Impact of genetic polymorphisms of drug transporters ABCB1 and ABCG2 and regulators of xenobiotic transport and metabolism PXR and CAR on clinical efficacy of dasatinib in chronic myeloid leukemia.

Introduction: Functional single-nucleotide polymorphisms (SNPs) in genes regulating cellular uptake, elimination, and metabolism of xenobiotics may potentially influence the outcome of chronic myeloid leukemia (CML) patients treated with BCR-ABL1 tyrosine kinase inhibitors (TKI). Dasatinib, a second-generation TKI, is a substrate of the ABC-superfamily xenobiotic transporters ABCB1 (MDR1, Pg-P) and ABCG2 (BCRP). Pregnane X receptor (PXR, NR1I2) and constitutive androstane receptor (CAR, NR1I3) are involved in the control of expression of ABCB1 and ABCG2. Aim of the study: In this study, we assessed the impact of inherited variants in ABCB1, ABCG2, PXR, and CAR genes on dasatinib efficacy and toxicity in CML. Materials and methods: Sixty-one tagging SNPs in ABCB1, ABCG2, PXR, and CAR genes were analyzed by real-time quantitative PCR with specific probes in 86 CML patients who failed imatinib therapy. Results: We found the associations between SNPs rs7787082 (ABCB1, OR = 0.2; 95% CI = 0.06-0.66, p = 0.008), rs12505410 (ABCG2, OR = 3.82; 95% CI = 1.38-10.55; p = 0.010), and rs3114018 (ABCG2, OR = 0.24; 95% CI = 0.08-0.71; p = 0.010) and the probability of achieving CCyR. Furthermore, progression-free survival (PFS) was significantly influenced by SNPs rs3732357 (HR = 0.2, 95% CI = 0.26-0.70; p = 0.001), rs3732360 (HR = 0.59; 95% CI = 0.38-0.93; p = 0.020), rs11917714 (HR = 0.58; 95% CI = 0.36-0.92; p = 0.020), and rs3732359 (HR = 0.57; 95% CI = 0.36-0.91; p = 0.024) in PXR; rs2307418 (HR = 2.02; 95% CI = 1.19-3.43; p = 0.048) in CAR; and rs2235023 (HR = 2.49; 95% CI = 1.13-5.50; p = 0.011) and rs22114102 (HR = 1.90; 95% CI = 1.00-3.63; p = 0.028) in ABCB1. Moreover, overall survival (OS) was impacted by rs3842 (HR = 1.84; 95% CI = 1.01-3.33; p = 0.012) and rs2235023 (HR = 2.28; 95% CI = 1.03 = 5.02; p = 0.027) in ABCB1, rs11265571 (HR = 1.59; 95% CI = 0.82-3.08; p = 0.037) and rs2307418 (HR = 73.68; 95% CI = 4.47-1215.31; p = 0.003) in CAR, and rs3732360 (HR = 0.64; 95% CI = 0.40 = 1.04; p = 0.049) in PXR. Taking into account the influence of the tested SNPs on treatment toxicity, we found a significant relationship between allele G of polymorphism in the ABCB1 rs7787082 (OR = 4.46; 95% CI = 1.38-14.39 p = 0.012) and hematological complications assuming the codominant gene inheritance model as well as a significant correlation between the presence of minor allele (G) of SNP rs2725256 in the ABCG2 gene (OR = 4.71; 95% CI = 1.20-18.47; p = 0.026) and the occurrence of non-hematological complications assuming a recessive gene inheritance model. Conclusion: Our data suggest that inherited variants in the genes encoding for proteins involved in the transport of xenobiotics may modify the toxicity and efficacy of dasatinib therapy in CML patients.

Detection and verification of quantitative trait loci for resistance to Dothistroma needle blight in Pinus radiata.

Six related radiata pine ( Pinus radiata) full-sib families were used to detect and independently verify quantitative trait loci (QTLs) for resistance to Dothistroma needle blight, caused by Dothistroma septospora. The detection families had from 26 to 30 individuals each, and had either a common maternal (31053) or paternal (31032) parent; one family (cross 4) consisted of progeny from both parents, 31053 x 31032. Approximately 200 additional progeny from cross 4 were clonally replicated and planted at two sites, with at least five to seven ramets of each individual per site. Marker segregation data were collected from a total of 250 RFLP and microsatellite markers, and single factor ANOVAs were conducted separately for each family and marker. A number of putative associations were observed, some across more than one family. Permutation tests were used to confirm expected probabilities of multiple associations based on chance alone. Seven markers representing at least four QTLs for resistance to Dothistroma were identified as being significant in more than one family; one of these was significant at P<0.05 in three families and highly significant at P<0.01 in a fourth. Further confirmation was obtained by testing those markers that were significant in more than one of the detection families (or highly significant in cross 4) in the clonally replicated progeny from cross 4. Four QTL positions were verified in the clonal populations, with a total percent variation accounted for of 12.5.

