Long-term survival in Japanese patients with far advanced carcinoma of the stomach

Among 1,220 Japanese patients with gastric carcinoma who had undergone resection in the Department of Surgery II, Kyushu University Hospital, Fukuoka, Japan from 1965 to 1980, there were 432 (35.4%) with far advanced carcinoma, designated as a lesion with factors such as peritoneal dissemination, hepatic metastasis, widespread nodal involvement extending to tertiary (hepatoduodenal, retropancreatic, and mesenteric) or quaternary (middle colic and paraaortic) nodes, or direct invasion to adjacent organs. The overall 5-year survival rate in these 432 patients was 10.2%. The 5-year survival rate in patients with a single factor was 16.3%, being significantly higher than the 2.8% or less in cases with more than 2 factors ( p<0.01). Patients with tertiary nodal involvement or directly invaded organs alone survived at a rate of 26.1% and 21.8% in the 5-year follow-up, respectively. Radical procedures such as extensive lymphadenectomy and combined resection of the invaded organs further lengthened the survival time. The 5-year survival rates were less than 10% in patients with other factors, singly or more than 2 factors in combination. There appear to be 2 subgroups in whom the rates of survival differ: potentially curable and noncurable patients. More intensive therapeutic regimens corresponding to both groups need to be considered.

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Resumen Entre 1,220 pacientes japoneses con carcinoma gástrico sometidos a resección en el Departamento de Cirugía II, Hospital de la Universidad de Kyushu, Fukuoka, Japan entre 1965 y 1980, hubo 432 (35.4%) con carcinoma avanzado, entendiéndose como tal una lesión con hallazgos tales como diseminación peritoneal, metástasis hepáticas, extensión ganglionar amplia hasta los ganglios terciarios (hepatoduodenales, retropancreáticos, y mesentéricos) o cuaternarios (cólicos medios y paraaórticos), o invasión directa de órganos adyacentes. La tasa global de supervivencia a 5 años en estos 432 pacientes fue 10.2%. La tasa de supervivencia a 5 a~nos en pacientes con uno solo de tales hallazgos fue 16.3%, que es significativamente mayor que la de 2.8% o menos en pacientes con más de 2 de tales hallazgos (p<0.01). Los pacientes con invasión ganglionar terciaria o con invasión directa de órganos solamente, sobrevivieron a una tasa de 26.1% y 21.8%, respectivamente, en el seguimiento a 5 años. Procedimientos radicales tales como la linfadenectomía amplia y la resección combinada de los órganos afectados resultó en prolongación del periodo de supervivencia. Las tasas de supervivencia a 5 años fueron menores de 10% en pacientes con otros hallazgos en combinaciones Únicas o de más de 2. Parece haber 2 subgrupos en quienes las tasas de supervivencia difieren: los pacientes potencialmente curables y los no curables. Regimenes terapéuticos correspondientes a los 2 grupos deben ser considerados.

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Résumé Parmi 1,220 japonais atteints de cancer de l'estomac qui ont subi une résection dans le Département de Chirurgie II de l'hÔpital Universitaire Kyushu, Fukuoka, Japan de 1965 à 1980, 432 (35.4%) présentaient des lésions avancées qu'il s'agisse de dissémination péritonéale, de métastases hépatiques, d'une extension ganglionnaire importante intéressant les groupes tertiaires (hépatoduodénal, rétro-pancréatique, et mésentérique) ou quaternaires (coliques moyens et paraaortiques) ou encore l'invasion directe d'organes voisins. Le taux de survie totale à 5 ans de ces 432 malades a été de 10.2%. Ce taux a été de 16.3% en présence d'un seul des facteurs et 2.8% ou moins en présence de plus de 2 facteurs (p<0.01). Le taux de survie à 5 ans fut respectivement de 26.1% et de 21.8% selon qu'existait un envahissement ganglionnaire tertiaire ou l'invasion isolée d'un organe voisin. Les techniques radicales: lymphadénectomie élargie et résection combinée des organes envahis sont suivies d'un allongement du temps de survie. Les taux de survie à 5 ans furent inférieurs à 10% chez les malades atteints d'autres facteurs isolés ou supérieurs à deux. Il apparaÎt ainsi que dans le cancer de l'estomac deux sous-groupes, dont le temps de survie est différent, sont à distinguer: les malades potentiellement curables et les malades incurables. Il est donc nécessaire de mettre au point des méthodes thérapeutiques efficaces en fonction des 2 groupes individualisés.

