Tal Grenader

Metformin As an Addition to Conventional Chemotherapy in Breast Cancer

metformin inbreast cancer may be related to activation of adenosine monophosphate‐activated protein kinase, which may ultimately result in a rapid inhibition of cellular protein synthesis and growth of tumor cells. We suggest, however, that additional mechanisms may play a part. It is a well-accepted fact that chronic inflammation is a major contributory factor to cancer development and progression, and elevated levels of various nonspecific markers of inflammation in the serum have been shown to be associated with poor survival in a number of different cancers. Pierce et al 3 have recently assessed the relationship between circulating levels of C-reactive protein and serum amyloid A and breast cancer survival. They showed that raised levels of these inflammatory markers were associated with a significantly reduced overall survival and a trend toward a reduced diseasefreesurvival.Patientswithtype2diabetesmellitustendtohavehigher C-reactive protein concentrations than those without it, suggesting that inflammation may contribute to the higher risk of breast cancer and worse prognosis of malignant disease in these patients. 4 Thereisevidencetosuggestthatmetforminhasapositiveimpact on inflammation and endothelial dysfunction. Metformin was compared with another oral hypoglycaemic agent, repaglinide, in nonobese patients with type 2 diabetes and shown to be more effective in

Long-term response to pegylated liposomal doxorubicin in patients with metastatic soft tissue sarcomas.

Doxorubicin and ifosfamide are currently considered the cornerstones of treatment for advanced soft tissue sarcomas (STSs). Pegylated liposomal doxorubicin (PLD) has been shown to have equivalent activity to doxorubicin and an improved toxicity profile. A review of the medical records of 11 patients with a variety of STSs treated with PLD was performed. The median age of the patients was 54.8 years. Of the 11 patients, seven received no earlier systemic therapy for their sarcoma. The initial dose per course was 40–60 mg/m2 every 4 weeks with dose reduction to 40 mg/m2 in the second or third cycle. A median of 11 cycles was given (range, two to 29 cycles). Treatment was generally well tolerated. We did observe some toxic effects as described earlier with PLD, including mild myelosuppression, skin toxicity and fatigue. No cardiotoxicity was observed. Of the 11 treated patients, six had a partial response, two had a best response of stable disease and three had progressive disease. All six patients with a partial response had an extended time to progression. To date, two patients continue on treatment (15 and seven cycles); one patient has stable disease 60 months after withdrawal of PLD (after eight cycles) and one patient had progression of disease 7 months after the withdrawal of therapy after 20 cycles. Of the two patients with stabilization of their disease, one had progression after 29 months and one continues on treatment for 6 months. PLD is active and safe for long-term treatment of metastatic STSs and may be important in maintaining response.

The 21-Gene Recurrence Score Assay (Oncotype DX™) in Estrogen Receptor-Positive Male Breast Cancer: Experience in an Israeli Cohort

Objective: The 21-gene recurrence score (RS) assay has been widely adopted for use in early estrogen receptor (ER)-positive breast cancer to assess the risk for distant recurrence and the potential benefit of adjuvant chemotherapy. The primary aim of this study was to assess RS distribution in Israeli male breast cancer (MBC) patients. Methods: The study population included 65 newly diagnosed Israeli MBC patients. Clinical and pathologic data were collected at the time of referral. Pathologic examinations were conducted at the pathology departments of the referring centers. The RS assay (Oncotype DX™) was performed on paraffin-embedded tumor samples at Genomic Health laboratories. Results: The mean age of the patients was 65.1 years (range 38-88 years). Low-risk (RS <18), intermediate-risk (RS 18-30) and high-risk (RS ≥31) scores were noted in 29 patients (44.6%), 27 patients (41.5%) and 9 patients (13.9%), respectively. The distribution of RS in male patients was similar to the distribution in 2,455 female patients from Israel referred during the same time period. Conclusion: Our data suggest that the distribution of Oncotype DX RS in ER-positive MBC patients is similar to that of female breast cancer patients.

Monitoring long-term treatment with pegylated liposomal doxorubicin: how important is intensive cardiac follow-up?

