Samuel Ariad

The impact of the 21-gene recurrence score assay on decision making about adjuvant chemotherapy in early-stage estrogen-receptor-positive breast cancer in an oncology practice with a unified treatment policy

BACKGROUND The 21-gene recurrence score (RS) assay has been validated in retrospective studies as prognostic of distant disease recurrence and predictive of the benefit of adjuvant chemotherapy in estrogen-receptor-positive breast cancer (BC). There is limited published data on the impact of the assay on clinical practice, particularly in the context of a single practice with a unified treatment policy. PATIENTS AND METHODS Between 2006 and 2009, RS was obtained on 135 patients in a single practice with a uniform treatment policy. Treatment recommendations before and after RS result were analyzed retrospectively. Pre-RS treatment recommendations were based on clinicopathological features and Adjuvant! Online (AO) calculated survival advantage. RS and AO survival advantage for adding chemotherapy were compared for each patient. RESULTS The distribution by risk group of RS was low- 49.6%, intermediate-37.8%, and high-12.6%. In 34 patients (25.2%, 95% confidence interval 17.9% to 32.5%), recommendation for chemotherapy was changed after obtaining assay result. Most changes (70.6%) were from chemotherapy to no chemotherapy. The RS correlated poorly with AO predictions. CONCLUSION The 21-gene assay, when applied in a consistent manner in early-stage BC, changes treatment recommendations in one-quarter of patients tested.

Measurement of circulating cell-free DNA levels by a new simple fluorescent test in patients with primary colorectal cancer.

Elevated circulating cell-free DNA (CFD) levels were found in patients with cancer. The standard CFD assays are work-intensive and expensive. The aim was to evaluate in patients with cancer a new simple CFD assay. In mice inoculated with cancer cells, CFD levels correlated with tumor size. Compared with healthy subjects, 38 patients with colorectal cancer (CRC) had higher preoperative CFD levels (798 ± 409 vs 308 ± 256 ng/mL; P < .0001). Compared with patients free of disease at 1 year, CFD levels were elevated in patients who remained with disease or died (DD). CFD correlated with DD (P = .033), and a combined index of carcinoembryonic antigen × CFD exhibited a better correlation to DD than did pathologic staging (P = .0027 vs P = .0065). For patients with CRC, CFD levels were prognostic of death and disease. A large prospective study will need to be performed to truly evaluate the efficacy of this method for early detection, follow-up, and evaluation of patient response to treatment.

Early Peripheral Lymph Node Involvement of Human Herpesvirus 8–Associated, Body Cavity–Based Lymphoma in a Human Immunodeficiency Virus–Negative Patient

Human herpesvirus 8 (HHV-8), or Kaposi sarcoma-associated herpesvirus, is a gamma herpesvirus first detected in a specimen of Kaposi sarcoma from a human immunodeficiency virus (HIV)-positive patient. Human herpesvirus 8 is also found in an unusual clinicopathologic form of body cavity-based B-cell lymphoma, which has been named primary effusion lymphoma (PEL) and occurs primarily in HIV-positive patients. PEL is characterized by the formation of lymphomatous effusions, without obvious lymphadenopathy, tumor masses, or bone marrow involvement. Only a few cases of PEL in HIV-seronegative patients have been reported. We describe a case of an HHV-8-associated lymphoma, with ascites, pleural effusion, and axillary lymphadenopathy in an HIV-negative patient. The patient was a 68-year-old Jewish man of North African extraction, with a previous history of coronary bypass surgery and multiple blood transfusions. The pleural fluid contained large atypical lymphoid cells and was suggestive of lymphoma but could not provide a conclusive diagnosis of PEL. The lymph node contained groups of large anaplastic lymphoid cells. Polymerase chain reaction for HHV-8 performed on the lymph node specimen was positive, establishing the diagnosis of PEL. Polymerase chain reaction for Epstein-Barr virus was negative. Results of a gallium scan were normal. The patient did not respond to combination chemotherapy with cyclophosphamide, doxorubicin, vincristine sulfate, and prednisone and progressively developed, massive intra-abdominal solid tumor formation. To our knowledge, this is the first report of a case of PEL that demonstrates peripheral lymph node involvement at diagnosis and the first report of PEL in an Israeli patient.

Manifestations of three HHV-8-related diseases in an HIV-negative patient: immunoblastic variant multicentric Castleman's disease, primary effusion lymphoma, and Kaposi's sarcoma.

