Molecular evidence for the clonal origin of blast crisis in chronic myeloid leukaemia.

Cytogenetic and enzymatic studies have shown that chronic myeloid leukemia (CML) represents the clonal proliferation of a pluripotent stem cell. The Philadelphia chromosome (Ph') is the characteristic karyotypic abnormality seen in this disease, although the exact role of this clonal marker in the pathogenesis of CML is uncertain. At a molecular level, the Ph' has recently been shown to represent the translocation of c-abl to a limited (breakpoint cluster region, bcr) on chromosome 22. We have used probes for the bcr gene to obtain molecular evidence for the clonal origin of blast crisis in 2 patient with CML. In both cases, the first with myeloid and the second with lymphoid blast crisis, there was rearrangement of the bcr gene. The patterns of rearrangement varied between patients but were identical when comparing acute and chronic phases within the same individual. As the Ph' translocation is thought to represent a random recombination event these data not only provide further evidence for the clonal origin of blast crisis in CML, but also suggest that in the second patient this translocation event had already occurred at the pluripotent stem cell

EUS-FNA Biopsies to Guide Precision Medicine in Pancreatic Cancer: Results of a Pilot Study to Identify KRAS Wild-Type Tumours for Targeted Therapy

Background: Pancreatic ductal adenocarcinoma (PDAC) is a leading cause of cancer death and lacks effective treatment options. Diagnostic endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) biopsies represent an appealing source of material for molecular analysis to inform targeted therapy, as they are often the only available tissue for patients presenting with PDAC irrespective of disease stage. However, EUS-FNA biopsies are typically not used to screen for precision medicine studies due to concerns about low tissue yield and quality. Epidermal growth factor receptor (EGFR) inhibition has shown promise in clinical trials of unselected patients with advanced pancreatic cancer, but has not been prospectively tested in KRAS wild-type patients. Here, we examine the clinical utility of EUS-FNA biopsies for molecular screening of KRAS wild-type PDAC patients for targeted anti-EGFR therapy to assess the feasibility of this approach. Patients and Methods: Fresh frozen EUS-FNA or surgical biopsies from PDAC patient tumours were used to screen for KRAS mutations. Eligible patients with recurrent, locally advanced, or metastatic KRAS wild-type status who had received at least one prior line of chemotherapy were enrolled in a pilot study (ACTRN12617000540314) and treated with panitumumab at 6mg/kg intravenously every 2 weeks until progression or unacceptable toxicity. The primary endpoint was 4-month progression-free survival (PFS). Results: 275 patient biopsies were screened for KRAS mutations, which were detected in 88.3% of patient samples. 8 eligible KRAS wild-type patients were enrolled onto the interventional study between November 2017 and December 2020 and treated with panitumumab. 4-month PFS was 14.3% with no objective tumour responses observed. The only grade 3/4 treatment related toxicity observed was hypomagnesaemia. Conclusions: This study demonstrates proof-of-principle feasibility to molecularly screen patients with pancreatic cancer for targeted therapies, and confirms diagnostic EUS-FNA biopsies as a reliable source of tumour material for molecular analysis. Single agent panitumumab was safe and tolerable but led to no objective tumour responses in this population

Inheritance of chromosome 7 is associated with a drug-resistant phenotype in somatic cell hybrids.

A major form of drug resistance in tumour cells known as classical multidrug resistance (MDR) is associated with the overexpression of the mdr1 gene product, the membrane protein P-glycoprotein (P-gp), which acts as an energy-dependent drug efflux pump. In this study the inheritance of P-gp expression was examined using hybrids formed after somatic cell fusion between a drug-sensitive human T-cell leukaemia cell line, CEM/CCRF, and a drug-resistant derivative, CEM/A7, which is characterized by a clonal chromosomal duplication dup(7)(q11.23q31.2). Fourteen hybrids, chosen at random, were analysed by reverse transcriptase-polymerase chain reaction (RT-PCR) and by binding studies involving the monoclonal antibody MRK16, which recognises an external P-gp epitope. Only two hybrids were positive for both MRK16 antibody labelling and mdr1 mRNA. Partial karyotypic analysis of all hybrids revealed that only the MRK16-positive hybrids contained the duplication in chromosome 7 seen in the CEM/A7 parental MDR line. Therefore, P-gp overexpression in the MRK16-positive hybrids may be linked to the inheritance of chromosome 7 from CEM/A7 and possibly associated with the chromosome 7 abnormality

