Serum LDH predicts benefit from bevacizumab beyond progression in metastatic colorectal cancer.

BACKGROUND: Different antiangiogenics are currently indicated in the second-line treatment of metastatic colorectal cancer (mCRC), following a first-line bevacizumab-containing treatment. The magnitude of benefit is limited, but no predictors of benefit have been identified. METHODS: A total of 184 mCRC patients progressing to a first-line bevacizumab-containing treatment were randomised in the BEBYP study to continue or not the antiangiogenic in combination with a second-line chemotherapy. A subgroup analysis according to baseline serum lactate dehydrogenase (LDH) levels was carried out. RESULTS: A significant interaction effect between LDH levels and treatment was found in terms of progression-free survival (PFS; P=0.002). Although patients with low LDH levels achieved significant PFS benefit from the continuation of bevacizumab (HR: 0.39 (95% CI: 0.23-0.65)), patients with high levels did not (HR: 1.10 (95% CI: 0.74-1.64)). Consistent results were reported in overall survival (OS; P=0.075). CONCLUSIONS: As preclinical evidence suggests that serum LDH may be a marker of tumour angiogenesis activation, low levels may indicate that bevacizumab is still efficacious in inhibiting angiogenesis. Validation of present results in subgroup analyses of other randomised trials of second-line angiogenesis inhibitors is warranted.

Prospective, randomised, multicentre, open-label trial, designed to evaluate the best timing of closure of the temporary ileostomy (early versus late) in patients who underwent rectal cancer resection and with indication for adjuvant chemotherapy: the STOMAD (STOMa closure before or after ADjuvant therapy) randomised controlled trial.

INTRODUCTION: Temporary ileostomy is a valuable aid in reducing the severity of complications related to rectal cancer surgery. However, it is still unclear what is the best timing of its closure in relation to the feasibility of an adjuvant treatment, especially considering patient-reported outcomes and health system costs. The aim of the study is to compare the results of an early versus late closure strategy in patients with indication to adjuvant chemotherapy after resection for rectal cancer. METHODS AND ANALYSIS: This is a prospective multicentre randomised trial, sponsored by Rete Oncologica Piemonte e Valle d'Aosta (Oncology Network of Piedmont and Aosta Valley-Italy). Patients undergone to rectal cancer surgery with temporary ileostomy, aged >18 years, without evidence of anastomotic leak and with indication to adjuvant chemotherapy will be enrolled in 28 Network centres. An early closure strategy (between 30 and 40 days from rectal surgery) will be compared with a late one (after the end of adjuvant therapy). Primary endpoint will be the compliance to adjuvant chemotherapy with and without ileostomy. Complications associated with stoma closure as well as quality of life, costs and oncological outcomes will be assessed as secondary endpoints. ETHICS AND DISSEMINATION: The trial will engage the Network professional teams in a common effort to improve the treatment of rectal cancer by ensuring the best results in relation to the most correct use of resources. It will take into consideration both the patients' point of view (patient-reported outcome) and the health system perspective (costs analysis). The study has been approved by the Ethical Review Board of Città della Salute e della Scienza Hospital in Turin (Italy). The results of the study will be disseminated by the Network website, medical conferences and peer-reviewed scientific journals. TRIAL REGISTRATION NUMBER: NCT04372992.

Occurrence, survival, and persistence of human adenoviruses and F-specific RNA phages in raw groundwater.

Detection of specific genetic markers can rapidly identify the presence of enteric viruses in groundwater. However, comparison of stability characteristics between genetic and infectivity markers is necessary to better interpret molecular data. Human adenovirus serotype 2 (HAdV2), in conjunction with MS2 phages or GA phages, was spiked into raw groundwater microcosms. Viral stability was periodically assessed by both infectivity and real-time PCR methods. The results of this yearlong study suggest that adenoviruses have the most stable persistence profile and an ability to survive for a long time in groundwater. According to a linear regression model, infectivity reductions of HAdV2 ranged from 0.0076 log(10)/day (4°C) to 0.0279 log(10)/day (20°C) and were significantly lower than those observed for phages. No adenoviral genome degradation was observed at 4°C, and the reduction was estimated at 0.0036 log(10)/day at 20°C. Occurrence study showed that DNA of human adenoviruses could be observed in groundwater from a confined aquifer (7 of the 60 samples were positive by real-time PCR), while no fecal indicators were detected. In agreement with the persistence of genetic markers, the presence of adenoviral DNA in groundwater may be misleading in term of health risk, especially in the absence of information on the infective status.

Efficacy and skin toxicity management with cetuximab in metastatic colorectal cancer: outcomes from an oncologic/dermatologic cooperation.

