Prognostic significance of the prognostic nutritional index in esophageal cancer patients undergoing neoadjuvant chemotherapy.

Nutritional status is one of the most important issues faced by cancer patients. Several studies have shown that a low preoperative nutritional status is associated with a worse prognosis in patients with various types of cancer, including esophageal cancer (EC). Recently, neoadjuvant chemotherapy (NAC) and/or radiotherapy have been accepted as the standard treatment for resectable advanced EC. However, NAC has the potential to deteriorate the nutritional status of a patient. This study aimed to evaluate the prognostic significance of the nutritional status for EC patients who underwent NAC. We retrospectively reviewed 66 squamous cell EC patients who underwent NAC consisting of docetaxel, cisplatin, and 5-fluorouracil followed by subtotal esophagectomy at Nara Medical University Hospital between January 2009 and August 2015. To assess the patients' nutritional status, the prognostic nutritional index (PNI) before commencing NAC and prior to the operation was calculated as 10 × serum albumin (g/dl) + 0.005 × total lymphocyte count in the peripheral blood (per mm3). The cutoff value of the PNI was set at 45. A multivariable analysis was performed to identify prognostic factors for overall survival (OS) and relapse-free survival (RFS). The mean pre-NAC and preoperative PNI were 50.2 ± 5.7 and 48.1 ± 4.7, respectively (P = 0.005). The PNI decreased following NAC in 44 (66.7%) patients. Before initiating NAC, 9 (13.6%) patients had a low PNI, and 12 (18.2%) patients had a low PNI prior to the operation. The pre-NAC PNI and preoperative PNI were significantly associated with the OS (P = 0.013 and P = 0.004, respectively) and RFS (P = 0.036 and P = 0.005, respectively) rates. The multivariable analysis identified the preoperative PNI as an independent prognostic factor for poor OS and RFS, although the pre-NAC PNI was not an independent predictor. Our results suggest that the preoperative PNI is a useful marker for predicting the long-term outcomes of EC patients undergoing NAC and subsequent subtotal esophagectomy. Therefore, patients with a low preoperative nutritional status may be at a higher risk of EC recurrence.

Endothelin B receptor expression correlates with tumour angiogenesis and prognosis in oesophageal squamous cell carcinoma.

BACKGROUND: The endothelin axis has been shown to have a pivotal role in several human malignancies. The aim of this study was to clarify the clinical importance of endothelin receptor type B (ETBR) in human oesophageal squamous cell carcinoma (OSCC). METHODS: We evaluated ETBR expression in 107 patients with OSCC by immunohistochemistry. Microvessel density (MVD) and lymphatic vessel density were assessed by CD31 and D2-40 immunostaining, respectively. Furthermore, CD4, CD8, and CD45RO+ tumour-infiltrating lymphocytes (TILs) were immunohistochemically analysed. RESULTS: Sixty-one (57%) cases showed high expression of ETBR. Endothelin receptor type B expression was correlated with several clinicopathological factors including tumour differentiation, tumour depth, and lymph node metastasis. The overall and disease-specific survival rates were significantly lower in patients with high ETBR expression than patients with low expression. Furthermore, multivariate analysis revealed that ETBR status was an independent prognostic factor for patient survival. Mechanistic analysis indicated that MVD was significantly higher in tumour tissues with high ETBR expression compared with those with low expression, suggesting that angiogenesis may be a key mechanism in tumour progression and metastasis of OSCC mediated by ETBR expression. By contrast, there were no significant correlations between TILs and ETBR expression. CONCLUSION: Endothelin receptor type B has a pivotal role in oesophageal cancer and may be therapeutic target for this intractable malignancy.

Simultaneous blockade of programmed death 1 and vascular endothelial growth factor receptor 2 (VEGFR2) induces synergistic anti-tumour effect in vivo.