Pegylated liposomal doxorubicin (PLD; Doxil or Caelyx) has been shown to be as effective as conventional doxorubicin, and to have a significantly better cardiac safety profile. The aim of this study was to assess the safety of delivering doses exceeding 700 mg/m2 of PLD to patients with solid tumors. A review of the medical records of 149 patients with a variety of solid tumors treated with PLD was performed. The findings in 12 patients who had reached or exceeded cumulative doses of 700 mg/m2 (median=1.071 mg/m2, range 712–1856 mg/m2) were reviewed. Changes in left ventricular ejection fraction (LVEF), and in clinical cardiac status were analyzed. The median age of the patients was 53.9 years and the median follow-up from the start of PLD treatment was 44.6 months. None of the 12 patients had clinical congestive heart failure secondary to cardiomyopathy. Seven of the 12 patients underwent further assessment of LVEF by echocardiography or multiple gated acquisition scan, which revealed a stable or improved ejection fraction.PLD is cardiac safe for long-term treatment of metastatic solid tumors. Its maximal cumulative dose remains undefined. Frequent determinations of LVEF, as routinely done for other anthracyclines, do not appear to have any clinical value in patient follow-up. In metastatic patients with no evidence of cardiac risk factors, it may be sufficient to measure LVEF at baseline.

Absence of founder BRCA1 and BRCA2 mutations in coetaneous malignant melanoma patients of Ashkenazi origin

Introduction Several epidemiologic studies have provided suggestive evidence of a link between coetaneous malignant melanoma (CMM) and breast cancer. The Breast Cancer Linkage Consortium (BCLC) reported approximately 2.6-fold increase in the risk for CMM among BRCA2 carrier families. Methods To evaluate the role of BRCA1/2 mutations in CMM, we screened 92 Jewish patients of Ashkenazi origin diagnosed with CMM for the three Ashkenazi founder mutations: 185delAG and 5382insC in the BRCA1 and 6174delT in the BRCA2 gene. Information about personal demography, family history of cancer, and occupational and lifestyle history was collected. Results Thirty-seven of 92 (40.2%) CMM patients reported a family history of cancer in a first-degree relative. In 14 patients, history of breast cancer (BC) was recorded; however, no family had features associated with BRCA carrier status (i.e., young age at BC onset, history of several BC cases or ovarian cancer in the family). None of the patients were found to carry any of these three mutations. Conclusion Our results suggest a limited role for the three Ashkenazi BRCA founder mutations in CMM risk among the Ashkenazi Jewish population. Therefore, screening patients with CMM for these BRCA1/2 mutations is not warranted.

Brain metastases: a rare initial presentation of prostate cancer

Although brain metastases are common in cancer patients, carcinoma of the prostate rarely metastasizes to the brain. Cerebral metastases as an initial clinical presentation of prostate carcinoma are extremely rare. We report a patient, who presented with confusion and behavioral changes. Cranial magnetic resonance imaging revealed a large right temporal lobe lesion. The pathological diagnosis of the tumor was consistent with metastatic prostate carcinoma. Further evaluation revealed widespread bony metastases by technetium 99 bone scan and high level of prostate-specific antigen.

Indwelling central venous access port insertion during bevacizumab-based therapy.

Indwelling central venous catheters and implantable port systems are widely used in the care of patients with cancer. Bevacizumab, a humanized monoclonal antibody against vascular endothelial growth factor, significantly prolongs survival when added to intravenous 5-fluorouracil-based chemotherapy as first-line treatment for metastatic colorectal cancer. It has also been shown to be of value in a range of other malignant diseases. Some elements of the toxicity profile of bevacizumab, however, such as bleeding and impaired wound healing, could interfere with surgical procedures involved in the treatment of the diseases. The aim of this study was to evaluate the possible effect of bevacizumab in increasing the morbidity associated with an indwelling central venous access port in patients currently receiving the drug, or those who had received it in the preoperative run-up to surgery. An analysis of the medical records of 57 patients with a variety of cancers, who had received an indwelling central venous access port, either during the course of treatment with bevacizumab or in the 4-week period before the commencement of therapy was carried out, with particular emphasis on periprocedural complications. Eight of the patients also had diabetes mellitus. There were no instances of delay in wound healing, abnormal bleeding, or wound infection in any of the patients and no episodes of skin ulceration during bevacizumab treatment. Although this is a relatively small study, and no definitive conclusions can be drawn at this stage, our data suggest that an indwelling central venous access port insertion may be carried out shortly before or during bevacizumab treatment without increasing periprocedural morbidity.

