Bevacizumab with peri-operative epirubicin, cisplatin and capecitabine (ECX) in localised gastro-oesophageal adenocarcinoma: a safety report.

BACKGROUND: Peri-operative chemotherapy and surgery is a standard treatment of localised oesophagogastric adenocarcinoma; however, the outcomes remain poor. PATIENTS AND METHODS: ST03 is a multicentre, randomised, phase II/III study comparing peri-operative ECX with or without bevacizumab (ECX-B). The primary outcome measure of phase II (n = 200) was safety, specifically gastrointestinal (GI) perforation rates and cardiotoxicity. RESULTS: Two hundred patients were randomised between October 2007 and April 2010. Ninety-one/101 (90%) ECX and 86/99 (87%) ECX-B patients completed pre-operative chemotherapy; 7 ECX and 9 ECX-B patients stopped due to toxicity. Gastrointestinal perforations (3 ECX, 1 ECX-B), cardiac events (1 ECX, 4 ECX-B) and venous thromboembolic events (VTEs, 8 ECX, 7 ECX-B) were uncommon. Arterial thromboembolic events (ATEs, myocardial infarction (MI) or cerebrovascular accident) were more frequent with ECX-B (5 versus 1 with ECX). Delayed wound healing, anastomotic leaks and GI bleeding rates were similar. More asymptomatic left ventricular ejection fraction (LVEF) falls (≥15% and/or to <50%) occurred with ECX-B (21.2% versus 11.1% with ECX). Clinically significant falls (≥10% to below lower limit of normal, LLN) occurred in (15.3%) and (8.9%) respectively, with no associated cardiac failure (median 22 months follow-up). CONCLUSIONS: Addition of bevacizumab to peri-operative ECX chemotherapy is feasible with acceptable toxicity and no negative impact on surgical outcomes.

Current status of GV1001 and other telomerase vaccination strategies in the treatment of cancer.

GV1001 is a telomerase-specific, promiscuous class II peptide vaccine which is currently in an advanced stage of clinical development. This article reviews the biological rationale underpinning the design of ongoing studies with the vaccine as well as its immunogenicity and clinical activity. It places GV1001 in the context of other immunotherapeutic approaches targeting telomerase and assesses the chances of the vaccine becoming a future standard of care in the treatment of cancer.

Diagnostic accuracy of 99Tcm-HIDA with cholecystokinin and gallbladder ejection fraction in acalculous gallbladder disease.

The diagnostic accuracy and clinical impact of 99Tcm hepatic iminodiacetic acid (HIDA) imaging with cholecystokinin (CCK) was investigated in a prospective study of 359 patients over an 11 year period. All patients presented with right upper quadrant biliary type pain and had a normal ultrasound investigation prior to imaging. CCK was administered as a 3 min infusion at peak gallbladder uptake of HIDA. A gallbladder ejection fraction (GBEF) was used to quantify the gallbladder response to CCK. Two hundred and forty-four of 359 (68%) patients had an abnormal GBEF (< or = 35%). One hundred and thirty-four of 141 (95%) patients who underwent cholecystectomy had abnormal surgical/histological findings and/or relief of symptoms on long-term (mean 5.7 years) follow-up. Clinical follow-up, mean of 5.9 years, of the patients with GBEF > 35% showed 73/79 (92%) of them with little evidence of gallbladder disease. For a total 261 patients with mean clinical follow-up of 5.7 years the sensitivity of GBEF measurement is 95%, specificity is 92% and overall accuracy is 94%. It is concluded that 99Tcm-HIDA imaging, with a 3 min infusion of CCK, is a highly accurate technique and valuable in the diagnostic management of patients with suspected acalculous gallbladder disease.

Investigating lymphadenopathy--report on the first 12 months of the lymph node diagnostic clinic at the Royal Marsden Hospital.

The lymph node diagnostic clinic was set up at the Royal Marsden Hospital to provide a direct access service for general practitioners. In the first year 82 patients were seen. The malignancy pick-up rate was 19.5% which compares very favourably to rates in breast and colorectal clinics. Patient and general practitioner satisfaction with the service was high.

Good symptom relief with palliative MVP (mitomycin-C, vinblastine and cisplatin) chemotherapy in malignant mesothelioma.

