NONO constitutes a novel and attractive therapeutic target for CRPC.

Patterns of Relapse after Definitive Chemoradiotherapy in Stage II/III (Non-T4) Esophageal Squamous Cell Carcinoma.

PURPOSE: The purpose of this study was to investigate the utility of surveillance after definitive chemoradiotherapy (dCRT) in patients with squamous cell carcinoma. METHODS: Patients who underwent dCRT for stage II/III (excluding T4) esophageal squamous cell carcinoma were analyzed. First failures following complete response were classified into luminal relapse (LR), regional relapse (RR), distant metastasis (DM), new cancer diagnosed by esophagogastroduodenoscopy (NC-E), and new cancer other than NC-E (NC-O). We focused on LR, RR, and NC-E, and analyzed their frequency, timings and survival outcomes after local treatments. RESULTS: Among 302 patients treated with dCRT, 204 achieved complete response. The number of patients who recurred with LR, RR, DM, NC-E, and NC-O were 28 (14% of 204), 13 (6%), 39 (19%), 34 (17%), and 16 (8%). Ninety-three percent of LRs were diagnosed within 3 years after dCRT, and all RRs were diagnosed within 2 years. Annual odds of NC-E did not decrease over time. Twenty-three patients with LR, 6 with RR, and 32 with NC-E underwent local treatment, and their median overall survivals were 49.2, 19.5, and 108.9 months. CONCLUSION: Surveillance with esophagogastroduodenoscopy may be important in the first 3 years after dCRT to detect LR and to detect NC-E beyond 3 years.

A phase II study of combination therapy with oral S-1 and cisplatin in elderly patients with advanced gastric cancer.

BACKGROUND: A combination of S-1 and cisplatin is recognized as one of the standard first-line chemotherapy regimens for patients with advanced gastric cancer. However, demographic analyses of pivotal phase III studies have showed that only a minority of treated patients were aged 76 years or older. The purpose of this phase II study was to evaluate the safety and efficacy of combination therapy with S-1 and cisplatin in elderly patients with chemotherapy-naive advanced gastric cancer. METHODS: Patients aged 76 years or older received S-1 40 mg/m2 orally twice daily for 21 days and cisplatin 60 mg/m2 intravenously infused at day 8 of each 35-day cycle. Dose modification was performed according to creatinine clearance. The primary endpoint was overall survival (OS). Secondary endpoints included response rate, progression-free survival (PFS), time to treatment failure (TTF), and adverse events. RESULTS: A total of 40 patients were enrolled. Median OS was 12.3 months, PFS was 7.8 months, and TTF was 4.3 months. The response rate was 54%. The most common grade 3-4 adverse events were anorexia (25%), neutropenia (23%), hyponatremia (20%), anemia (18%), and febrile neutropenia (8%). No treatment-related death occurred. CONCLUSIONS: Combination chemotherapy with S-1 and cisplatin is an effective and well-tolerated regimen for elderly patients with advanced gastric cancer when the dose is adjusted according to renal function.

[Comparison of Response to Chemotherapy between Ovarian and Extraovarian Metastasis of Gastric Cancer].

BACKGROUND: Ovarian metastasis of gastric cancer is thought to be less sensitive to chemotherapy. METHODS: The subjects of this retrospective study were 15 gastric cancer patients with ovarian metastasis treated with first-line chemotherapy between January 1998 and April 2015. Response to chemotherapy was compared between ovarian metastasis and other measurable lesions; progression free survival(PFS), post progression survival(PPS), and overall survival(OS)were compared among the patients showing disease progression only at the ovary(group A), only at lesions other than the ovary(group B), and at both sites(group C). RESULTS: The patient characteristics were as follows: median age 58 years(range 34-79); performance status 0/1, 4/11; histology of diffuse/intestinal type, 15/0; unilateral/bilateral ovarian metastasis, 5/10; metastasis to the perito- neum/lymph node/bone/pleura, 15/5/2/1; and chemotherapy regimen with S-1+cisplatin/S-1/methotrexate+5-fluorour- acil(5-FU)/5-FU, 9/3/2/1. Partial response/stable disease/progressive disease were obtained in 1/11/3 patients, respectively. In 5 patients having measurable lesions in the ovary and lymph nodes, the median of the largest decrease in size after chemotherapy was 2.8%(range -8.2 to 31.7)at the ovary and 39.4%(range 5.4 to 75.4)at the lymph nodes(p=0.018). The number of patients in the groups A/B/C who experienced disease progression were 6/5/4, respectively; there were no differences in PFS(median 8.6/6.3/7.3months, respectively). Group A showed the longest PPS and OS compared to group B and C(median OS 19.0/9.1/13.8 months and PPS 11.4/4.3/2.5 months, respectively). CONCLUSION: Compared with other metastatic sites, our findings suggest that ovarian metastasis of gastric cancer may show less chemo-response; however, its progression may have a smaller impact on survival.