Mitomycin C and vinblastine: an active regimen in previously treated breast cancer patients.

Background Metastatic breast cancer has a substantial mortality burden on women worldwide. Presented herein is our experience with the combination of mitomycin-C and vinblastine in heavily pretreated breast cancer patients. Methods Candidates were women with measurable metastatic disease, previously exposed to two or more chemotherapy regimens. Mitomycin-C was given at the dose of 10 mg/mý on day 1 and vinblastine at 6 mg/mý on days 1 and 21 of each 42-day cycle. Analysis included patients exposed to one or more cycles of therapy. Kaplan-Meier curves were used to generate overall survival and time-to-treatment progression curves. Results Forty patients previously exposed to a median of three prior regimens were included. Partial response and stable disease were reported in 14 (35%) and 10 (25%), patients, respectively, for a clinical benefit of 60%. With a median follow-up of 11 months, the median time to progression and survival durations lasted 4 and 12 months, respectively. In a subgroup of 17 women with prior anthracycline and taxane exposure, partial response and stable disease were reported in 4 (23.5%) and 5 (29%), respectively. Treatment was generally well tolerated, with grade 3-4 hematologic and non-hematologic toxicity reported in 8 (20%) and 3 (7.5%) patients, respectively. Two cases of fatalities (5%) occurred with pulmonary toxicity in women heavily exposed to mitomycin-C (cumulative doses of ≥40 mg/mý) and soon after red blood cell transfusion. Conclusions Chemotherapy with mitomycin-C and vinblastine is active and well-tolerated in heavily pretreated breast cancer patients. Caution should be taken to avoid blood transfusion alone with mitomycin-C therapy.

Combination therapy with oxaliplatin and 5-fluorouracil in a patient with severe hepatic dysfunction associated with metastatic adenocarcinoma of the large bowel

Oxaliplatin has been shown to be valuable in the treatment of patients with colorectal cancer. Many of these patients will develop liver metastases during the course of their disease, with, in some cases, severe hepatic dysfunction. Although single agent oxaliplatin can be administered safely in patients with severely compromised liver function (as it is not metabolized by the liver), little is known of its safety in these patients when administered in the preferred combination with 5-fluorouracil (which is metabolized by the liver) and leucovorin (FOLFOX protocol). We report on a very sick patient with major liver dysfunction, a bilirubin of 11.2 mg/dl (190 micromol/dl) and an open abdominal wound, for whom palliative hospice care alone was originally proposed, who responded dramatically to the combination. His bilirubin fell to 0.6 mg/dl (10.2 micromol/dl) and his liver function tests returned to near normal levels. The combination was well tolerated and clinical improvement continued for more than 11 months before disease progression was observed.

Tumor Lysis Syndrome in a Patient with Merkel Cell Carcinoma and Provoked Pathologic Sequence of Acute Kidney Injury, Reduced Clearance of Carboplatin and Fatal Pancytopenia

Background: Merkel cell carcinoma (MCC) is a rare, highly malignant cancer of the skin primarily affecting the elderly, with a tendency for local recurrence and regional lymph node metastasis. It is very unusual for this kind of tumor to induce clinically apparent tumor lysis syndrome (TLS) which is a consequence of spontaneous cytolysis or massive tumor cell lysis, beginning a few hours after the initiation of treatment. Case Report: We report here on a patient with metastatic MCC, who developed TLS following combination chemotherapy with carboplatin and etoposide. Conclusion: The evolving acute kidney injury (AKI) provoked a pathologic sequence of reduced renal clearance leading to protracted clearance of carboplatin and subsequent fatal pancytopenia. When AKI occurs in close association with the administration of carboplatin, the institution of rescue hemodialysis is recommended to decrease plasma carboplatin levels and avoid this lethal complication.