Members Responses Regarding the Future of the APOCP(C) and APJCP(C)

In response to the request for comments and suggestions from interested individuals and institutions as tohow the APJCP, and by extension the APOCP, should be organized and financed, we have received a number ofemails. I would like to persaonally thank the individuals involved and hope to make a coordinated response inthe future.     

Pigmentations of the nails (chromonychia)

Nails, particularly fingernails, may show signs that are important not only for detection of diseases of the nails themselves, but of diseases of other organs or the system as a whole. Changes of color in nail plates or nail beds sometimes seem to suggest the parts are windows to what is happening in the body. Above all, changes of color in nails that compel investigation for malignant melanoma, the most dread of diseases, are most important.     

A comparative study of the distribution in the male rat of platinum-labelled cis-dichlorodiammine platinum (II), cis-trans-dichlorodihydroxy-bis-(isopropylamine) platinum (I), and cis-dichloro-bis-cyclopropylamine platinum (II)

Summary Three platinum derivatives, cis-dichlorodiammine platinum (II), (DDP), cis-trans-dichlorodihydroxy-bis-(isopropylamine)platinum (IV) (CHIP) and cis-dichloro-bis-cyclopropylamine platinum (II) (CP), have been prepared with a gamma-emitting platinum label. The distribution of these complexes was studied in male rats.The results are presented as fractions of the administered radiolabel per gram of tissue and per total organ. Accumulation in the liver was highest initially following CP and lowest after DDP, but by 14 days the levels in kidney and liver were highest with CP. The concentration in the skin was relatively high after all the compounds, but was the most conspicuous after DDP at the early times. In general, patterns of distribution between the other organs were similar with DDP and CP.CHIP, however, exhibited a different pattern of distribution. Over the first 24 h the level of platinum in most tissues declined more rapidly than after either of the other two compounds but the residual label persisted for a longer period. In the kidney there appeared to be a secondary uptake of labelled material, presumably from other tissues. The level present at 14 days after CHIP was also significantly higher in a number of other organs than after the other two drugs. The increase in label in the spleen at the later times may be due to the removal of circulating damaged cells and consistent with the higher levels of residual platinum in the blood. There was also a higher level of residual platinum in the blood especially after IV administration of the labelled agent.The results show that CHIP was cleared at a faster rate from blood and kidney than the other two complexes, results which closely resembled clinical findings with these three agents, to be published elsewhere.The greater retention time of label after CHIP also suggests that longer-term toxicity may follow its repeated administration. Present address: Radiochemical Centre, Amersham International     

Role of the Ha-ras (RasH) oncogene in mediating progression of the tumor cell phenotype (review)

Recent experimental evidence indicates that the c-Ha-ras (rasH) oncogene may be causally involved in the etiology and evolution of specific human neoplasms. In addition, cultured cells transformed by the rasH oncogene can induce both a tumorigenic and a metastatic phenotype when expressed in appropriate cultured cells. To begin to define the molecular and biochemical mechanism(s) by which the rasH oncogene induce their effects on expression of the transformed state we have employed a cloned rat embryo fibroblast (CREF) cell line. Transformation of CREF cells with wild-type 5 adenovirus (Wt) results in transformed cells which display anchorage-independence and an increased saturation density in monolayer culture, but are non-tumorigenic in both athymic nude mice and syngeneic Fischer rats. In contrast, when CREF cells are transformed with mutant type 5 adenoviruses, such as H5hrl, or the ElA transforming gene from hrl (0-4.5), tumors are induced in both nude mice and syngeneic rats. However, hrl (0-4.5)-transformed CREF cells are not metastatic following intravenous injection into the tail vein of syngeneic rats. Insertion of an activated T24 rasH oncogene or a wild-type v-rasH oncogene into CREF, wt-transformed CREF or hrl (0-4.5)-transformed CREF cells results in acquisition of a metastatic phenotype by these cells. A mutant v-rasH oncogene (mutant 116K), which is defective in GTP binding and the induction of transformation of NIH 3T3 cells, does not induce transformation in CREF cells, but it can progress wt-transformed CREF cells to a tumorigenic-non-metastatic state. Employing this model system which displays well-defined and stable stages in the tumor cell progression lineage, we have analyzed the potential role of changes in the phosphatidylinositol (PI) cycle and phospholipase A2 (PLA2) enzyme activity during progression to a tumorigenic and metastatic phenotype. An increase in PI cycle intermediates (primarily inositol triphosphate; IP3) were observed only in the wt-transformed and hrl (0-4.5)-transformed CREF cell lines transfected with the rasH oncogene. In the case of PLA2, all rasH-transformed CREF cell lines displayed increased activity. In contrast, CREF cells transformed only by Ad5 (Wt or hrl (0-4.5)) or the 116K v-rasH oncogene did not display increased PLA2 activity similar to that observed in rasH transfected cells. Since one important metabolite generated by PLA2 is arachidonic acid, which is converted into prostaglandins and leukotrienes by cyclooxygenase or lipooxygenase, respectively, the levels of prostaglandin E2 (PGE2) in the various cell lines were monitored.(ABSTRACT TRUNCATED AT 400 WORDS)     

