Hyperthermo-chemotherapy combined with cytoreductive surgery for the treatment of gastric cancer with peritoneal dissemination

Continuous hyperthermic peritoneal perfusion (CHPP) with anticancer agents (mitomycin C and cisplatin) in warm saline was performed in patients with peritoneal dissemination of gastric cancer following resection of the primary lesion. The effect of CHPP was examined by a second-look operation. This study includes 41 cases of gastric cancer with peritoneal dissemination but without liver metastasis treated during the past 6 years. The overall median survival was 14.6 months to 64.2 months from CHPP to death and the 3-year survival rate was 28.5%. Second look surgery revealed a remarkable diminution in the degree of peritoneal dissemination in 7 (50%) of 14 patients with disappearance of ascites after only one course of CHPP in 7 (77.8%) of 9 patients. Long-term 3 year-survival was noted in 4 (9.8%) patients on CHPP. Side effects were renal insufficiency in 2 (5%) patients, leukopenia in 2 (5%) patients, and perforation of the small intestine in 1 (2%) patient. These results suggest the effectiveness of CHPP in the treatment of gastric cancer with peritoneal dissemination.

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Resumen La perfusión hipertérmica continua (PHTC) con agentes anticancerosos (mitocina G y cisplatino) y solutión salina fue realizada en pacientes con cáncer gástrico con diseminación peritoneal después de resección de la lesión primaria, y el efecto de PHTC fue determinado mediante reexploración (operación de second look, OSL). La población de pacientes está constituída por 41 casos de cáncer gástrico con diseminación peritoneal pero sin metástasis hepáticas, tratdos en el curso de los últimos 6 años. La sobrevida media global fue de 437 dias (rango 28 a 1925 días) desde la PHTC hasta la muerte y la tasa de sobrevida a 3 años fue 28.5%. La OSL reveló una notoria disminución de la diseminación peritoneal en 7 (50%) de 14 casos y desaparición de la ascites después de sólo un ciclo de PHTC en 7 de 9 casos con ascitis. Sobrevida de 3 años ocurrió en 4 casos. Los efectos colaterales fueron insuficiencia renal en 2 casos (5%), leucopenia en 2 casos (5%) y perforación del intestino delgado en 1 caso (2%). Los anteriores resultados sugieren que la PHTC es eficaz en el tratamiento del cáncer gástrico con diseminación peritoneal.

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Résumé La perfusion péritonéale continue hyperthermique (PPCH) avec des agents anticancéreux comme le mitomycine C et la cis-platine avec sérum physiologique chauffé a été instaurée lorsqu'une carcinose d'origine gastrique a été trouvée. Les effets de la PCH ont été évalués chez 16 patients lors d'un second-look (SL). Cette étude concerne 41 patients avec carcinose péritonéale sans métastase hépatique observés au cours des 6 dernières années. La survie globale médiane était de 437 jours (extrêmes 28 à 1925 jours): le taux de survie a 3 ans était de 28.5%. Les lésions avaient diminué de façon notable chez 7 (50%) de 14 patients. L'ascite a disparu dans 7 des 9 cas. Une survie à long terme (3 ans) a été notée dans 4 cas. Les effets secondaires ont été une insuffisance rénale dans 2 cas (5%), une leucopénie dans 2 cas (5%) et une perforation de l'intestin grêle dans un cas (2%). Les résultats suggèrent que la PPCH est efficace dans le traitement du cancer gastrique avec dissémination péritonéale.

     

Hemiparkinsonism associated with the unilateral striatal necrosis: a case report

We report a patient with hemiparkinsonism associated with unilateral striatal necrosis of the contralateral side. The patient was an 18-year-old woman who had a two-month-history of difficulty in executing skilled movements with her right upper extremity. Neurological examination revealed that she had cogwheel rigidity and bradykinesia in her right upper and lower extremities. MRI revealed a well-delineated low signal intensity in T1-weighted and high signal intensity in T2-weighted images in the region of the putamen on the left side. Her laboratory data were unremarkable and mitochondrial gene mutation studies revealed no abnormality. It is extremely rare to encounter a case of parkinsonism associated with unilateral striatal necrosis.     

The conduct of in vitro and in vivo drug-drug interaction studies: a Pharmaceutical Research and Manufacturers of America (PhRMA) perspective.

