OV21/PETROC: a randomized Gynecologic Cancer Intergroup phase II study of intraperitoneal versus intravenous chemotherapy following neoadjuvant chemotherapy and optimal debulking surgery in epithelial ovarian cancer.

Background: The purpose of this multistage, adaptively, designed randomized phase II study was to evaluate the role of intraperitoneal (i.p.) chemotherapy following neoadjuvant chemotherapy (NACT) and optimal debulking surgery in women with epithelial ovarian cancer (EOC). Patients and methods: We carried out a multicenter, two-stage, phase II trial. Eligible patients with stage IIB-IVA EOC treated with platinum-based intravenous (i.v.) NACT followed by optimal (<1 cm) debulking surgery were randomized to one of the three treatment arms: (i) i.v. carboplatin/paclitaxel, (ii) i.p. cisplatin plus i.v./i.p. paclitaxel, or (iii) i.p. carboplatin plus i.v./i.p. paclitaxel. The primary end point was 9-month progressive disease rate (PD9). Secondary end points included progression-free survival (PFS), overall survival (OS), toxicity, and quality of life (QOL). Results: Between 2009 and 2015, 275 patients were randomized; i.p. cisplatin containing arm did not progress beyond the first stage of the study after failing to meet the pre-set superiority rule. The final analysis compared i.v. carboplatin/paclitaxel (n = 101) with i.p. carboplatin, i.v./i.p. paclitaxel (n = 102). The intention to treat PD9 was lower in the i.p. carboplatin arm compared with the i.v. carboplatin arm: 24.5% (95% CI 16.2% to 32.9%) versus 38.6% (95% CI 29.1% to 48.1%) P = 0.065. The study was underpowered to detect differences in PFS: HR PFS 0.82 (95% CI 0.57-1.17); P = 0.27 and OS HR 0.80 (95% CI 0.47-1.35) P = 0.40. The i.p. carboplatin-based regimen was well tolerated with no reduction in QOL or increase in toxicity compared with i.v. administration alone. Conclusion: In women with stage IIIC or IVA EOC treated with NACT and optimal debulking surgery, i.p. carboplatin-based chemotherapy is well tolerated and associated with an improved PD9 compared with i.v. carboplatin-based chemotherapy. Clinical trial number: clinicaltrials.gov, NCT01622543.

Vitamin D: do we get enough? A discussion between vitamin D experts in order to make a step towards the harmonisation of dietary reference intakes for vitamin D across Europe.

UNLABELLED: On September 29, 2011, acknowledged experts in the field of vitamin D, mainly European, were brought together in order to discuss the recent scientific advances in relation to vitamin D: the current requirements and associations with various health outcomes. In this article, the discussions resulting from the meeting are summarized. INTRODUCTION: Several groups at risk for developing vitamin D insufficiency have been identified. Accordingly, reviews indicate that a significant percentage of the population worldwide have serum 25-hydroxyvitamin D levels below 50 nmol/l. In addition to the role of vitamin D in bone health, recent studies suggest that it may play a pivotal role in other systems, e.g., the cardiovascular system, pancreas, muscle, immune system and brain. Most evidence, however, is obtained from observational studies and yet inconclusive. METHODS: To exchange and broaden knowledge on the requirements for vitamin D and its effect on various health outcomes, a workshop entitled "Vitamin D Expert Meeting: Do we get enough?", was organized. RESULTS: Despite low vitamin D levels worldwide, consensus on the definition of deficiency is not yet reached. In order to define cut-off points for vitamin D whilst taking into account extraskeletal health effects, randomized controlled trials in these fields are warranted. The experts do emphasize that there is evidence to suggest an important role for vitamin D in the maintenance of optimal bone health at all ages and that vitamin D supplementation, in most studies co-administered with calcium, reduces fracture risk in the senior population. CONCLUSION: To reach a serum 25-hydroxyvitamin D level of 50 nmol/l older adults aged ≥65 years are therefore recommended to meet a mean daily vitamin D intake of 20 µg (800 IU), which is best achieved with a supplement.

Using MRI to plan breast-conserving surgery following neoadjuvant chemotherapy for early breast cancer.