     

Antithrombin ameliorates endotoxin-induced organ dysfunction more efficiently when combined with danaparoid sodium than with unfractionated heparin

Objective This study investigated the potential benefits of combination therapy using antithrombin (AT) with danaparoid sodium (DA) compared with the use of AT with unfractionated heparin (UFH) in the treatment of sepsis.Methods Rats infused with lipopolysaccharide were treated with either DA alone, AT alone, AT plus DA, AT plus UFH, or human serum albumin as controls. AT (125 U/kg) was injected into the AT group immediately after lipopolysaccharide infusion. The AT/DA and AT/UFH groups received the same dose of AT in conjunction with either DA (400 U/kg) or UFH (400 U/kg). The status of the mesenteric microcirculation was examined by intra-vital microscopy and the laboratory indices of coagulation, inflammation, and organ dysfunction were measured.Results The coagulation markers were improved following the administration of DA or UFH. The decreases in the WBC counts were significantly suppressed in the AT/DA group. The elevation of IL-6 decreased in the AT, DA, and AT/DA groups (all p<0.01) but not in the AT/UFH group. The prostaglandin I₂ levels were significantly elevated only in the AT/DA group (p<0.05). The WBC adhesion was significantly suppressed in the DA, AT/UFH, and AT/DA groups (p<0.05), and the RBC velocity was best maintained in the AT/DA group with no associated increase in capillary hemorrhage. The elevation of ALT and BUN significantly improved only in the AT/DA group.Conclusion Organ dysfunction can thus be alleviated by even moderate doses of AT replacement when co-administered with DA.     

Effect of differences in cancer cells and tumor growth sites on recruiting bone marrow-derived endothelial cells and myofibroblasts in cancer-induced stroma

Cancer-stromal interaction is well known to play important roles during cancer progression. Recently we have demonstrated that bone marrow-derived vascular endothelial cells (BMD-VE) and myofibroblasts (BMD-MF) are recruited into the human pancreatic cancer cell line Capan-1 induced stroma. To assess the effect of the difference in cancer cell types on the recruitment of BMD-VE and BMD-MF, 10 kinds of human cancer cell line were implanted into the subcutaneous tissue of the immunodeficient mice transplanted with bone marrow of double-mutant mice (RAG-1-/- beta-gal Tg or RAG-1-/- GFP Tg). The recruitment frequency of BMD-VE (%BMD-VE) and BMD-MF (%BMD-MF), and tumor-associated parameters [tumor volume (TV), microvessel density (MVD) and stromal proportion (%St)] were measured. The correlation among them was analyzed. Although %BMD-VE and %BMD-MF varied (from 0 to 21.6%, 0 to 29.6%, respectively), depending on the cancer cell line, both parameters were significantly correlated with %St (p < 0.005). Furthermore %BMD-VE and %BMD-MF also significantly correlated (p < 0.005). In order to assess the effect of tumor growth sites on the recruitment of the cells of interest, a human pancreatic cancer cell line, Capan-1, was transplanted into 5 different sites: subcutaneous tissue, peritoneum, liver, spleen and lung. Tumors in the subcutaneous tissue and peritoneum induced desmoplastic stroma (%St = 22.7%, 19.5%, respectively) and contained BMD-VE (%BMD-VE = 21.6%, 16.5% respectively) and BMD-MF (%BMD-MF = 29.6%, 24.5%, respectively), but weak stromal induction without recruitment of BMD-VE or -MF was observed in the tumors at of the liver, spleen and lung (%St = 9.7%, 9.1%, 5.4%, respectively). cDNA microarray analysis identified the 29 genes that expression was especially up- or down-regulated in the cell line that induced an abundant stromal reaction. However they did not encoded the molecules that were directly involved in stromal cell recruitment (chemokines), differentiation (cytokines) or proliferation (growth factors). These results indicate that the recruitment of BMD-VE and -MF is required for stromal formation during cancer progression and that the cancer microenvironment is important in stromal reaction and the recruitment of BMD-VE and -MF.     