An appraisal of analytical tools used in predicting clinical outcomes following radiation therapy treatment of men with prostate cancer: a systematic review

Background: Prostate cancer can be treated with several different modalities, including radiation treatment. Various prognostic tools have been developed to aid decision making by providing estimates of the probability of different outcomes. Such tools have been demonstrated to have better prognostic accuracy than clinical judgment alone. Methods: A systematic review was undertaken to identify papers relating to the prediction of clinical outcomes (biochemical failure, metastasis, survival) in patients with prostate cancer who received radiation treatment, with the particular aim of identifying whether published tools are adequately developed, validated, and provide accurate predictions. PubMed and EMBASE were searched from July 2007. Title and abstract screening, full text review, and critical appraisal were conducted by two reviewers. A review protocol was published in advance of commencing literature searches. Results: The search strategy resulted in 165 potential articles, of which 72 were selected for full text review and 47 ultimately included. These papers described 66 models which were newly developed and 31 which were external validations of already published predictive tools. The included studies represented a total of 60,457 patients, recruited between 1984 and 2009. Sixty five percent of models were not externally validated, 57% did not report accuracy and 31% included variables which are not readily accessible in existing datasets. Most models (72, 74%) related to external beam radiation therapy with the remainder relating to brachytherapy (alone or in combination with external beam radiation therapy). Conclusions: A large number of prognostic models (97) have been described in the recent literature, representing a rapid increase since previous reviews (17 papers, 1966–2007). Most models described were not validated and a third utilised variables which are not readily accessible in existing data collections. Where validation had occurred, it was often limited to data taken from single institutes in the US. While validated and accurate models are available to predict prostate cancer specific mortality following external beam radiation therapy, there is a scarcity of such tools relating to brachytherapy. This review provides an accessible catalogue of predictive tools for current use and which should be prioritised for future validation.Elspeth Raymond, Michael E. O’Callaghan, Jared Campbell, Andrew D. Vincent, Kerri Beckmann, David Roder, Sue Evans, John McNeil, Jeremy Millar, John Zalcberg, Martin Borg and Kim Morett

A phase II study in advanced breast cancer: ZD1694 ('Tomudex') a novel direct and specific thymidylate synthase inhibitor.

ZD1694 ('Tomudex'), a novel, direct and specific thymidylate synthase (TS) inhibitor, was developed in a collaborative research programme between Zeneca Pharmaceuticals and the Institute of Cancer Research (UK) and entered clinical trials in 1991; phase II studies began in 1992, using 3.0 mg m-2 every 3 weeks as a short 15 min infusion. Forty-six patients entered a phase II study of ZD1694 in advanced breast cancer. A total of 74% of patients had received prior systemic therapy (either as adjuvant cytotoxic or hormonal therapy or hormone therapy for advanced disease); 39% had received prior adjuvant cytotoxic chemotherapy. All patients had measurable disease and 50% had liver metastases. In all 43 patients were evaluable for response. Of these patients 26% achieved complete (CR) or partial response (PR) (95% Cl 14-42%). A response rate of 44% was seen in liver metastases. Two patients achieved CR of 265 and 301 days' duration respectively, one in locoregional disease, and one in liver metastases. The most common grade 3/4 adverse events were nausea and vomiting (11%), diarrhoea (11%) and leucopenia (20%). Grade 3/4, self-limited and reversible increases in transaminases were seen in 22% of patients. ZD1694 has useful single agent activity in patients with hormone-refractory advanced breast cancer, comparable with that reported for other anti-metabolites, with acceptable tolerability

A phase I trial of Capecitabine+Gemcitabine with radical radiation for locally advanced pancreatic cancer