Assessment of Dothistroma Needle Blight of Pinus radiata Using Airborne Hyperspectral Imagery.

ABSTRACT Dothistroma needle blight is a serious foliar disease in Australian Pinus radiata plantations causing defoliation, decreased productivity and, in extreme cases, tree death. Conventional methods of monitoring forest health such as aerial survey and ground assessments are labor intensive, time consuming, and subjective. Remote sensing provides a synoptic view of the canopy and can indicate areas affected by damaging agents such as pests and pathogens. Hyperspectral airborne remote sensing imagery (CASI-2) was acquired over pine stands in southern New South Wales, Australia which had been ground assessed and ranked on an individual tree basis, according to the extent of Dothistroma needle blight. A series of spectral indices were tested using two different approaches for extracting crown-scale reflectance measurements and relating these to ground-based estimates of severity. Dothistroma needle blight is most severe in the lower crown and statistically significant relationships were found between crown reflectance values and ground estimates using a 'halo' approach (which ignored each tree crown's brightest central pixels). Independent accuracy assessment of the method indicated that the technique could successfully detect three levels of Dothistroma needle blight infection with an accuracy of over 70%.

Ceratocystis pirilliformis, a new species from Eucalyptus nitens in Australia.

Several species of Ceratocystis have been recorded on Eucalyptus. These include C. fimbriata, C. eucalypti, C. moniliformis and C. moniliformopsis. Of these, only C. fimbriata is known as a pathogen; it recently has been found causing serious wilt diseases in Uganda, Congo and Brazil. This study was undertaken to collect Ceratocystis species, including C. eucalypti, from artificially induced wounds on Eucalyptus nitens near Canberra in southeastern Australia. Trees were wounded in October 2000, and wounds were examined approximately one month later. Ascomata characteristic of a Ceratocystis species were found covering the wounds, and this fungus also was isolated from the wood using carrot baiting. This species of Ceratocystis has hat-shaped ascospores similar to those of C. fimbriata, but it differs from C. fimbriata and all other species of Ceratocystis in that it possesses ascomata with a pyriform base. Comparison of DNA sequences from the ITS and 5.8S rRNA operon confirmed that the fungus from E. nitens in Australia is unique, and we describe it here as a new species, C. pirilliformis.

Climatic mapping to identify high-risk areas for Cylindrocladium quinqueseptatum leaf blight on eucalypts in mainland South East Asia and around the world.

Cylindrocladium quinqueseptatum is a pathogen on a wide range of hosts. It affects at least 20 species of eucalypts and is an important causal agent of leaf blight of Eucalyptus camaldulensis in central and southern Vietnam. Results from previous studies and observations of broadscale infection patterns in mainland South East Asia were used to derive simple rules (i.e. mean minimum temperature of coldest month > or =16 degrees C and mean annual precipitation > or =1400 mm) to identify locations which are likely to have a high risk of C. quinqueseptatum leaf blight (CqLB). Climatic mapping programs, which include interpolated climatic data estimated for numerous locations, were used to map these high risk areas in Africa, Australia and Latin America as well as in South East Asia. The predicted high-risk areas included several regions where CqLB has already been reported and the maps generated suggested other areas which may be at risk under present climatic conditions given the presence of C. quinqueseptatum and susceptible hosts. Some simple climate change scenarios were also used to suggest areas in mainland South East Asia which may become vulnerable to CqLB over the next 50 years. It is concluded that climatic mapping programs can assist the broadscale evaluation of risk of CqLB infections, although it is recognised that more detailed models and survey information are also needed.

Cytogenetic profile of uterine sarcomas.

BACKGROUND: Diagnostic and consistent chromosomal abnormalities have been reported in several soft tissue sarcomas, but few studies have reported the frequency of chromosomal abnormalities in uterine sarcomas. METHODS: Cytogenetic studies were performed on specimens of uterine sarcoma from 14 patients. The specimens included five of leiomyosarcoma (LMS), four of endometrial stroma sarcoma (ESS), and five of malignant mixed mesodermal tumor (MMMT). RESULTS: Chromosomal abnormalities were detected in 10 of 14 (71%) patients. Chromosome 1 was involved in 7 of 13 (54%) of the patients, chromosome 11 in 6 of 13 (46%), and chromosome 7 in 6 of 13 (46%). A site-specific chromosomal abnormality, del(11)(q22) was found in two patients with LMS and three patients with MMMT, and 7q31 also was involved frequently. Marked genomic instability characterized the MMMT studied. CONCLUSIONS: These findings suggest that abnormalities of chromosomes 1, 7, and 11 may play a role in tumor initiation or progression in uterine sarcomas. Genomic alterations in the region 11q22 may be specific for malignant smooth muscle tumors of the uterus.