Fatigue in survivors of childhood acute lymphoblastic and myeloid leukemia in Japan

Background: Fatigue in cancer survivors is a serious problem in pediatric oncology, but reports on this issue are limited, especially in Asian countries. Methods: Sixty‐three patients with acute lymphoblastic leukemia and 18 patients with acute myeloid leukemia who attended a follow‐up outpatient clinic were enrolled. Participants were required to be >8 years of age, in remission, and without any cancer treatment for at least the previous 1 year. A control group consisted of 243 subjects whose age and gender were matched with the patient group. A questionnaire consisting of 12 items was devised for fatigue measurement. Results: Principal factor analysis identified three dimensions, defined as physical fatigue, decreased function, and altered mood. The mean total and the three fatigue dimension scores tended to be higher in the control group, but significant differences between the scores were seen only in the total and physical fatigue scores. Multiple regression analysis indicated an association of present older age or shorter duration after completion of treatment with total and physical fatigue, and an association of presence of total body irradiation with decreased function. Conclusion: Pediatric leukemia survivors in Japan experience equal or less fatigue compared with that of controls in different fatigue dimensions. Elucidation of underlying mechanisms of cancer‐related fatigue including the differences of cultural background among different countries is necessary for future study of this issue.     

A case of late-onset right ventricular failure after implantation of a continuous-flow left ventricular assist device

Postoperative right ventricular failure is usually apparent perioperatively or soon after left ventricular assist device insertion. Here, we report a case complicated by right ventricular failure that manifested 3 weeks after HeartMate II implantation. This case is also unique because the postoperative right ventricular failure was progressive over the years. We discuss how the smaller size of the left ventricle and untreated tricuspid regurgitation contributed to the development of right ventricular failure in this case.     

How to demonstrate the reversibility of end-organ function before implantation of left ventricular assist device in INTERMACS profile 2 patients?

For the time being, in Japan, two recently approved implantable ventricular assist devices (VADs) are indicated only when a patient has been listed for heart transplantation or approved to be eligible for heart transplantation by in-hospital committee. The reversibility of end-organ dysfunction must be expected before VAD implantation, but it is often hard to prove during worsening clinical status. We report two patients whose end-organ dysfunction had been eventually demonstrated to be reversible by invasive procedures such as transluminal liver biopsy or transient insertion of intra-aortic balloon pumping.     

Acid-insoluble human dentin as carrier material for recombinant human BMP-2

The aim of this study is to estimate the increase of bone-inductive potency by human demineralized dentin matrix (DDM) with recombinant human bone morphogenetic protein-2 (BMP-2). Human teeth were crushed, completely demineralized in 0.6M HCl, and freeze-dried. The tooth-derived material is called DDM. The shape of DDM was a particle type and its size varied from 0.4 to 0.8 mm. The BMP-2 dose-dependent study in the rat subcutaneous tissues demonstrated that the volume of induced bone and marrow increased at a dose-dependent manner. The time-course study of bone induction by the BMP-2 (5.0 μg)/DDM (70 mg) was estimated histologically and biochemically. Histological findings showed that the BMP-2/DDM increased bone and marrow sequentially between the DDM particles. Calcium content in the BMP-2/DDM-induced tissue was compatible to the histological findings. ALP activity in the BMP-2/DDM showed a maximal value at 1 week and gradually decreased. The morphometric analysis demonstrated that the BMP-2/DDM showed 66.9%, 79.0% in the volume of bone and marrow, and 32.4%, 21.0% in that of DDM at 8, 32 weeks, respectively. We confirmed that BMP-2 significantly accelerated bone formation in the acid-insoluble human-dentin carriers. These results indicate that human DDM should be an effective carrier for delivering BMP-2 and superior scaffold for bone-forming cells.     