Current regulatory guidances do not address specific study designs for in vitro and in vivo drug-drug interaction studies. There is a common desire by regulatory authorities and by industry sponsors to harmonize approaches, to allow for a better assessment of the significance of findings across different studies and drugs. There is also a growing consensus for the standardization of cytochrome P450 (P450) probe substrates, inhibitors and inducers and for the development of classification systems to improve the communication of risk to health care providers and to patients. While existing guidances cover mainly P450-mediated drug interactions, the importance of other mechanisms, such as transporters, has been recognized more recently, and should also be addressed. This article was prepared by the Pharmaceutical Research and Manufacturers of America (PhRMA) Drug Metabolism and Clinical Pharmacology Technical Working Groups and represents the current industry position. The intent is to define a minimal best practice for in vitro and in vivo pharmacokinetic drug-drug interaction studies targeted to development (not discovery support) and to define a data package that can be expected by regulatory agencies in compound registration dossiers.     

An alternative method of arterial reconstruction after hepatic arterial thrombosis following living-related liver transplantation

BACKGROUND: Hepatic artery thrombosis (HAT) remains an important cause of graft loss after liver transplantation. Emergency rearterialization methods are limited in cases of living-related liver transplantation in which the graft hepatic artery is thin and short. CASE: A 19-year-old woman who underwent living-related liver transplantation for biliary atresia developed HAT on the 4th postoperative day. During the emergency laparotomy the recipient hepatic artery was found to be too short to anastomose, so the recipient's right gastroepiploic artery was anastomosed to the graft hepatic artery. The patient is now alive and well 6 months after reoperation, and she has experienced no further episode of HAT. CONCLUSION: The right gastroepiploic artery can be used easily and safely for hepatic graft revascularization without causing ischemia of the stomach. An additional skin incision is not required, and the artery is long enough to anastomose to the graft artery directly. The method of hepatic graft rearterialization described here is an important option for patients who undergo living-related or split liver transplantation.     

Thoracoscopic lung biopsy for diffuse infiltrative lung disease

Thoracoscopic lung biopsy is becoming the procedure of first choice for the diagnosis of many localized and diffuse lung diseases. We have performed thoracoscopic lung biopsy for 17 patients with diffuse infiltrative lung disease, in Kurume University Hospital. There were 13 females and 4 males with a mean age of 48 years (range: 19-71 years). Thoracoscopic surgical biopsy was performed in the right lung in 12 and in the left lung in 5. Adequate lung tissue from each case was obtained for pathological examination. The mean surgical biopsy time was 49 min (range: 25-72 min) and bleeding was negligible. The mean duration for chest tube drainage was 2.6 days. No postoperative complication such as prolonged air leakage occurred. A specific diagnosis from the biopsy was achieved in 13 (76.4%) of the 17 cases. In only 6 (35.2%) of the 17 cases, the pathological diagnosis was the same as that from the thoracoscopic biopsy. In these 6 cases, the same diagnosis was obtained only in those with idiopathic interstitial pneumonitis or diffuse panbronchitis. Thoracoscopic lung biopsy was safe and useful for diagnosis for diffuse infiltrative lung disease.     

Human metabolism of the proteasome inhibitor bortezomib: identification of circulating metabolites.

Bortezomib [N-(2,3-pyrazine)carbonyl-L-phenylalanine-L-leucine boronic acid] is a potent first-in-class dipeptidyl boronic acid proteasome inhibitor that was approved in May 2003 in the United States for the treatment of patients with relapsed multiple myeloma where the disease is refractory to conventional lines of therapy. Bortezomib binds the proteasome via the boronic acid moiety, and therefore, the presence of this moiety is necessary to achieve proteasome inhibition. Metabolites in plasma obtained from patients receiving a single intravenous dose of bortezomib were identified and characterized by liquid chromatography/mass spectrometry (LC/MS) and liquid chromatography/tandem mass spectrometry (LC/MS/MS). Metabolite standards that were synthesized and characterized by LC/MS/MS and high field nuclear magnetic resonance spectroscopy (NMR) were used to confirm metabolite structures. The principal biotransformation pathway observed was oxidative deboronation, most notably to a pair of diastereomeric carbinolamide metabolites. Further metabolism of the leucine and phenylalanine moieties produced tertiary hydroxylated metabolites and a metabolite hydroxylated at the benzylic position, respectively. Conversion of the carbinolamides to the corresponding amide and carboxylic acid was also observed. Human liver microsomes adequately modeled the in vivo metabolism of bortezomib, as the principal circulating metabolites were observed in vitro. Using cDNA-expressed cytochrome P450 isoenzymes, it was determined that several isoforms contributed to the metabolism of bortezomib, including CYP3A4, CYP2C19, CYP1A2, CYP2D6, and CYP2C9. The development of bortezomib has provided an opportunity to describe the metabolism of a novel boronic acid pharmacophore.     