PURPOSE: The aim of this study was to investigate the efficacy of the combination of irinotecan/cetuximab and to plan related skin toxicity management with an oncologic/dermatologic team. PATIENTS AND METHODS: Thirty-four patients with epidermal growth factor receptor (EGFR)-expressing metastatic colorectal cancer received cetuximab 400 mg/m2 as an initial dose and 250 mg/m2 weekly thereafter. In addition, patients received irinotecan 180 mg/m2 every 2 weeks. RESULTS: Thirty-two patients were evaluated for response rate (RR) and skin toxicity to establish the best management. In our study, the responses observed with cetuximab treatment were complete response in 1 patient (3%), partial response in 11 patients (34%), disease stabilization in 6 patients (19%), and progressive disease in 14 patients (44%). Of 34 patients evaluable for cutaneous toxicity, 10 patients (29%) presented with grade 1 eruption, 13 (38%) with grade 2 eruption, and 4 (12%) with grade 3 eruption. Allergic reactions such as flushing and urticaria (grade 2) were seen in 2 patients (6%). CONCLUSION: Cutaneous reactions consisted of follicular rash, xerosis, painful fissures in palms and soles, alterations in hair growth, and mucositis. In the majority of patients (80%-90%), the worst recorded skin effects were mild (grade 1) to moderate (grade 2). The incidence of severe cases (grade 3) was approximately 15%. All dermatologic effects were reversible and generally without sequelae within 4 weeks after treatment discontinuation. We observed significant correlations between degree of cutaneous toxicity and increased RR. Correct identification and treatment by oncologic/dermatologic cooperation of EGFR cutaneous side effects help to improve quality of life.

Treatment of stage IV colorectal carcinoma in elderly patients.

Colorectal adenocarcinoma ranks second as a cause of death due to cancer in the Western world. In Europe, 40% of patients with colorectal cancer are over 70 years old and the incidence increased through the 1980's. Without any treatment the median survival after the detection of liver metastases is approximately 9 months, depending on the extent of disease at the time of diagnosis but not on the patients age. In the elderly there are only few data apt to define the standard regimen in the advanced disease, but results seem similar to those observed in younger patients. As a result of exclusion criteria and screening, elderly patients entering clinical trials are usually a select group, with good performance status, access to transportation, and limiting numbers of coexisting conditions. This paper examines the factors pertinent to the small number of clinical trials designed for metastatic colorectal cancer in this group of persons.

Role of fibrinolytic and clotting parameters in the diagnosis of liver veno-occlusive disease after hematopoietic stem cell transplantation in a pediatric population.

Hepatic veno-occlusive disease (VOD) is a severe complication after hematopoietic stem cell transplantation (HSCT). Recent studies, mainly in adults receiving HSCT, have identified an increase in the plasminogen activator inhibitor-1 (PAI-1) as a possible marker of VOD. To confirm this finding, the fibrinolytic, coagulation and liver function parameters were assayed before and weekly for 1 month after 61 HSCT performed in 53 consecutive children. Non-VOD patients had a slight increase in t-PA antigen, fibrinogen and P-selectin levels, as well as a mildly longer aPTT and a drop in antithrombin after HSCT. The 6 children with VOD (9.84%) had an early and significant increase in PAI-1 antigen and activity (p<0.0001), t-PA antigen (p<0.0001) and D-dimer (p<0.01) levels, and a decrease in plasminogen, alpha 2-antiplasmin and PT emerged 2(+/-1) days before the clinical diagnosis of VOD by comparison with mean post-HSCT values in the non-VOD patients. Significant differences were also detected for these parameters and antithrombin levels between non-VOD and VOD patients soon after the clinical onset of VOD, whereas the rise in bilirubin levels became significant only later on. In conclusion, variations in fibrinolytic test findings after HSCT, and PAI-1 in particular, may facilitate the early diagnosis of VOD in pediatric patients after HSCT.

FOLFOX versus FOLFIRI: a comparison of regimens in the treatment of colorectal cancer metastases.

Colorectal adenocarcinoma ranks second as a cause of death due to cancer in the Western world. Already at the time of the primary tumor, 15-25% of the patients present with liver metastases while another 20% will develop metastasis following treatment of the colorectal primary. Without any treatment the median survival after the detection of metastases is approximately 9 months, depending on the extent of the disease at the time of diagnosis. Clinical trials with the "FOLFOX and FOLFIRI families" of drugs, designed for the treatment of metastatic colorectal cancer, their results and the costs of each therapy are examined. For each drug, the cost/mg, the cost/mg/m2 and the cost/therapy (according to its duration) are evaluated according to the prices reported in the Italian Directory of Medicines and Manufacturers, 63rd Edition, November 2003.

Review of the prognostic factors in medulloblastoma of children and adults.