Evaluation of Influenza Virus A/H3N2 and B Vaccines on the Basis of Cross-Reactivity of Postvaccination Human Serum Antibodies against Influenza Viruses A/H3N2 and B Isolated in MDCK Cells and Embryonated Hen Eggs

The vaccine strains against influenza virus A/H3N2 for the 2010-2011 season and influenza virus B for the 2009-2010 and 2010-2011 seasons in Japan are a high-growth reassortant A/Victoria/210/2009 (X-187) strain and an egg-adapted B/Brisbane/60/2008 (Victoria lineage) strain, respectively. Hemagglutination inhibition (HI) tests with postinfection ferret antisera indicated that the antisera raised against the X-187 and egg-adapted B/Brisbane/60/2008 vaccine production strains poorly inhibited recent epidemic isolates of MDCK-grown A/H3N2 and B/Victoria lineage viruses, respectively. The low reactivity of the ferret antisera may be attributable to changes in the hemagglutinin (HA) protein of production strains during egg adaptation. To evaluate the efficacy of A/H3N2 and B vaccines, the cross-reactivities of postvaccination human serum antibodies against A/H3N2 and B/Victoria lineage epidemic isolates were assessed by a comparison of the geometric mean titers (GMTs) of HI and neutralization (NT) tests. Serum antibodies elicited by the X-187 vaccine had low cross-reactivity to both MDCK- and egg-grown A/H3N2 isolates by HI test and narrow cross-reactivity by NT test in all age groups. On the other hand, the GMTs to B viruses detected by HI test were below the marginal level, so the cross-reactivity was assessed by NT test. The serum neutralizing antibodies elicited by the B/Brisbane/60/2008 vaccine reacted well with egg-grown B viruses but exhibited remarkably low reactivity to MDCK-grown B viruses. The results of these human serological studies suggest that the influenza A/H3N2 vaccine for the 2010-2011 season and B vaccine for the 2009-2010 and 2010-2011 seasons may possess insufficient efficacy and low efficacy, respectively.     

Two-Stage Operation for High-Risk Patients with Thoracic Esophageal Cancer: An Old Operation Revisited

Purpose

An esophagectomy followed by reconstruction for esophageal cancer is a highly aggressive operation. The purpose of this study was to justify a two-stage operation for high-risk patients with esophageal cancer.

Methods

The clinical results of 27 patients who underwent two-stage operation were compared with 118 patients who underwent a simultaneous resection and reconstruction (control subjects). The reasons for the selection of the two-stage operation were underlying general disease in 13 patients (liver dysfunction, n = 6; pulmonary disease, n = 3; poor performance status, n = 2; diabetes and renal failure, n = 1 each) and high-risk operation in 14 other patients (colon interposition, n = 7; salvage operation after definitive chemoradiotherapy, n = 4; and intraoperative events, n = 3). The patients initially underwent an esophagectomy and a cervical esophagostomy. Reconstruction was usually performed 2–3 weeks later.

Results

The patients in the two-stage group were older than the control patients (mean 67.8 vs. 61.6 years old). The morbidity rate of the two-stage operation was 29.6%, which was not statistically different than control patients (32.2%). Postoperative complications in the two-stage operation were anastomotic leakage in 5 patients, and pneumonia and wound infection in 1 patient each. No patient experienced in-hospital death. The survival rates were not statistically different between the two groups.

Conclusion

A two-stage operation is a safe operation that prevents the occurrence of critical postoperative complications, and it thus may be considered an important treatment strategy for high-risk patients with esophageal cancer.