Endometrioid carcinoma of the ovary presenting with an enlarged inguinal lymph node without evidence of abdominal carcinomatosis.

It is generally recognized that ovarian cancer tends to remain intraabdominal even in advanced cases and that dissemination is usually by invasion of adjacent viscera, diffuse intraperitoneal implantation, and metastatic involvement of aortic and pelvic lymph nodes. Primary ovarian lymphatic drainage occurs via the infundibulopelvic ligament to the paraaortic nodes. The presence of an ovarian tumor extending into adjacent pelvic viscera may allow direct lymphatic continuity with inguinal, external, and common iliac lymph nodes. In the absence of such extension it is traditionally believed that the drainage via the infundibulopelvics is so important that only with its blockage, presumably by tumor emboli, can retrograde drainage to pelvic and inguinal nodes occur. We report a case of a patient presenting with a large metastatic inguinal lymph node from a primary epithelial ovarian cancer without evidence of disseminated intraabdominal disease or gross evidence of pelvic or paraaortic lymph node involvement.

Ovarian vein sampling in rapidly progressing virilization. A case report.

A woman presented with progressive hirsutism, deepening of the voice, clitoromegaly and increased libido. The preoperative serum testosterone level was 2,042 ng/dL. The intraoperative ovarian venous blood testosterone levels were 56,327 ng/dL on the left and 1,417 on the right. After a bilateral salpingo-oophorectomy, the serum testosterone level was 20.7 ng/dL. Initial pathologic examination of the ovaries revealed no potential source of testosterone, but reexamination revealed a pure lipoid cell tumor. Intraoperative ovarian vein androgen measurements can be helpful in establishing a histopathologic diagnosis in cases of microscopic virilizing ovarian neoplasms. Ovarian vein sampling for androgen was essential in locating this patient's microscopic tumor.

The mons pubis: an excellent graft donor site in gynecologic surgery.

Split-thickness skin grafting has many applications in gynecologic surgery. Selection of the donor site is an aspect of the procedure that is very important for preventing highly visible lifelong scars. In this regard the mons pubis is an excellent choice as a donor site. Scar visibility is minimized by regrowth of the pubic hair. Another advantage is the anterior location of the mons, which allows for healing without constant pressure in patients who must remain supine in the postoperative period. Graft harvesting requires shaving the mons pubis and injecting saline solution into the subcutaneous tissue to elevate the skin and thus provide a firm flat base for dermatome application. Hair growth does not occur in the recipient site because the hair follicles are not harvested. Healing of both donor and recipient sites has been excellent with minimal discomfort during pubic hair regrowth. Thus it is recommended that the mons pubis be given serious consideration as a graft donor site in gynecologic surgery.

Ovarian malignant luteinized thecoma--an unusual tumor in an adolescent.

Malignant luteinized thecoma is an extremely rare ovarian tumor. The fifth reported case of this tumor presenting in a 13-year-old epileptic child on anticonvulsant therapy with a rapidly enlarging pelvic-abdominal mass is discussed. At laparotomy, bilateral ovarian involvement, massive ascites, and omental and bowel serosal metastases were present. The pathological diagnosis was difficult with initial diagnoses of ovarian edema, endodermal sinus tumor, and ovarian fibrosarcoma. The final diagnosis of malignant luteinized thecoma was made by recognizing the presence of lutein cells with foamy vacuolated cytoplasm and intracytoplasmic staining for oil red O. Electron microscopy also demonstrated vacuolated cells with multiple fat globules. After surgical debulking the patient was treated with combination chemotherapy with complete response. The similarities of this case to three previously reported bilateral thecomas presenting in children on anticonvulsant therapy is discussed.

Primary squamous carcinoma of the ovary: a case report and review of the literature.

Only three cases of primary squamous carcinoma of the ovary have been reported to date. This fourth case serves to illustrate similarities between all known cases of this tumor. This tumor presents primarily as a simple cyst or has a major cystic component. Three of the reported cases (including the present one) had a prior diagnosis of carcinoma in situ of the uterine cervix. Accurate surgical staging and complete tumor excision appear to be optimal therapy for squamous carcinoma of the ovary.

Effects of massive ascites on measurement of cardiac ejection fraction via multi-gated acquisition (MUGA) scanning.

A patient with massive ascites secondary to ovarian carcinoma was found to have a low cardiac ejection fraction as measured by multi-gated acquisition (MUGA) scanning. Because of this low measurement, she was not treated with Adriamycin for fear of cardiac toxicity. Because the MUGA was felt to be incorrect, we performed simultaneous echocardiography and then repeated the MUGA scan after removal of 9000 cc of ascites fluid. The echocardiogram showed an ejection fraction in excess of 50% and the MUGA performed after paracentesis revealed an ejection fraction of 63% (an increase of 133%). We conclude that the MUGA is an inaccurate way to assess cardiac ejection fraction in the presence of massive ascites and that other ways to assess cardiac function should be used when there is need to determine such function in patients with massive ascites.