PURPOSE: To evaluate the therapeutic impact of a simple combination chemotherapy regimen on symptoms related to malignant mesothelioma. MATERIALS AND METHODS: Between October 1986 and June 1997, 39 patients with advanced inoperable malignant mesothelioma were treated with palliative MVP (mitomycin-C 8 mg/m2 q. six weeks, vinblastine 6 mg/m2 q. three weeks and cisplatin 50 mg/m2 q. three weeks) chemotherapy and assessed for objective response and relief of symptoms. RESULTS: Eight of 39 patients (20%) achieved an objective partial response with a median duration of nine months: only five patients had progression of disease during chemotherapy. Twenty-four of 39 (62%) had an overall improvement in their symptomology with particularly good responses for pain (79%). These benefits were independent of performance status. Resolution of symptoms was achieved in all responding patients within two treatment cycles. There was no statistically significant difference in duration and incidence of symptom response in those patients achieving radiological PR compared with those with no change and more than 60% of patients with radiological no change obtained useful symptom control. The treatment was well tolerated with only four patients developing grade 3 leucopenia and three with grade 3 nausea. CONCLUSIONS: MVP is a well tolerated regimen and its use in malignant mesothelioma provides useful symptomatic benefit. These results should be the basis for further trials of MVP in the management of mesothelioma with symptom control as a principal endpoint.

Role of CD34+ cells in engraftment after high-dose melphalan in multiple myeloma patients given peripheral blood stem cell rescue.

During the period December 1992 to June 1995, 95 patients were treated with high-dose melphalan (HDM) with peripheral blood stem cell rescue (PBSCR). Sixty-five had received previous treatment and 28 had relapsed. Among patients who had relapsed 21/28 had received HDM previously including one who received HDM twice during the course of the study. Seventy-five patients were given HDM/PBSCR for the first time. Comparisons have been made between engraftment times for platelets and neutrophils among patients who received less than or greater than 2 x 10(6) CD34+ cells at rescue. Analyses have also been done to evaluate the effect of previous HDM on recovery. Mobilization of progenitor cells was done with granulocyte colony-stimulating factor (G-CSF). Patients received only PBSCR. No growth factors were given to the PBSCR recipients during the recovery period. The percentage of patients from whom the number of CD34+ cells mobilized was > 2 x 10(6)/kg was similar in patients who received HDM for the first time (23%) compared with those who had had it previously (19%). The yield of CD34+ cells correlated with the number of granulocyte-macrophage colony forming units (CFU-GM). Although the number of CD34+ cells infused was < 2 x 10(6)/kg in 77% of patients, all engrafted for neutrophils to > 0.5 x 10(9)/l. This was delayed in patients who had had previous HDM (P < 0.02). Platelet recovery to > 25, 50 and 100 x 10(9)/l was delayed in all patients who received < 2 x 10(6) CD34+ cells/kg infused (P < 0.02). In patients who had had previous HDM both neutrophil (P < 0.05) and platelet recovery (P < 0.007) were delayed compared with recovery in patients who had not had HDM. In patients who had had previous HDM and received < 2 x 10(6) CD34+ cells/kg infused only 3/17 regained platelets to > 100 x 10(9)/l compared with 3/4 who had > 2 x 10(6) CD34+ cells/kg infused (P < 0.05 Fisher's exact test). There was no evidence that low numbers of CD34+ cells in the PBSCR were associated with early death. The data show that previous treatment with HDM had adverse effects on the subsequent engraftment of platelets among patients given HDM/PBSCR. The data suggest that additional measures are needed to achieve platelet reconstitution in these heavily pre-treated patients.

Interference from duodeno-gastric reflux of 99Tcm radiopharmaceuticals in SPET myocardial perfusion imaging.

Single photon emission tomographic (SPET) myocardial perfusion imaging was performed on 76 patients using 99Tcm-sestamibi (99Tcm-MIBI). Retrospective analysis of the data showed good cardiac uptake and adequate hepatobiliary clearance. However, duodeno-gastric reflux of the activity excreted from the liver and gallbladder was seen in 34% of the studies. This reflux was considered to be severe in 16% of the studies, resulting in interference with the myocardial uptake and requiring three studies to be repeated. In an attempt to minimize interference from duodeno-gastric reflux, a further 86 patients (18 using 99Tcm-MIBI and 68 using 99Tcm-tetrofosmin) were imaged after lying on their right side for 20 min prior to imaging. Good cardiac uptake with adequate hepatobiliary clearance was again achieved. The incidence of duodeno-gastric reflux was significantly lower (P < 0.001), occurring in 22% of studies, while severe reflux occurred in 6% of studies with no studies being repeated. There was no significant difference in the incidence of reflux between the two agents. Duodeno-gastric reflux of 99Tcm-MIBI and 99Tcm-tetrofosmin is common and can result in significant interference with myocardial uptake. It is concluded that having patients lie on their right side for 20 min prior to imaging is a simple and effective method for significantly reducing the likelihood of such interference.

Significant gastric reflux of technetium-99m-MIBI in SPECT myocardial imaging.

We present a case in which significant gastric reflux of 99mTc-methoxy isobutylisonitrile (MIBI) was observed in a patient who underwent stress/rest 99mTc-MIBI SPECT myocardial perfusion imaging for suspected coronary artery disease. The intense gastric activity partially obscured myocardial uptake of 99mTc MIBI, particularly in the inferolateral wall of the left ventricle. The presence of significant gastric activity should be considered when performing SPECT myocardial imaging with 99mTc MIBI, and, where necessary, steps should be taken to minimize this activity prior to commencing acquisition.