Contrast-enhanced magnetic resonance imaging (MRI) was used to monitor the response of patients undergoing neoadjuvant chemotherapy for breast cancer with the aim of undergoing breast-conserving surgery (BCS). Patients were prospectively recruited to undergo MRI as well as conventional methods of clinical examination, mammography (MM) and ultrasonography (USS) and response was assessed by each of these methods. Thirty-two patients with primary breast cancer were recruited. Magnetic resonance imaging correlation with histopathological size (r=0.71) was superior to USS (r=0.65) and to MM where tumour size was not measurable following chemotherapy in 71% of patients. Magnetic resonance imaging had 87.5% sensitivity (95% CI=68-97%) and 50% specificity (95% CI=16-84%) for a PPV (positive predictive value) of 99.8% and NPV (negative predictive value) of 80% for the detection of residual invasive cancer. Magnetic resonance imaging displayed 80% sensitivity (95% CI=28.4-99.5%) and 89% specificity (95% CI=71-98%) to detect pathological pCR in the breast. Eighty-four per cent of recruited patients were identified as potentially suitable candidates for BCS following chemotherapy and of those choosing to accept BCS, breast conservation was achieved in 90.5%, or 65.6% of all patients. Of those who proceeded to BCS, 9.5% required a re-do mastectomy because of positive margins; however, no residual tumour was found on histological examination of mastectomy specimens. Magnetic resonance imaging appears to be superior to conventional methods for assessing pathological response and the low rate of re-operation for positive margins indicates a valuable role in aiding the decision to undergo BCS or mastectomy.

Computed tomography features of recurrent ovarian carcinoma according to time to relapse.

BACKGROUND: Although the sites of recurrent ovarian cancer are individually described in the literature, patterns of recurrent disease are poorly understood. PURPOSE: To describe CT patterns of disease in recurrent ovarian cancer. To emphasize common patterns, recognise subtle and unusual sites of recurrent disease. MATERIALS AND METHODS: We identified patients between 1981-2004 presenting with clinical recurrence or elevated CA 125 after complete primary clinical and radiological response. CT imaging at primary diagnosis, during and after treatment and at recurrence was retrospectively reviewed. Site, distribution, stage of disease and time to relapse was recorded. RESULTS: 400 patients were treated for ovarian cancer. 214(54%) achieved complete primary response. 161(75%) relapsed with complete imaging available in 67 patients. Of the 67 patients, 14 (21%) recurred within 1 year, 44 (66%) relapsed between 1-5 years. Therefore 87% of relapses occurred within 5 years following primary treatment. Five (8%) relapsed between 5-10 years and 4 (6%) relapsed after 10 years. Commonest pattern of relapse was pelvic mass in 35 (48%) patients, solitary in 15 (22%). 27 (45%) relapsed with peritoneal thickening, 27 (45%) had small or large bowel serosal disease, 22 (33%) had enlarged lymphadenopathy, 6 as sole manifestation of recurrence, 20 (30%) presented with unusual sites of recurrence: 6 splenic, 10 hepatic, 2 biliary, 3 brain and 2 muscle. CONCLUSION: Our study is the first to describe common patterns of recurrence in ovarian cancer. Most frequent site is pelvis, followed by peritoneum, serosal surfaces and nodal disease. 30% presented with disease at 'unusual' sites.

Loci contributing to adult height and body mass index in African American families ascertained for type 2 diabetes.

Height and body mass index (BMI) have high heritability in most studies. High BMI and reduced height are well-recognized as important risk factors for a number of cardiovascular diseases. We investigated these phenotypes in African American families originally ascertained for studies of linkage with type 2 diabetes using self-reported height and weight. We conducted a genome wide scan in 221 families containing 580 individuals and 672 relative pairs of African American descent. Estimates of heritability and support for linkage were assessed by genetic variance component analyses using SOLAR software. The estimated heritabilities for height and BMI were 0.43 and 0.64, respectively. We have identified major loci contributing to variation in height on chromosomes 15 (LOD = 2.61 at 35 cM, p = 0.0004), 3 (LOD = 1.82 at 84 cM, p = 0.0029), 8 (LOD = 1.92 at 135 cM, p = 0.0024) and 17 (LOD = 1.70 at 110 cM, p = 0.0044). A broad region on chromosome 4 supported evidence of linkage to variation in BMI, with the highest LOD = 2.66 at 168 cM (p = 0.0005). Two height loci and two BMI loci appear to confirm the existence of quantitative trait loci previously identified by other studies, providing important replicative data to allow further resolution of linkage regions suitable for positional cloning of these cardiovascular disease risk loci.

Attitudes to chemotherapy in patients with ovarian cancer.