Analysis of the pathological severity degree of aortic stenosis （AS） and mitral stenosis （MS） using the discrete wavelet transform （DWT）.

The heart is the principal organ that circulates blood.In normal conditions it produces four sounds for each cardiac cycle.However,most often only two sounds appear essential: S1 and S2.Two other sounds: S3 and S4,with lower amplitude than S1 or S2,appear occasionally in the cardiac cycle by the effect of disease or age.The presence of abnormal sounds in one cardiac cycle provide valuable information on various diseases.The aortic stenosis(AS),as being a valvular pathology,is characterized by a systolic murmur due to a narrowing of the aortic valve.The mitral stenosis(MS) is characterized by a diastolic murmur due to a reduction in the mitral valve.Early screening of these diseases is necessary;it’s done by a simple technique known as: phonocardiography.Analysis of phonocardiograms signals using signal processing techniques can provide for clinicians useful information considered as a platform for significant decisions in their medical diagnosis.In this work two types of diseases were studied: aortic stenosis(AS) and mitral stenosis(MS).Each one presents six different cases.The application of the discrete wavelet transform(DWT) to analyse pathological severity of the(AS and MS was presented.Then,the calculation of various parameters was performed for each patient.This study examines the possibility of using the DWT in the analysis of pathological severity of AS and MS.     

Enhancement of the antitumor effect of 1,3-bis(2-chloroethyl)-l-nitrosourea (BCNU) by phenylethylbiguanide (phenformin).

Phenlethylbiguanide (phenformin) a commonly used antidiabetic medication has been found to enhance the antitumor effect of 1,3-bis(2-chloroethyl)-l-nitrosourea (BCNU) in advanced subcutaneously implanted murine L1210 leukemia. Enhancement required two doses of phenformin given twelve to 18 hours apart, the treatment starting either before or after BCNU administration. With BCNU alone median survival (MS) was 18 days with 5% cures. BCNU plus phenformin, in optimal dose and schedule, gave a MS of 25 days with 29% cures. Th mechanism of action of phenformin is unknown but may involve several established metabolic effects of this drug.     

Results of the association of intralesional recombinant alpha-interferon-2a (alpha-IFN) plus 13-cis-retinoic Acid (13cra) in the treatment of Basal-cell carcinomas (bcc) of the skin

In this phase II study, twenty-four patients (median age 72 years) with BCC of the skin were treated with intralesional alpha-IFN plus 13cRA. Alpha-IFN was administered intralesionally at the dose of 3x10(6) I.U. for injection, 3 times/week for 4 weeks (total dose 12x10(6) I.U./cycle); concomitantly, 13cRA was given per os at a 0.2-0.4 mg/kg/day dose. The 4-week cycles were repeated after a one week interval, in which only 13cRA was administered. Patients were evaluated after at least 2 cycles of treatment. Sixteen of the 20 assessable patients (80%) showed an objective response (OR), 12 of whom (60%) had a complete response (CR). The overall OR rate was 75% (12/16) in patients treated with 0.2 mg/kg/day of 13cRA, and 100% (4/4) in patients who received 0.4 mg/kg/day of the drug. The median response duration was 12 months (range, 6 to 20). Toxicity was mild and reversible in all cases; major side effects observed were fever, nausea, skin erythema, hypertriglyceridemia and hypercholesteremia. These results show the efficacy and the feasibility of alpha-IFN and 13cRA acid association in BCC treatment, with good compliance even in elderly patients; this medical approach could be a valid choice of therapy in addition to the traditional surgical modalities, as it also produces satisfactory aesthetical results.     