Recent basic and clinical studies have shown that the programmed death ligand (PD-L)/PD-1 pathway has a significant role in tumour immunity, and its blockade has a therapeutic potential against several human cancers. We hypothesized that anti-angiogeneic treatment might augment the efficacy of PD-1 blockade. To this end, we evaluated combining the blockade of PD-1 and vascular endothelial growth factor receptor 2 (VEGFR2) in a murine cancer model using Colon-26 adenocarcinoma. Interestingly, simultaneous treatment with anti-PD-1 and anti-VEGFR2 monoclonal antibodies (mAbs) inhibited tumour growth synergistically in vivo without overt toxicity. Blocking VEGFR2 inhibited tumour neovascularization significantly, as demonstrated by the reduced number of microvessels, while PD-1 blockade had no impact on tumour angiogenesis. PD-1 blockade might promote T cell infiltration into tumours and significantly enhanced local immune activation, as shown by the up-regulation of several proinflammatory cytokine expressions. Importantly, VEGFR2 blockade did not interfere with T cell infiltration and immunological activation induced by PD-1 blockade. In conclusion, simultaneous blockade of PD-1 and VEGFR2 induced a synergistic in-vivo anti-tumour effect, possibly through different mechanisms that might not be mutually exclusive. This unique therapeutic strategy may hold significant promise for future clinical application.

Prognostic importance of tumour-infiltrating memory T cells in oesophageal squamous cell carcinoma.

Memory T cells survive for many months and years and are critically important for host defence in humans. In tumour immunity, they have been also suggested to play a significant role in tumour progression and metastasis. However, the role of memory T cells in actual human cancer remains largely unknown. In this study, the clinical importance of tumour-infiltrating CD45RO(+) memory T cells was investigated in human oesophageal squamous cell carcinoma (OSCC). CD45RO(+) T cells were evaluated by immunohistochemistry in primary OSCC tumours from 105 patients. Patients were classified into two groups as CD45RO(+hi) or CD45RO(+lo) based on the number of cells stained positively for CD45RO. No significant difference was observed between CD45RO status and several clinicopathological prognostic factors. However, the postoperative overall and disease-free survival for CD45RO(+hi) patients was significantly better than for CD45RO(+lo) patients. Furthermore, there were significant correlations of CD45RO status in the primary tumour with postoperative lymph node and pulmonary recurrence, suggesting that memory T cells may control postoperative metastatic recurrence. Most importantly, CD45RO(+) memory T cell status has a significant prognostic value for OSCC independently of conventional tumour-node-metastasis (TNM) classification. Our study may provide a rationale for developing a novel immunotherapy in intentional induction of memory T cells for the treatment of oesophageal cancer.

A comparison of surgery and radiation therapy for cT1 esophageal squamous cell carcinoma.

Surgery and radiation therapy have been used to treat esophageal squamous cell carcinoma. However, treatment outcomes have not yet been extensively investigated. The aim of this study was to compare surgery and radiation therapy for clinical T1 esophageal squamous cell carcinoma. A total of 67 clinical T1 esophageal squamous cell carcinoma patients were treated between January 1997 and December 2005; 29 had undergone radical esophagectomy (surgery group) and 38 were treated with definitive radiation therapy (radiation group). The mean patient age was lower in the surgery group than in the radiation group. In surgery group, respiratory complications, anastomotic leaks, recurrent nerve palsies, and anastomotic stenosis occurred in 7, 8, 6, and 5 patients, respectively. In radiation group, leucopenia, esophagitis, pericarditis were observed in 15, 3, and 3 patients, respectively. The 5-year overall survival rate for the surgery group was 68.9%, and 74.3% for the radiation group. There were no significant difference between groups (P= 0.3780). The 5-year relapse-free survival rate in the surgery group was 61.8% and 38.8% in the radiation group. The relapse-free survival rate was significantly higher in the surgery group than in the radiation group (P= 0.0051). The 5-year overall and relapse-free survival rates for tumors invaded into but not through the muscularis mucosa were 83.3% and 75.0%, respectively, in the surgery group and 78.8% and 33.3%, respectively, in the radiation group. There were no significant differences. The 5-year overall survival rates for patients with tumors that invaded the submucosal layer was 64.9% in the surgery group and 66.5% in the radiation group. This difference was not significant (P= 0.8712). The 5-year relapse-free survival rate in the surgery group (56.0%) was significantly higher than that in the radiation group (41.8%; P= 0.0219). In conclusion, surgery may become a standard treatment for cT1 esophageal cancer that can offer longer relapse-free survival, particularly for patients with tumors that invade the submucosa.