BACKGROUND: Recurrent ovarian cancer (OVCA) has become the model for cancer as a chronic disease, yet little is known about what motivates patients and physicians in treatment choices. METHODS: We investigated the attitudes of patients with epithelial OVCA and staff towards palliative chemotherapy for recurrent OVCA with a cross-sectional questionnaire study. RESULTS: Instruments were developed and piloted in 15 patients. This exploratory study reflects substantial bias in the sample populations. One hundred twenty-two patients and 37 staff were enrolled in the US and 39 patients and 25 staff were enrolled in the UK. UK patients had a lower educational status (P = 0.001), lower stage disease (P = 0.025), and less prior lines of chemotherapy (P < 0.001). 61% of patients had recurrent OVCA and 67% of staff were physicians. Seventy-three percent of patients recalled a discussion about prognosis and 74% wanted to know details of the prognosis for a typical patient (US = UK). Most patients (48%) thought that their physician was realistic, and 57% of staff felt that they were optimistic. The vast majority of both staff and patients thought that patients positively reinterpreted what they were told. Five percent of staff thought that palliative care was "incompatible" when considering chemotherapy as an option for their second recurrence of OVCA, compared with 36% of US patients, significantly more than the 12% of UK patients (P = 0.007). Patients thought that standard chemotherapy for a second recurrence of OVCA produced remission in 50% and cure in 15% of patients. Staff reported 20% and 0%, respectively. Fifty percent of patients and 57% of staff would want chemotherapy as an asymptomatic patient with a normal CT and a rising CA-125. Patients generally appear to be very tolerant of grade II chemotherapy-induced toxicity with staff being less tolerant than patients of nausea, anorexia, diarrhea, and rash. Staff rated life prolongation by 3 months to 1 year very much less acceptable than patients (P < 0.001). Although possibly allowing comprehensive collection of sensitive data, the questionnaire was too distressing for some patients and made 11% of patients feel uncomfortably anxious. CONCLUSIONS: Patients are optimistic and in the US, may be more reluctant than staff to see the Palliative Care Team. These data challenge the assertion that the use of palliative chemotherapy is physician-driven.

Irinotecan, cisplatin and mitomycin in inoperable gastro-oesophageal and pancreatic cancers - a new active regimen.

Irinotecan, mitomycin and cisplatin all demonstrate activity in gastro-oesophageal cancers. This novel combination was administered to outpatients with previously untreated inoperable gastro-oesophageal or pancreatic cancer, in a 28-day cycle. A total of 26 out of 31 patients with gastro-oesophageal cancer and 12 out of 14 patients with pancreatic cancer have been treated with this combination, and were evaluable for response. The overall response rates for patients with gastro-oesophageal cancer was 42%, with a median survival of 9.5 months. In patients with pancreatic cancer, the overall response rate was 42% with a median survival of 8 months. There was a statistically significant increase in survival between those patients who achieved a stable disease response and those who achieved either a partial response or complete response. The toxicity profiles for both cancers were virtually identical. There were five treatment-related deaths, and a high admission rate (42%). Thus irinotecan, mitomycin and cisplatin is a new combination with activity in inoperable upper gastro-oesophageal cancers, but with a high toxicity profile. Future developments include reducing the dose of irinotecan and number of cycles of therapy to four.

Evidence for a schedule-dependent deleterious interaction between paclitaxel, vinblastine and cisplatin (PVC) in the treatment of advanced transitional cell carcinoma.

A phase II study to evaluate the efficacy and toxicity of the combination of vinblastine, paclitaxel and cisplatin (PVC) in previously untreated patients with advanced transitional cell carcinoma. Chemotherapy naive patients with locally advanced or metastatic transitional cell carcinoma received the intravenous combination of paclitaxel 175 mg/m(2)over three hours followed by cisplatin 70 mg/m(2)over 3 hours on day 1 and vinblastine 3 mg/m(2)as a bolus on days 1 and 8 on a 21-day cycle, to a maximum of 6 cycles. The day 8 vinblastine was omitted if the total neutrophil count was <1.0. 15 patients (13 M, 2 F) of median age 66 (54-75) received a median of 5 cycles of treatment. There were two complete responses (13%; 95% CI 2-40%) and five partial responses (33%; 95% CI 12-62%), for an overall response rate of 46% (95% CI 21-73%). Responses occurred only in those with locally recurrent tumours and/or lymph nodes involved. Neutropenia at Grade 3-4 occurred in 14 of 67 cycles (21%) resulting in 7 episodes of neutropenic sepsis. Grade 3-4 thrombocytopenia was not observed. Other Grade 3 toxicity included alopecia (10 pts), diarrhoea (2 pts), constipation resulting in bowel obstruction (2 pts), nephrotoxicity (1 pt), myalgic pain (1 pt) and peripheral neuropathy (1 pt). Six patients developed Grade 2 paraesthesia. The median time to progression was 6 months and the median survival was 11 months. The regimen PVC was both less effective against transitional cell carcinoma and less toxic than expected. This may reflect an inhibitory interaction between vinblastine and paclitaxel and this schedule cannot be recommended for further investigation.

