A genome-wide association study identifies four genetic markers for hematological toxicities in cancer patients receiving gemcitabine therapy.

OBJECTIVE: Genetic factors are thought to be one of the causes of individual variability in the adverse reactions observed in cancer patients who received gemcitabine therapy. However, genetic factors determining the risk of adverse reactions of gemcitabine are not fully understood. PATIENTS AND METHODS: To identify a genetic factor(s) determining the risk of gemcitabine-induced leukopenia/neutropenia, we conducted a genome-wide association study, by genotyping over 610 000 single nucleotide polymorphisms (SNPs), and a replication study in a total of 174 patients, including 54 patients with at least grade 3 leukopenia/neutropenia and 120 patients without any toxicities. RESULTS: We identified four loci possibly associated with gemcitabine-induced leukopenia/neutropenia [rs11141915 in DAPK1 on chromosome 9q21, combined P=1.27×10, odds ratio (OR)=4.10; rs1901440 on chromosome 2q12, combined P=3.11×10, OR=34.00; rs12046844 in PDE4B on chromosome 1p31, combined P=4.56×10, OR=4.13; rs11719165 on chromosome 3q29, combined P=5.98×10, OR=2.60]. When we examined the combined effects of these four SNPs, by classifying patients into four groups on the basis of the total number of risk genotypes of these four SNPs, significantly higher risks of gemcitabine-induced leukopenia/neutropenia were observed in the patients having two and three risk genotypes (P=6.25×10, OR=11.97 and P=4.13×10, OR=50.00, respectively) relative to patients with zero or one risk genotype. CONCLUSION: We identified four novel SNPs associated with gemcitabine-induced severe leukopenia/neutropenia. These SNPs might be applicable in predicting the risk of hematological toxicity in patients receiving gemcitabine therapy.

[Bladder stone at an ureterovesical anastomotic site after renal transplantation: a report of three cases].

Three cases of bladder stones at the ureterovesical anastomotic site after renal transplantation (RT) are reported. The three patients were successfully treated with kidney grafts. The method used for the ureter bladder anastomosis in all patients was the extravesical technique with polyglyconate (Maxon) for case 1 and a polydioxanone suture (PDSII) for cases 2 and 3. Calculi formation was found between 3 to 15 months after RT. Endoscopic vesicolithotripsy was performed and the stones adherent to the ureterovesical anastomotic site were removed successfully in all cases. Stone analysis revealed uric acid (case 1), CaOx and CaP (case 2). Stone analysis was not done in case 3. The patients' symptoms improved and no bladder stones could be discerned postoperatively.

[Urachal carcinoma treated with neoadjuvant intra-arterial chemotherapy: a case report].

A 43-year-old man visited our clinic with gross hematuria. Ultrasonography and computed tomography demonstrated a tumor at the bladder dome. Cold punch biopsy revealed well-differentiated adenocarcinoma and stage III A urachal carcinoma was diagnosed. Neoadjuvant intra-arterial chemotherapy with cisplatin, adriamycin and angiotensin II was performed and 40% reduction of tumor size was noted 3 weeks after this therapy. En bloc segmental resection was performed. Augmentation ilealcystoplasty was subsequently performed to secure bladder capacity. Adjuvant chemotherapy (UFT) was given for 1 year. Cystolithotomy and closure of ventral hernia were required 10 years after radical surgery for postoperative complications. The patient has survived 12 years with no evidence of local recurrence or distant metastasis.

[Renal transplantation surgery is closely linked with treatment for bilateral synchronous renal cell carcinomas or renal tumors in solitary kidney].

We describe 4 cases of bilateral synchronous renal cell carcinoma and 3 of renal tumor in solitary kidney. One of the 3 patients with renal tumor in solitary kidney underwent partial nephrectomy. The remaining 2 patients, who had renal tumors greater than 7 cm located in the central region, underwent extracorporeal surgery. Development of acute renal failure and renal bleeding after ex vivo surgery occurred in 1 female patient, who required autograftectomy and temporary dialysis but subsequently underwent a re-operative procedure for renal transplantation with a kidney donated by her 82-year-old mother. Two of the 4 patients underwent partial nephrectomy, 1 with multiple bone and lung metastases had all carcinoma foci extracted at the second stage and was administered UFT and IFN alpha, and the remaining 2 patients, who both had hereditary renal cell carcinoma with multiple tumors in both kidneys, received living-donor related renal transplantation soon after bilateral nephrectomy. In the period of follow-up, ranging from 2 to 14 years, all the patients are well with no relapse and have good renal function. These results indicate kidney transplant procedures may have been linked with the options of bilateral synchronous renal cell carcinoma and renal tumor in solitary kidney.

[Intra-arterial docetaxel chemotherapy with high-dose calcitriol in relapsing metastatic prostate cancer].

Ten patients with hormone relapsing metastatic prostate cancer who had been previously treated with extensive radiotherapy for metastasis and chemotherapy including docetaxel and platinum compounds were evaluated to determine the safety and efficacy of docetaxel with high-dose calcitriol and platinum compound combination intra-arterial chemotherapy. Nine patients with ECOG performance status 3 or greater, and 9 with 12-month survival probability less than 0.5 in the CALGB prognostic model, including 3 aged over 80, were assessable for therapeutic results, adverse events and clinical benefit response. Improvement of QOL and relief of the bone pain were seen immediately after the intra-arterial chemotherapy treatment. Considering that high-dose calcitriol and platinum compound combination intra-arterial chemotherapy is easily administered without major toxic events even to outpatients, it will be a treatment option for the clinical benefit of relapsing prostate cancer patients with poor prognoses.

[Multidisciplinary treatment for advanced bladder cancer--a case report].

The patient was a 63-year-old woman who had been diagnosed with advanced bladder cancer with renal dysfunction and bilateral bulky pulmonary metastasis. Initially, the primary lesion was resected and the implantation of an infusion catheter and port system was performed. Following surgery, she received intermittent intra-arterial (IA) low-dose CDDP chemotherapy via the infusion port and concurrent bronchial arterial infusion and radiation (40 Gy for the left lung). About 3 months later, the right and left lung metastases were reduced 63% and 91%, respectively, and a right lower lobectomy was performed. CDDP was administered through the outpatient clinic ever since. From January 2001, we began to use docetaxel (TXT) for CDDP because of continuous grade 2 nausea and appetite loss. There were no adverse effects by TXT. Repeated IA chemotherapy was discontinued from June 2001 because of neurological symptoms. In September 2001, a left skull base metastasis was detected and was treated by radiation 40 Gy. In November 2002, a left patella metastasis appeared and was treated by IA chemotherapy with angiotensin II and radiation 30 Gy. We confirmed that multidisciplinary treatment contributed to her approximately 3-year survival with good QOL. The cancers in both lungs could be kept under control until her death.