Identification of Ki23819, a highly potent inhibitor of kinase activity of mutant FLT3 receptor tyrosine kinase.

Constitutively active internal tandem duplication (ITD) in the juxtamembrane domain of Fms-like tyrosine kinase 3 (FLT3), a type III receptor tyrosine kinase, is the most common molecular defect associated with acute myeloid leukemia. Its presence confers a poor outcome in patients with acute myeloid leukemia who receive conventional chemotherapy. FLT3-ITD has therefore been considered to be an attractive molecular target for a novel therapeutic modality. We describe here the identification and characterization of Ki23819 as a novel FLT3 inhibitor. Ki23819 suppressed proliferation and induced apoptosis of FLT3-ITD-expressing human leukemia cell lines. The growth-inhibitory effect of Ki23819 on MV4-11 cells was superior to that of SU11248, another FLT3 inhibitor (IC(50)<1 vs 3-10 nM). Ki23819 inhibited the autophosphorylation of FLT3-ITD more efficiently than that of wild-type FLT3. FLT3-ITD-dependent activation of the downstream signaling proteins ERK and STAT5 was also inhibited within similar concentration ranges. Thus, Ki23819 is a potent in vitro inhibitor of FLT3.     

MUC 1 core protein as a marker of gallbladder malignancy.

AIM: The significance of MUC 1 expression in the gallbladder tissues in relation to cancer and non-cancer disease is not well understood. The aim of this study was to clarify the significance of MUC 1 expression. MATERIALS AND METHODS: A monoclonal antibody (CA 15--3; DF 3) was applied to stain MUC 1 core protein in surgical specimens. RESULTS: MUC 1 expression is significantly higher (p<0.0001) in gallbladder cancer (69/88) compare to non-cancerous tissue, while, very trace in normal and inflammatory tissues. The expression rate was significantly lower (p<0.0001) when the cancer did not penetrate the mucosal layer than when cancers did penetrate this layer. The MUC 1 expression rate was (4/14) in T1 tumours, (11/14) in T4, (40/45) in T3, and (14/15) in T2, respectively. Every cell of normal and inflammatory mucosa, and T1 cancers had the polarized pattern. The depolarized pattern was dominant in cancer cells from the advanced tumours of T2, T3 and T4. That is, (45/74) of cancer cells from the mucosal layer and (58/74) of penetrating cancer cells in submucosal layer had the depolarized pattern. There was no significant correlation of MUC 1 expression rate and staining pattern with cancer differentiation and microscopic venous invasion. On the other hand, lymphatic vessel invasion was significantly correlated with the staining pattern but not with expression rate. CONCLUSION: MUC 1 core protein expression rate and pattern are suggesting that MUC 1 core protein would be a marker of malignant transformation of gallbladder epithelium and its depolarized expression would also be a marker of invasion of gallbladder cancer.     

Thickened area of external granular layer and Ki-67 positive focus are early events of medulloblastoma in Ptch1+/− mice

Patched1 (Ptch1) encodes a receptor for Sonic hedgehog (Shh) and is major gene related to human medulloblastoma (MB) in the Shh subgroup. MB is thought to arise from residual granule cell precursors (GCPs) located in the external granular layer (EGL) of the developing cerebellum. As the detailed preneoplastic changes of MB remain obscure, we immunohistochemically clarified the derived cell, early events of MBs, and the cerebellar developmental processes of Ptch1^+/? (Ptch1) mice, an animal model of human MB of the Shh subgroup. In Ptch1 mice, the earliest proliferative lesions were detected at PND10 as focal thickened areas of outer layer of the EGL. This area was composed of GCP-like cells with atypia and nuclei disarrangement. In the latter cerebellar developmental period, GCP-like cell foci were detected at high incidence in the outermost area of the cerebellum. Their localization and morphological similarities indicated that the foci were derived from GCPs in the EGL. There were two types of the foci. A Ki-67-positive focus was found in Ptch1 mice only. This type resembled the GCPs in the outer layer of EGL characterized by having proliferating activity and a lack of neuronal differentiation. Another type of focus, Ki-67-negative, was observed in both genotypes and exhibited many of the same features of mature internal granule cells, suggesting that the focus had no preneoplastic potential. Due to morphological, immunohistochemical characteristics, our results indicate that the focal thickened area of EGL and Ki-67-positive foci are preneoplastic lesions of MB.