Medulloblastoma (MB) is rare in adults, accounting for 1% of all primary tumours of the central nervous system (CNS). Based on the assumption that the disease pattern in adults is similar to that in children, adults with medulloblastoma are treated using paediatric protocols. Thanks to progress made in recent years, long-term survival is now possible, with overall ranging from 50 to 60% at 5 years and 40 to 50% at 10 years. However, effective therapy may have devastating long-term side effects, including neuro-psychic and neuro-endocrine sequelae and cognitive dysfunction, especially in young adults. Great interest has been expressed in new biological and molecular prognostic factors, which, combined with clinical variables, may allow a more satisfactory stratification of patients.

Medulloblastomas: do molecular and biologic markers indicate different prognoses and treatments?

The origin and histological classification of embryonal tumors, which make up the largest group of malignant pediatric brain malignancies, are two controversial issues. However, in recent years, progress has been made in our understanding of the molecular genetic abnormalities that govern their onset and/or progression. Several of these abnormalities appear to involve alterations in the signaling system controlling normal cerebellar development. An improved understanding of both the biology and clinical relevance of these molecular defects is probably the only means by which neuro-oncologists will improve the management of these tumors, thus reducing disease- and treatment-related morbidity and mortality.

Common management of primary rectal carcinoma in patients with stage IV disease at the diagnosis.

Rectal cancer is one of the more common neoplasms of Western countries. It is commonly diagnosed at a precocious stage but, because of local relapse and/or metastatic disease, only half of radically resected patients can be considered free of disease. In patients presenting at diagnosis with stage IV disease the best treatment is still unknown. If the patient is a candidate for surgical resection, the primary tumor should be treated as in a patient without metastatic disease. If metastases are unresectable, the treatment of the primary lesion is palliative and, according to the patients' symptoms, it is usually represented by a chemotherapy approach. It is still unclear whether to reserve radiotherapy only for the symptomatic cases. This paper examines the factors pertinent to clinical trials designed for stage IV rectal cancer with resectable and unresectable metastases and reviews the existing data supporting palliative therapy for symptomatic and asymptomatic primary tumors.

Successful treatment of a catheter-related right atrial thrombosis with recombinant tissue plasminogen activator and heparin.

Deep venous thrombosis is a possible complication of indwelling central venous catheters (CVC), with an incidence as high as 61%. We report a case of successful thrombolysis of a CVC-related right atrial thrombus in a pediatric cancer patient with recombinant human tissue plasminogen activator (0.1 mg/kg per h for 12 h) and heparin (10 IU/kg per h for 24 h) administered for 6 days. Daily echocardiographic examination showed progressive lysis of the thrombus. The thrombolytic treatment was associated with mild oozing from the venipuncture sites, but no major bleeding was noted; moreover, thrombin, thromboplastin time and fibrinogen were normal or only minimally altered. Anticoagulant therapy, with or without CVC removal, is the treatment of choice for uncomplicated CVC-related thrombosis. Fibrinolytic therapy may be indicated in some cases at risk of pulmonary embolism or to avoid open heart surgery. Recombinant human tissue plasminogen activator is increasingly used for thrombolytic treatment of organ and limb thrombosis, but experience with it in the pediatric hematology-oncology setting is still limited. This report showed that administering recombinant human tissue plasminogen activator in a pediatric cancer patient prior to hematopoietic stem cell transplantation was effective and safe under strict biochemical and instrumental monitoring. Further studies are needed to determine the best antithrombotic treatment for CVC-related thrombosis, and also the dosage of the medication selected and the duration of treatment.

Temozolomide in patients with glioblastoma at second relapse after first line nitrosourea-procarbazine failure: a phase II study.

OBJECTIVES: To investigate the efficacy of temozolomide (TMZ) in relationship to progression free survival at 6 months (PFS-6), median time to progression (TTP), response rate and toxicity, a phase II study was conducted in patients with recurrent glioblastoma multiforme (GBM) following surgery plus radiotherapy and a first-line regimen based on nitrosourea, procarbazine and vincristine. METHODS: Forty-two patients with GBM were administered TMZ at the dose of 150 mg/m(2)/daily for 5 days every 4 weeks. RESULTS: The PFS-6 and at 12 months (PFS-12) was 24% (95% Confidence Interval [CI] = 14-42%) and 8% (CI = 2-27%), respectively, with a median TTP of 11.7 weeks (CI = 9-22 weeks). The response was assessed in all 42 patients; we observed 2 complete responses (CR) (4.7%), 6 partial responses (PR) (14.3%), and 9 stable disease (SD) (21.4%), with CR+PR = 19% (CI = 7-31%). CONCLUSION: TMZ as a second line regimen is a valid option in patients with heavily pretreated GBM.