Standard chemoradiotherapy with infusional 5FU for locally advanced pancreatic cancer (LAPC) has limited efficacy in this disease. The combination of Capecitabine (Cap) and Gemcitabine (Gem) are synergistic and are potent radiosensitisers. The aim of this phase I trial was thus to determine the highest administered dose of the Cap plus Gem combination with radical radiotherapy (RT) for LAPC. Patients had LAPC, adequate organ function, ECOG PS 0–1. During RT, Gem was escalated from 20–50 mg m−2 day−1 (twice per week), and Cap 800–2000 mg m−2 day−1 (b.i.d, days 1–5 of each week). Radiotherapy 50.4 Gy/28 fractions/5.5 weeks, using 3D-conformal techniques. Three patients were entered to each dose level (DL). Dose-limiting toxicity(s) (DLTs) were based on treatment-related toxicities. Twenty patients were accrued. Dose level (DL) 1: Cap/Gem; 800/20 mg m−2 day−1 (3 patients), DL2: 1000/20 (12 patients), DL3: 1300/30 (5 patients). Dose-limiting toxicities were observed in DL3; grade 3 dehydration (1 patient) and grade 3 diarrhoea and dehydration (1 patient). Dose level 2 was the recommend phase 2 dose. Disease control rate was 75%: PR=15%, SD=60%. Median overall survival was 11.2 months. The addition of Cap and Gem to radical RT was feasible and active and achieved at relatively low doses

Symptoms and feelings valued by patients after a percutaneous coronary intervention: A discrete-choice experiment to inform development of a new patient-reported outcome

Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ. Objective To inform the development of a patient-reported outcome measure, the aim of this study was to identify which symptoms and feelings following percutaneous coronary intervention (PCI) are most important to patients. Design Discrete-choice experiment consisting of two hypothetical scenarios of 10 symptoms and feelings (pain or discomfort; shortness of breath; concern/worry about heart problems; tiredness; confidence to do usual activities; ability to do usual activities; happiness; sleep disturbance; dizziness or light-headedness and bruising) experienced after PCI, described by three levels (never, some of the time, most of the time). Preference weights were estimated using a conditional logit model. Setting Four Australian public hospitals that contribute to the Victorian Cardiac Outcomes Registry (VCOR) and a private insurer's claim database. Participants 138 people aged >18 years who had undergone a PCI in the previous 6 months. Main outcome measures Patient preferences via trade-offs between 10 feelings and symptoms. Results Of the 138 individuals recruited, 129 (93%) completed all 16 choice sets. Conditional logit parameter estimates were mostly monotonic (eg, moving to worse levels for each individual symptom and feeling made the option less attractive). When comparing the magnitude of the coefficients (based on the coefficient of the worst level relative to best level in each item), feeling unhappy was the symptom or feeling that most influenced perception of a least-preferred PCI outcome (OR 0.42, 95% CI 0.34 to 0.51, p<0.0001) and the least influential was bruising (OR 0.81, 95% CI 0.67 to 0.99, p=0.04). Conclusion This study provides new insights into how patients value symptoms and feelings they experience following a PCI

Avaliação de risco em mioloma múltiplo: resultados preliminares do grupo brasileiro de estudos de mieloma

The Durie/Salmon staging system continues to be used worldwide in patients with multiple myeloma. However, in recent years, new systems have been proposed. The International Myeloma Working Group performed a retrospective study with 11,179 patients and proposed an "International Staging System" utilizing serum levels of â2 microglobulin and albumin. In addition, current research has focused on the usefulness of cytogenetic and molecular data as prognostic factors. These data suggest that these parameters are powerful discriminators of a poor prognostic group of myeloma patients. Indeed, these prognostic indexes have been utilized in clinical trials, with interesting and encouraging results.O esquema de Durie / Salmon continua a ser utilizado para estadiar os pacientes com mieloma múltiplo. Recentemente, um novo sistema mais simples e eficaz foi proposto. O "International Myeloma Working Group" realizou um estudo retrospectivo com 11.179 pacientes e a partir destes dados propôs a criação de um "International Staging System (ISS)" utilizando os níveis séricos de ß2 microglobulina e de albumina ao diagnóstico. Além do ISS a pesquisa está voltada para identificar alterações citogenéticas e moleculares que se correlacionem com o prognóstico no mieloma múltiplo. Estes fatores prognósticos têm sido utilizados para estratificar pacientes em ensaios clínicos com resultados promissores