Clinical trial of the effect of S-2-(3-aminopropylamino)-ethylphosphorothioic acid (WR-2721) (NSC 296961) on the toxicity of cyclophosphamide

S-2-(3-Aminopropylamino)-ethylphosphorothioic acid (WR-2721) is reported to protect normal tissues from the effects of ionizing radiation and possibly alkylating agents as well. The present trial assessed the ability of this compound to modify the clinical toxicity of cyclophosphamide. Patients with advanced cancer first received a dose of 1000 mg/m2 cyclophosphamide intravenously and were observed for toxicity, principally myelosuppression. After the nadir in white blood cell counts and/or platelets had been documented and adequate recovery had occurred, a second course of cyclophosphamide was given, this time preceded by WR-2721 30 min earlier. In this fashion, each patient served as his own control. Doses of WR-2721 ranging from 250 to 1000 mg/m2 were tested. A total of 13 evaluable courses of WR-2721 were given with cyclophosphamide. In no instance did the prior administration of WR-2721 diminish the bone marrow toxicity of cyclophosphamide alone. At the end of the trial two additional patients received the WR-2721 in a split dose, one-half prior to the cyclophosphamide and one-half 6 hr later; again there was no protection. The side effects of WR-2721 included nausea, vomiting, hypotension, sneezing, and swelling of the tongue. We conclude that WR-2721 is a potentially toxic compound that produces no amelioration of cyclophosphamide toxicity in the doses used. Because of the severity of the side effects of WR-2721, principally hypotension, the trial was terminated after 1000 mg/m2 WR-2721 failed to protect against the toxicity of 1000 mg/m2 cyclophosphamide.     

Interaction of the retinoblastoma protein (pRb) with the catalytic subunit of DNA polymerase delta (p125)

The retinoblastoma gene product (pRb) interacts with many cellular proteins to function in the control of cell division, differentiation, and apoptosis. Several pRb binding proteins complex with pRb through an amino acid sequence called the LXCXE motif. The catalytic subunit of DNA polymerase delta (p125) contains a LXCXE motif. To further study the biochemical function of this polymerase, we sought to determine if p125 interacts with pRb. Experiments using GST-pRb fusion proteins showed that p125 from breast epithelial (MCF10A) cell extracts associates with pRb. In addition, GST-p125 fusion proteins bound pRb from the same cell extracts. The pRb that associated with GST-p125 was largely unphosphorylated. Coimmunoprecipitation experiments using cell cycle synchronized cells revealed that p125 and pRb form a complex predominantly during G1 phase, the phase during which pRb is mostly unphosphorylated. In vitro phosphorylation of GST-pRb by the cyclin dependent kinases reduced the ability of p125 to associate with GST-pRh. Addition of the LXCXE containing protein SV40 large T antigen to GST-pRb blocks the ability of p125 to associate with pRb, suggesting that it may be through a LXCXE sequence by which p125 interacts with pRb. Finally, in vitro polymerase assays demonstrate that GST-pRb fusion protein stimulates DNA polymerase delta activity.     

The history of the Gynecologic Cancer Study Group (GCSG) of the Japan Clinical Oncology Group (JCOG)

The Gynecologic Cancer Study Group (GCSG) of the Japan Clinical Oncology Group (JCOG) was organized in 1994. The GCSG has developed under the leadership of three successive group representatives, five principal study investigators, the cooperation of group members and the support of several public research funds. At present, 38 institutions are participating as active members of the GCSG of the JCOG. In addition to gynecologic oncologists, medical oncologists, pathologists and radiotherapists are participating in our group. Our group manages female genital malignancies including uterine cervical, endometrial, ovarian, tubal and vulvar cancers. Because the incidences of uterine cervical (in younger women), endometrial and ovarian cancer have increased in Japan in recent years, we are developing new standard treatments especially for these malignancies. As of 31 May 2011, our group has conducted six JCOG clinical trials (three completed and three ongoing) and completed one JCOG accompanying study, which is now in preparation for publication. Our group has also conducted several retrospective studies, and Phase I and II trials independent of the JCOG Data Center. Our aim is to conduct unique and high-quality clinical trials which we can appeal to the world. In this review, we present the organization and achievements of our group, along with a list of participating institutions, as the history of the GCSG of the JCOG.