Another look at the second-assessment procedure for ovarian epithelial carcinoma.

Over a 10-year period, 65 of 196 patients (33%) with ovarian epithelial malignancy, previously treated with chemotherapy, had a second-look operation if the disease was clinically absent. All procedures were done by one of three gynecologic oncologists, and 48% of the patients had a positive second-look procedure. Of patients with original stage I, II disease, 25% had a positive second-look operation, contrasting with 61% of patients with stage III, IV. Significant perioperative morbidity occurred: one patient had intraoperative vascular collapse; 15% had prolonged ileus; 17% had small bowel resections at the time of the second-look operation or in the postoperative period. Of all patients with negative second-look operations, 24% have had recurrent disease from 5 to 23 months after the procedure. These recurrences were in the liver or distant sites in 63% of the patients. Second-look operations, if still indicated by negative noninvasive techniques, should be performed in tertiary care centers under study situations in a standard fashion.

DNA content in cervical neoplasia and its relationship to prognosis.

Aneuploidy is commonly associated with malignancy and certain premalignant conditions. Recent studies have demonstrated an association between prognosis and the presence of aneuploidy. In this study, flow cytometry was used to determine the deoxyribonucleic acid (DNA) content of tissues with cervical intraepithelial neoplasia or invasive cervical carcinoma. Of 41 evaluable patients with cervical intraepithelial neoplasia, aneuploidy was demonstrated in the specimens of three of ten patients with cervical intraepithelial neoplasia II and six of 13 with cervical intraepithelial neoplasia III. No specimens with cervical intraepithelial neoplasia I, with condylomata, or without pathologic diagnosis contained aneuploid populations. Of the 22 evaluable specimens with invasive cervical carcinoma, 13 contained aneuploid populations. In stage I cervical lesions, aneuploidy appeared to be a poor prognostic factor with an overall survival of two of five patients with aneuploid tumors versus five of five patients with diploid tumors.

Computed tomography in evaluation of patients with ovarian carcinoma in complete clinical remission. Correlation with surgical-pathologic findings.

Computed tomography (CT) of the abdomen and pelvis was performed in 47 patients who were in complete clinical remission from ovarian carcinoma. Results of CT were correlated with surgical-pathologic findings at surgical reexploration. Overall, CT had a sensitivity of 0.32, specificity of 0.77, positive predictive value of 0.79, and negative predictive value of 0.30. Accuracy of CT did not vary by intraperitoneal or retroperitoneal site studied. Computed tomography detected only 7% of tumor nodules 1 cm or less in diameter and only 37% of nodules over 1 cm in diameter. The utility of CT in this clinical setting was limited to approximately 20% of patients with true-positive CT findings who might have been saved surgical reexploration. Due to a high false-negative rate, a normal CT cannot replace a second-look laparotomy for accurate assessment of disease status.

Percutaneous nephrostomy in gynecologic oncology.

Percutaneous nephrostomy is a useful method of supravesical diversion when ureteral obstruction occurs at initial diagnosis of gynecologic cancer or recurrence of disease. Although survival is prolonged, the attendant quality of life would indicate that percutaneous nephrostomy should be performed only in those cases in which there is a reasonable chance for palliation or a hope for cure or when temporization is needed to define adequately the etiology of ureteral obstruction following therapy.

Giant basal cell carcinoma of the vulva.

A giant basal cell carcinoma of the vulva is reported. The lesion was atypical in its large size and gross morphology, therefore making clinical diagnosis difficult. Diagnosis of this lesion is often delayed because of its varied clinical appearance. The importance of adequate biopsy and careful pathological evaluation of vulvar lesions is stressed. Differentiation from metatypical or basosquamous cell carcinoma is discussed, and proper therapy is reviewed.

Hyperprolactinemic response after bromocriptine withdrawal in women with prolactin-secreting pituitary tumors.

In patients with prolactin (PRL)-secreting tumors, plasma PRL concentrations after discontinuation of bromocriptine therapy have been used clinically as an index of tumor activity. To investigate the pattern of PRL response under these conditions, seven women on chronic bromocriptine therapy for PRL-producing pituitary tumors were followed with serial PRL determinations for 2 months after bromocriptine withdrawal. In these patients, peak PRL concentrations were achieved 28.1 days (mean; range, 14 to 49 days) after bromocriptine discontinuation. However, PRL concentrations did not usually plateau until at least 40 days after cessation of therapy, and the pattern of PRL response was highly variable. Because of the inconsistent pattern of serum PRL response during the first 40 days after discontinuation of bromocriptine, decisions regarding tumor activity based on PRL concentrations should not be made until at least 6 weeks after withdrawal of the drug.