P2Y(1) purinoceptor-mediated Ca(2+) signaling and Ca(2+) wave propagation in dorsal spinal cord astrocytes.

ATP is known to act as an extracellular messenger mediating the propagation of Ca(2+) waves in astrocyte networks. ATP mediates Ca(2+) waves by activating P2Y purinoceptors, which mobilize intracellular Ca(2+) in astrocytes. A number of P2Y purinoceptor subtypes have been discovered, but it is not known which P2Y subtypes participate in transmitting astrocyte Ca(2+) waves. Here, we show that ATP analogs that are selective agonists for the P2Y(1) subtype of purinoceptor caused release of intracellular Ca(2+) in astrocytes from the dorsal spinal cord. The Ca(2+) responses were blocked by adenosine-3'-phospho-5'-phosphosulfate, an antagonist known to selectively inhibit P2Y(1) but not other P2Y purinoceptor subtypes. Also, we show that P2Y(1) mRNA is expressed in dorsal spinal cord astrocytes. Furthermore, expression of P2Y(1) in an astrocytoma cell line lacking endogenous purinoceptors was sufficient to permit propagation of intercellular Ca(2+) waves. Finally, Ca(2+) wave propagation in dorsal spinal cord astrocytes was suppressed by pharmacologically blocking P2Y(1) purinoceptors. Together, these results indicate that dorsal spinal astrocytes express functional P2Y(1) purinoceptors, which participate in the transmission of Ca(2+) waves. Ca(2+) waves in astrocytes have been implicated as a major signaling pathway coordinating glial and neuronal activity; therefore, P2Y(1) purinoceptors may represent an important link in cell-cell signaling in the CNS.

Should high-dose chemotherapy be used to consolidate second or third line treatment in relapsing germ cell tumours?

Thirty consecutive patients with relapsing germ cell tumours (GCT) were treated with induction chemotherapy and high-dose chemotherapy consolidation (HDCT). Overall, 47% were progressionfree and 53% were alive with a median follow up of 40 months. Initially, HDCT was given as consolidation of third line VIP (etoposide/ifosfamide and cisplatin), following failure of a weekly cisplatin regimen. During 1995, paclitaxel was introduced into second line therapy with cisplatin and ifosfamide (TIP), with immediate consolidation using HDCT. At the same time the carboplatin dosing calculation was changed and an area under the curve (AUC) formula rather than by mg/m2 was used to calculate this. The main determinant of post-treatment renal dysfunction was pretreatment renal function rather than the AUC dose of carboplatin. Only a raised LDH prior to induction or absolute refractory disease in response to induction chemotherapy predicted poor survival following HDCT. In patients relapsing following HDCT, the outcome was poor with many patients relapsing in the central nervous system and other new sites of disease. Further responses were seen to chemotherapy or radiotherapy but these were not sustained. The failure to improve results when HDCT was used as second line rather than third line chemotherapy consolidation was disappointing and adds to further uncertainty of the role of this approach as far as timing and the ideal preparative regimen are concerned.

Sixty percent salvage rate for germ-cell tumours using sequential m-BOP, surgery and ifosfamide-based chemotherapy.

