A short outpatient hydration schedule for cisplatin administration.

BACKGROUND: Cisplatin remains a principal chemotherapy agent in the treatment of many solid tumours. However because of its nephrotoxicity, inpatient hydration schedules have been utilized to ensure safe administration. In May 1995, due to significant load on in-patient bed availability, the Medical Oncology Department of the Cancer Therapy Centre, Liverpool Hospital, developed a short, intravenous fluid hydration protocol to be used on an out-patient setting. METHODS: Following an initial pilot program of the abbreviated hydration regimen, a retrospective study of all adult in-patients and out-patients who received cisplatin (60-100 mg/m2) from May 1995 to August 1998 was conducted. Biochemistry was performed prior to the start of chemotherapy, and a repeat serum creatinine level was taken immediately prior to each subsequent cycle of chemotherapy, unless clinically indicated at an earlier time. The in-patient hydration protocol was 6000 ml of normal saline with 60 mmol/L KCL, and 30 mmol/L MgSO4 over 24 to 28 hours, and the out-patient hydration was 4000 ml of normal saline over 6 hours. RESULTS: A total of 145 patients were included, 57 in-patient (39%) and 88 out-patients (61%), 95 males, and 50 females. The mean age was 56 years. The maximum mean percentage change in creatinine from baseline for all cycles of chemotherapy for in-patients was 32.5% ranging from -7% to 288% (95% CI=19.9-45.11), and for outpatients 19.9% ranging from -20% to 154% (95% CI=13.47-26.39). Although the mean increase was higher in the in-patient group by 12.6%, it was not statistically significant (p=0.079). CONCLUSION: In patient's eligible for cis-platinum therapy on the basis of good performance status and normal renal function, this agent can be safely administered in the out-patient setting with an abbreviated duration, moderate volume intravenous hydration regimen.

Growth arrest-specific gene 6 expression in human breast cancer.

Growth arrest-specific gene 6 (Gas6), identified in 1995, acts as the ligand to the Axl/Tyro3 family of tyrosine kinase receptors and exerts mitogenic activity when bound to these receptors. Overexpression of the Axl/Tyro3 receptor family has been found in breast, ovarian and lung tumours. Gas6 is upregulated 23-fold by progesterone acting through the progesterone receptor B (PRB). Recently, Gas6 has been shown to be a target for overexpression and amplification in breast cancer. Quantitative real-time PCR analysis was used to determine the levels of Gas6 mRNA expression in 49 primary breast carcinomas. Expression of PRB protein was evaluated immunohistochemically with a commercially available PRB antibody. The results showed a positive association between PRB protein and Gas6 mRNA levels (P=0.04). Gas6 correlated positively with a number of favourable prognostic variables including lymph node negativity (P=0.0002), younger age at diagnosis (P=0.04), smaller size of tumours (P=0.02), low Nottingham prognostic index scores (P=0.03) and low nuclear morphology (P=0.03). This study verifies for the first time the association between PRB and Gas6 in breast cancer tissue.

Anemia is a common but neglected complication of adjuvant chemotherapy for early breast cancer.

In this study, we set out to determine the frequency and severity of anemia and the corrective interventions used during adjuvant chemotherapy for breast cancer.We conducted a retrospective electronic chart review of 702 patients who received adjuvant breast cancer chemotherapy at four BC Cancer Agency centres in 2002 and 2003. For these patients, we recorded the initial hemoglobin reading and the date of the first hemoglobin reading in the ranges 110-119 g/L, 100-109 g/L, 90-99 g/L, and <90 g/L. We also recorded any discussion about, or delivery of, interventions for anemia [transfusion, epoetin (epo) or both].Median age of the study population was 51 years, and it varied with chemotherapy type. Among the patients, 12% had a hemoglobin reading <120 g/L before the start of chemotherapy. Overall, the proportion of patients with at least one hemoglobin reading <120 g/L was 78%; <110 g/L, 54%; <100 g/L, 31%; and <90 g/L, 14%. Depending on chemotherapy type, a hemoglobin reading <100 g/L occurred in 5% to 54% of patients. Intervention rates increased as hemoglobin declined. For 99 patients with a hemoglobin reading <90 g/L, a discussion of anemia was documented in the treatment chart in 49% of cases, a transfusion was delivered in 23%, epo was used in 11%, and transfusion and epo were both delivered in 5%.Anemia was relatively common and varied with chemotherapy type. Documentation of a discussion of anemia occurred in fewer than 20% of the patients with a hemoglobin reading of 90-99 g/L and in only half the patients with a hemoglobin reading <90 g/L. Intervention rates were low at hemoglobin readings for which randomized trials have shown that intervention can improve quality of life.

Formalin-fixed paraffin-embedded clinical tissues show spurious copy number changes in array-CGH profiles.

Formalin-fixed paraffin-embedded (FFPE) archival clinical specimens are invaluable in discovery of prognostic and therapeutic targets for diseases such as cancer. However, the suitability of FFPE-derived genetic material for array-based comparative genomic hybridization (array-CGH) studies is underexplored. In this study, genetic profiles of matched FFPE and fresh-frozen specimens were examined to investigate DNA integrity differences between these sample types and determine the impact this may have on genetic profiles. Genomic DNA was extracted from three patient-matched FFPE and fresh-frozen clinical tissue samples. T47D breast cancer control cells were also grown in culture and processed to yield a fresh T47D sample, a fresh-frozen T47D sample and a FFPE T47D sample. DNA was extracted from all the samples; array-CGH conducted and genetic profiles of matched samples were then compared. A loss of high molecular weight DNA was observed in the FFPE clinical tissues and FFPE T47D samples. A dramatic increase in absolute number of genetic alterations was observed in all FFPE tissues relative to matched fresh-frozen counterparts. In future, alternative fixation and tissue-processing procedures, and/or new DNA extraction and CGH profiling protocols, may be implemented, enabling identification of changes involved in disease progression using stored clinical specimens.