Factors influencing users' return home on discharge from a geriatric intermediate care facility in Japan.

OBJECTIVES: To determine the factors that influence users' destinations on discharge from Geriatric Intermediate Care Facilities (GICFs), which were established in Japan in 1987 to help hospitalized older people return home. DESIGN: Retrospective chart review. SETTING: A 94-bed GICF attached to Saku Central Hospital in Japan. SUBJECTS: Charts of all users (N = 437) aged 65 years and older, discharged from the GICF between July 1987 and February 1991, were reviewed. MEASUREMENTS: The independent variables, obtained from users' admission records, were age, sex, place of residence before admission, length of stay, intellectual impairment (assessed by Karasawa's diagnostic criteria for senile dementia), ability to perform activities of daily living (ADLs), and living arrangement of users in the GICF. The dependent variable was destination after discharge from the GICF. MAIN RESULTS: Multiple logistic regression analyses revealed that, compared with users who were able to successfully return home, users with little ability to perform ADLs, male users, and those admitted from other institutions were more likely to be hospitalized. Such analyses also revealed that users who came from institutions, had low ability to perform ADLs, and lived alone were more likely to be institutionalized in nursing homes. CONCLUSIONS: Evaluating a user's physical, mental, and socioeconomic conditions at an early stage of admission to a GICF may allow us to predict whether the user can be successfully discharged to his or her home or will have to remain in the GICF for an extended period.

[Autonomic nerve-sparing surgery combined with preoperative radio-chemotherapy in advanced lower rectal cancer patients].

Since 1985, we have studied autonomic nerve-sparing surgery combined with preoperative radiochemotherapy in patients with advanced rectal cancer to preserve genitourinary function without compromising radicality. The aim of this study was to evaluate postoperative genitourinary function and prognosis. A total of 84 patients with advanced rectal cancer underwent curative surgery combined with preoperative radio-chemotherapy. Of them, 76 underwent curative nerve-sparing surgery using radiation (42.6 Gy) and tegafur suppository. Postoperative genitourinary function, survival, and pelvic recurrence were investigated in these patients. The 5-year and 10-year disease-free survival rate was 80.7%, and the pelvic recurrence rate was 7.9% in patients receiving curative nerve-sparing surgery combined with radio-chemotherapy. All of these patients could micturate spontaneously, but preservation of sexual function was not as successful. Although this combined therapy is useful for curability and good postoperative quality of life, a new approach is needed to preserve sexual function.

Cholecystokinin antagonistic activities of loxiglumide.

Cholecystokinin (CCK) antagonistic activities of loxiglumide ((+/-)-4-(3,4-dichlorobenzamido)-N-(3-methoxypropyl)-N-pentylgl utaramic acid, CR1505, CAS 107097-80-3) were investigated in the gastrointestine and gallbladder in vivo. Intravenous administration of loxiglumide antagonized the CCK-induced reduction of gastric emptying in rats, acceleration of intestinal transport in mice, increase in ileal motility in rabbits, gallbladder contraction in guinea pigs and acceleration of gallbladder emptying in mice. Orally administered loxiglumide also antagonized the CCK-induced gallbladder emptying in mice. Furthermore, egg yolk-stimulated gallbladder emptying in mice was also inhibited by loxiglumide, indicating that this agent antagonizes not only exogenous but also endogenous CCK. These results demonstrate that loxiglumide is an intravenously and orally effective, potent CCK antagonist.

Effects of loxiglumide on pancreatic exocrine secretion stimulated by cholecystokinin-8 in conscious dogs.

The effects of loxiglumide (CAS 107097-80-3, CR 1505), a novel cholecystokinin-A(CCK-A) receptor antagonist, on pancreatic exocrine secretion stimulated by exogenously administered CCK-8 were examined in conscious dogs with chronic pancreatic fistula. Pancreatic exocrine secretion in dogs was significantly increased by intravenous infusion of CCK-8 at a dose of 0.06 microgram/kg/h. Loxiglumide inhibited CCK-8-augmented outputs of pancreatic protein, trypsin and amylase at intravenous doses of 1, 3, 10 mg/kg/h (p < 0.05 or 0.01), and inhibited pancreatic juice volume at a dose of 10 mg/kg/h (p < 0.05). These results demonstrated that the selective CCK-A antagonist loxiglumide inhibited the increase of pancreatic exocrine secretion stimulated by CCK-8 based on selective blockade of receptor binding of CCK in dogs.