Is gall bladder ejection fraction a reliable predictor of acalculous gall bladder disease?

The use of quantitative 99Tcm-EHIDA imaging with cholecystokinin and the measurement of gall bladder ejection fraction in a prospective study of 89 patients with right upper quadrant pain is described. Correlation with surgical and histological findings and clinical follow-up suggests that gall bladder ejection fraction < or = 35% is a reliable and accurate indicator of acalculous gall bladder disease.

AIDS lymphomas.

PIP: Chronically immunosuppressed individuals are susceptible to lymphoreticular tumors. Up to 15% of patients with congenital deficiencies such as ataxia=telangiectasia may develop malignancies, mainly high-grade B cell non=Hodgkin's lymphomas (NHLs). AIDS lymphomas are comprised of NHLs including Burkitt's lymphoma (BL) and primary cerebral lymphomas (PCLs). Almost 3% of all AIDS patients (2824 of 97,258 cases) developed NHL. Epstein-Barr virus (EBV) as a co-factor in AIDS lymphomagenesis has been studied: in 12 cases of 24 AIDS lymphomas EBV by DNA in situ hybridization was found. In an analysis of 6 primary cerebral lymphomas, .5 were positive for EBV DNA by Southern blotting. In Burkitt's lymphoma the characteristic genetic alteration affects the c-myc oncogene. In 1/3 of BL p53 mutations were found but none in the 43 NHLs suggesting that p53 mutations and c-myc activation act synergistically in the pathogenesis of these tumors. Cytotoxic agents dideoxyinosine, dideoxycytosine, and zidovudine may cause secondary neoplasia. 8 of 55 AIDS patients under zidovudine treatment developed high-grade lymphoma 23.8 months subsequently; recently doses were reduced. PCL was found in 21 of 90 patients. A 5.2 months survival was associated with combined treatment with cyclophosphamide, Oncovin (vincristine), methotrexate, etoposide, and cytosine arabinoside compared with 11.3 months with chemotherapy. Colony-stimulating factors (CSFs) alleviate drug-induced myelotoxicity and zidovudine-induced neutropenia, however, l8 of 11 patients receiving granulocyte-macrophage CSF developed hematological toxicity. Interleukine-2 produced by T-helper cells enhancing tumor cells cytotoxicity has been used in AIDS-associated cryptosporidial diarrhea and in 4 patients with AIDS lymphoma with modest response, but its stimulation of the HIV-infected substrate may increase viral proliferation.^ieng

A multiple regression analysis for accurate background subtraction in 99Tcm-DTPA renography.

A technique for accurate background subtraction in 99Tcm-DTPA renography is described. The technique is based on a multiple regression analysis of the renal curves and separate heart and soft tissue curves which together represent background activity. It is compared, in over 100 renograms, with a previously described linear regression technique. Results show that the method provides accurate background subtraction, even in very poorly functioning kidneys, thus enabling relative renal filtration and excretion to be accurately estimated.

Prediction of outcome in Graves' disease after carbimazole treatment.

In a prospective study to determine which factors would predict remission or relapse, 65 patients with hyperthyroid Graves' disease were treated for six months with a blocking replacement regimen of carbimazole, 40 mg daily, and triiodothyronine (T3). They were followed for one year after stopping treatment, by which time 32 (49 per cent) had relapsed. Although the treatment protocol, relapse rate and frequency of the HLA-DR3 antigen in this population were similar to those of a regionally separate Graves' population investigated previously, the predictive value of HLA-DR3 status together with thyroid stimulating antibody (TSAB) levels was strikingly different. In the present study there was no significantly abnormal distribution of any HLA antigen in the relapse group compared with those patients who achieved remission. Thyroid stimulating antibodies were detected in 62 patients (95 per cent) and fell significantly (p less than 0.05) after carbimazole treatment, irrespective of DR3 status or outcome; TSAB levels only became undetectable in nine patients (28 per cent) who subsequently relapsed and in nine patients (30 per cent) who maintained remission. T3-suppressed 20 min 123I uptake fell equally after treatment in the relapse and remission groups but continued to fall thereafter in the group which maintained remission. In these patients, 123I uptake was significantly lower at the end of the study period than at the end of treatment (p less than 0.05). Serum free T4 levels were higher before treatment in the patients who later relapsed than in those whose disease remitted (p less than 0.02). This proved the only significant marker associated with outcome but was of little predictive value in any patient. This study highlights the problem in predicting the outcome of antithyroid drug treatment, since even within the same country under similar conditions, divergent results have been obtained. It appears that the loci controlling the immune response in Graves' disease are likely to include genes lying outside the HLA-DR region. The results also suggest that the immunological effects of antithyroid drugs are maintained after stopping treatment in those patients whose disease remits.