BACKGROUND: In germ-cell tumours (GCT), there is continuing controversy over the relative merits of dose dense therapy (increased frequency over a given time) versus vertical intensification (increased dose per fraction). The value of using a cisplatin-based dose dense approach in the salvage setting has not been documented and in addition the role of methotrexate remains uncertain. This paper reviews results from our investigations of these issues. PATIENTS AND METHODS: Between 1987 and 1996, 65 patients with relapsing or refractory germ-cell tumour received weekly m-BOP (methotrexate, bleomycin, vincristine and cisplatin) as salvage therapy. Residual masses were excised if possible and patients progressing after this received cisplatin and ifosfamide based chemotheraphy with or without high dose chemotherapy (HDCT) consolidation. RESULTS: With a median follow-up of 33 months, 34% are progression free following m-BOP, 11% who had surgery for residual masses which showed viable cancers are progression free. A further 15% who progressed following m-BOP with or without surgery were rendered progression free by third-line therapy. CONCLUSIONS: The use of m-BOP as second line therapy with deferment of cisplatin and ifosfamide based treatment to third line therapy with consolidation of third line responses with HDCT, leads to an overall progression-free survival of 60%. It does not appear that M-BOP prejudiced the response to third line therapy suggesting a lack of cross resistance. The potentially lower risk of leukaemia and infertility from m-BOP requires further evaluation.

Phase II study of paclitaxel in pretreated patients with locally advanced/metastatic cancer of the bladder and ureter.

Fourteen patients with previously treated, locally advanced/metastatic transitional cell carcinoma (TCC) of the bladder or ureter received paclitaxel at a dose of 200 mg m-2 administered as a 3-h infusion every 21 days. The activity of paclitaxel in this group of patients was modest. The response rates were one partial response (PR) (7%) and three stable disease (SD). There were two early deaths.

Long-term follow-up of gonadotrophin-releasing hormone analog treatment for recurrent endometrial cancer.

To test the antitumor effect of gonadotrophin-releasing hormone (GnRH) analogs, 32 consecutive patients with recurrent endometrial cancer that had progressed through conventional treatments were entered into an open observational trial of treatment with this class of compounds. Patients recruited had progressive, symptomatic, and measurable disease. Treatment was with monthly subcutaneous injections of GnRH analog. Measurements of gonadotrophins, sex hormones, and tumor dimensions were made together with repeat biopsy when possible to assess response to treatment. An objective response was seen in nine patients (28%, 95% CI 13-43%). Responses were seen within the first 2 months of treatment and included pelvic as well as distant sites of recurrence. Significantly greater response rates were seen in previously irradiated sites when compared with nonirradiated sites of recurrence (0.01 > P > 0.001). There was no significant difference between the response in patients with G3 lesions compared with patients with G1/G2 lesions (P > 0.5). Response did not correlate with previous progestogen exposure. No evidence of disease flare or drug toxicity was observed. GnRH analogs have a significant and durable antitumor effect in recurrent endometrial cancer which warrants further examination in comparison with progestogens.

The expression of gonadotropin-releasing hormone and its receptor in endometrial cancer, and its relevance as an autocrine growth factor.

The presence of a direct extra-pituitary action of gonadotropin-releasing hormone (GnRH) via specific receptors in endometrial cancer (EC) has been suggested as an explanation for the therapeutic effect of GnRH analogue (GnRHa) in recurrent disease. We have sought the expression of the GnRH peptide and functional GnRH receptor (GnRH-R) in human tissues and cell lines to investigate the possibility of an autocrine growth regulation mechanism. Using reverse transcription-PCR, differing GnRH mRNA transcripts were detected in two EC cell lines (Ishikawa and HEC-1A), a choriocarcinoma (JEG3) cell line, and tissues from endometrium and placenta. However, secretion of immunoreactive GnRH could be detected by RIA in only 1 of 10 EC tissues in primary culture, and in none of the cell lines. Low levels of GnRH-R mRNA expression were found in the same cells, which were only detectable by reverse transcription-PCR and Southern blotting of the PCR product. In radioligand binding assays using GnRHa goserelin, no pituitary-like, high-affinity GnRH binding sites could be found in either EC cell lines or tissues. Low affinity binding (Kd = 1.0 - 3.1 x 10(-7)M) was detected in three of eight (37%) EC tissues. Furthermore, receptor signal transduction measurements carried out in these cells showed no increases in either total inositol phosphate, cyclic AMP production, or cytosolic Ca2+ in response to either GnRH or GnRHa. Finally, no effect of either GnRH or GnRHa on the growth of EC cell lines was detected in vitro, under estrogen-free conditions, assessed by DNA content. Our data suggest that although there is a potential for autocrine activity for GnRH in EC as judged by the presence of mRNA for peptide and receptor, no functional receptor activity could be detected in vitro. Alternative mechanisms should be studied to explain the in vitro action of GnRHa.