Effects of loxiglumide on pancreatic exocrine secretion stimulated by meal in conscious dogs.

The effects of loxiglumide (CAS 107097-80-3, CR 1505), a novel cholecystokinin-A(CCK-A) receptor antagonist, on pancreatic exocrine secretion stimulated by meal were examined in conscious dogs with chronic pancreatic fistula. Pancreatic exocrine secretion was stimulated by intraduodenal infusion of a liquid test meal and postprandial plasma CCK levels were apparently elevated. Loxiglumide inhibited the meal-stimulated outputs of pancreatic protein, amylase and bicarbonate at an intravenous dose of 10 mg/kg/h (p < 0.05). However, loxiglumide did not show apparent inhibition of pancreatic juice volume and trypsin output. These results show that the selective CCK-A antagonist loxiglumide may inhibit the increase of pancreatic exocrine secretion based on selective blockade of receptor binding of CCK endogenously induced by meal in dogs.

General pharmacological profile of the novel cholecystokinin-A antagonist loxiglumide.

The general pharmacological properties of a novel cholecystokinin-A antagonist, loxiglumide ((+/-)-4-(3,4-dichlorobenzamido)-N-(3-methoxypropyl)-N-pentylgl utaramic acid, CR 1505, CAS 107097-80-3) on central nervous system, autonomic nervous system, cardio-respiratory system, gastrointestinal system, hematological and miscellaneous systems were investigated in experimental animals. 1. Central nervous system: At a dose of 30 mg/kg, i.v. loxiglumide showed ptosis in one of 6 mice, but at doses of 3 and 10 mg/kg, i.v. no change on gross behavior in mice. Loxiglumide had no effect on locomotor activity and thiopental-induced hypnosis, anti-convulsive activity, analgesic activity in mice and rectal temperature changes in rats. 2. Autonomic nervous system: In vitro, loxiglumide at concentrations of 10(-4) and 3 x 10(-4) mol/l slightly inhibited agonist-induced contractions in the isolated guinea pig ileum and spontaneous rhythmic contractions in the isolated non-pregnant rat uterus. But loxiglumide had no effect on oxytocin-induced contraction in isolated non-pregnant rat uterus. 3. Cardio-respiratory system: Loxiglumide had no effect on heart rate and electrocardiogram in anesthetized dogs. But it slightly increased blood pressure and decreased the frequency of respirations at a dose of 30 mg/kg, i.v. Furthermore, loxiglumide slightly decreased femoral arterial blood flow at doses of more than 3 mg/kg, i.v. On the other hand, it had no effect on contractile force or contraction rate in the isolated guinea pig atrium and resting tension in the isolated rabbit aorta. 4. Gastrointestinal system: Loxiglumide increased bile secretion at doses of 10 and 30 mg/kg, i.v. in anesthetized rats and at doses of 3, 10 and 30 mg/kg, i.v. in anesthetized dogs. However, total bile acid output was not affected by loxiglumide. On the other hand, loxiglumide had no effect on pancreatic secretion, gastric secretion and gastric emptying in rats and intestinal transport activity in mice. 5. Hematology: In vitro, in the case of samples without bovine serum albumin, at concentrations of more than 1.9 x 10(-3) mol/l loxiglumide showed hemolysis, while in the case of samples with bovine serum albumin, at concentrations of more than 6.9 x 10(-3) mol/l loxiglumide showed hemolysis, and its maximal potency was weak compared to albumin-free conditions. On the other hand, in vivo, loxiglumide had no effect on hemolysis. In addition, it had no effect on platelet aggregation, prothrombin time and activated partial thromboplastin time. 6. Miscellaneous pharmacological actions: Loxiglumide had no effect on local anesthetic activity in guinea pigs and renal function in mice. These results suggest that loxiglumide seems to produce no serious side effects on the central nervous system, autonomic nervous system, cardio-respiratory system, gastrointestinal system, hematological and miscellaneous systems at pharmacologically effective doses.