Phase II study of gemcitabine and oxaliplatin in patients with recurrent ovarian cancer: an Australian and New Zealand Gynaecological Oncology Group study.

Gemcitabine and oxaliplatin have shown single-agent activity in relapsed ovarian cancer. This combination was used to determine response rates, time-to-event efficacy measures, and toxicity in patients with recurrent ovarian cancer. Patients with prior platinum-based chemotherapy who had measurable lesions and/or elevated CA-125 levels were identified as group A (platinum-refractory/platinum-resistant patients) and group B (platinum-sensitive patients). All patients received gemcitabine 1000 mg/m(2) on days 1 and 8 and oxaliplatin 130 mg/m(2) on day 8 every 21 days for up to eight cycles. Seventy-five patients (21 in group A and 54 in group B), with a median age of 58 years (range, 37-78), were enrolled. A median of six cycles (range, 1-8) was administered. By intent-to-treat analysis, 15 patients with measurable disease achieved partial response for an overall best response rate of 20.0% (9.5% in group A and 24.1% in group B). CA-125 response was observed in 48.4% patients (30.0% in group A and 57.1% in group B). Median time to progressive disease was 7.1 months (95% CI, 5.6-9.0 months) with 5.0 months in group A and 8.3 months in group B. Median overall survival was 17.8 months (95% CI, 12.9-21.3 months) with 9.2 months for group A and 20.0 months for group B. Major grade 3/4 toxicities were neutropenia (61.3%), leukopenia (24.0%), nausea (16.0%), and vomiting (22.7%). We conclude that the combination of oxaliplatin and gemcitabine is active in patients with recurrent ovarian cancer, but the regimen is unsatisfactory for further study due to modest response and relatively high toxicity.

Phase II trial of weekly docetaxel for patients with relapsed ovarian cancer who have previously received paclitaxel--ANZGOG 02-01.

OBJECTIVE: To determine the response rate of weekly docetaxel in women with relapsed epithelial ovarian cancer previously treated with paclitaxel and at least one line of platinum-based chemotherapy. METHODS: In this multi-center phase II trial, 37 patients with relapsed disease were enrolled and treated with weekly docetaxel at 35 mg/m for 5 out of 6 consecutive weeks. Two patient cohorts were considered, those who progressed or relapsed within 4 months (N=7) or at greater than 4 months (N=30) from the time of completing their last course of paclitaxel. RESULTS: Patients in both cohorts received a median of 2 cycles of treatment (range; 1-4). In evaluable patients, the combined overall response rate, using both CA125 and RECIST response criteria was 18.9% (7/37; 95% CI; 10-34%). The combined overall progression-free survival was 3.1 months (95% CI; 2.5-3.8), and the combined overall survival was 12.3 months (95% CI; 8.2-16.4). Treatment was generally well tolerated with the only grade 4 toxicity being skin toxicity (3%). The most common grade 3 toxicities were fatigue (14%) and watery eyes (8%) with grade 3 neutropenia observed in only 5% of patients. CONCLUSION: Weekly docetaxel is well tolerated and has activity in patients with relapsed ovarian cancer previously treated with platinum and paclitaxel.

Gain of imprinting of SLC22A18 sense and antisense transcripts in human breast cancer.

The 11p15.5 region harbors three imprinted sense/antisense transcript pairs, SLC22A18/SLC22A18AS, IGF2/IGF2AS (PEG8), and KCNQ1/KCNQ1OT1 (LIT1). SLC22A18 (solute carrier family 22 (organic cation transporter) member 18) and its antisense transcript SLC22A18AS are paternally suppressed in fetal samples. In adult tissue, SLC22A18 displays polymorphic imprinting, but the imprinting status of SLC22A18AS remains elusive. SLC22AI8 DNA-PCR-RFLP analysis using NlaIII restriction digestion identified SLC22A18 heterozygotes within this breast tissue cohort (n = 89). Commercial sequencing identified informative SLC22A18AS samples. Random hexamer-primed cDNA synthesis, SLC22A18/SLC22A18AS-specific PCR, and imprinting evaluation by commercial sequencing demonstrated that SLC22A18AS displays a nonimprinted profile in reduction mastectomies (n = 6). However, SLC22A18 showed a gain of imprinting (GOI) in 1/4 of these normal cases. In the malignant cohort, GOI was also demonstrated in 18% for SLC22A18 and 14% for SLC22A18AS, occurring concomitantly in one case. This study reports the imprinting status of SLC22A18AS in adult tissue, and shows that GOI affects both the sense, and antisense transcripts at this locus in human breast tissue.

Solid variant of alveolar rhabdomyosarcoma with unbalanced t(2;13) and hypotetraploidy, without MYCN amplification.

The histological subtype of alveolar rhabdomyosarcoma (AR) is characterised by the cytogenetic translocation t(2;13)(q35;q14) in approximately 70% of cases, a rearrangement rarely present in the embryonal rhabdomyosarcoma (ER) subtype. The MYCN gene is amplified in some cases of AR. We present a young man with an unusual pattern, namely solid variant of AR with hypotetraploidy and the t(2;13) in an unbalanced form. The MYCN gene was not amplified on FISH, but showed increased copy number, consistent with ploidy.