We describe a 73‐year‐old HIV negative patient who presented with symptomatic hypoglycemia. Over the course of several months she was diagnosed with three human herpesvirus‐8 related diseases: multicentric Castlemans disease, primary effusion lymphoma and Kaposis sarcoma. No improvement was observed following cytotoxic therapy and she died 16 months after her initial presentation. The etiology of the hypoglycemia remained obscure over the course of this patients disease. This case is the first report of a patient with three human herpesvirus‐8 related diseases, and the first report of severe hypoglycemia as the presenting symptom of any of these diseases. Am. J. Hematol. 65:310–314, 2000.

Apoptotic Index as a Prognostic Factor in Hodgkin's Disease

Hodgkins disease (HD) is an unusual malignant neoplasm, mainly because of the rarity of tumor cells in the diseased tissues, but also due to a relatively favorable response to treatment. In a previous study, we have shown a variable degree of apoptosis in lymph nodes from HD patients. We now looked for clinicopathological correlations of apoptosis with special emphasis on the prognosis in this disease. A retrospective study of 92 patients was carried out, using in situ end labelling of DNA fragments and an apoptosis detection kit. An apoptotic index (Al) was calculated in each case, as the percentage of apoptotic Hodgkin-Reed-Sternberg cells out of the total number of tumor cells in 10 selected high power fields. An association between a high Al and advanced stages was noted. A Kaplan-Meier analysis showed a negative correlation between Al and survival (p=0.05). In a multivariable analysis adjusting for Ann Arbor stage, a high Al carried a 3.27 fold risk of dying of HD (OR=3.27; Cl=0.89-11.94). However, in our limited cohort of HD patients, Al was not an independent prognostic factor. The results of this study confirm the important role played by apoptosis in HD and suggest that the apoptotic index is probably a negative prognostic marker in this disease. Its assessment in patients with HD may provide a new, important clinical tool.

Differential Expression of Sialyl and Non-Sialyl-CD15 Antigens on Hodgkin-Reed-Sternberg Cells: Significance in Hodgkin's Disease

CD15 expression has been used for years to confirm the diagnosis of Hodgkins disease (HD). Little is, however, known on the relevance of the CD15 antigen to the pathobiology of the disease and there is conflicting evidence as to the prognostic value of its expression. To investigate the significance of the differential expression of CD 15 in Hodgkins disease, a retrospective study of 102 patients with “classical” Hodgkins disease was performed. Immuno-histochemical studies were carried out using antibodies against two types of CD 15: non-sialylated CD15 (LeuM1 and 80H5) and sialylated CD15 (FH6 and CSLEX1). Cases that were negative for non-sialylated CD 15 or positive for the sialylated variant were stained again following neuraminidase pretreatment. The cohort included 27 patients in whom sequential biopsies were available. Both CD15 expression in its non-sialylated form and absence of sialyl-CD15 expression correlate with a favorable outcome. Subsequent biopsies show a preferential expression of sialyl-CD15, notably in bone marrow metastases. Our findings suggest that, in the progression of HD towards a widely disseminated disease, the LewisX moiety of the CD 15 antigen on the tumor cells acquires a sialyl-group. This change may confer on the tumor cells the capacity to metastasize.

A Study of Inflammation-Based Predictors of Tumor Response to Neoadjuvant Chemoradiotherapy for Locally Advanced Rectal Cancer

Background: The ability of pretreatment laboratory markers of acute-phase inflammatory reactions like serum albumin level (SAL), hemoglobin (Hb), and absolute blood cell counts to predict complete pathological response (CPR) to neoadjuvant chemoradiotherapy (NACRT) in patients with locally advanced rectal cancer (LARC) has not yet been fully studied. Methods: We retrospectively examined the relation between SAL, Hb and absolute blood cell counts, and CPR rates in 140 LARC patients treated with NACRT. Results: Univariate analysis showed a significantly higher probability of CPR to NACRT in patients with clinical stage (CS) III LARC who had SAL >3.5 mg/dl (OR = 2.39; p = 0.04) and a neutrophil-to-lymphocyte ratio (NLR) value <5 (OR = 2.86; p = 0.03). The relation of CPR with SAL (OR = 2.11; p = 0.048) and NLR (OR = 2.54; p = 0.04) was confirmed by multivariate analysis in the same subset of patients. None of the parameters studied predicted CPR in patients with CS II disease. Patients who achieved CPR to NACRT had a higher probability of 5-year overall survival (HR 0.48; p = 0.01) and 5-year disease-free survival (HR 0.33; p = 0.003). Conclusions: Our data indicate that SAL >3.5 mg/dl and NLR <5 may be positively related to CPR after NACRT in patients with CS III LARC. Hypoalbuminemia and a high NLR may be considered an indication for a more aggressive approach to NACRT and postoperative adjuvant chemotherapy in this subset of patients. This hypothesis requires confirmation in a randomized study.

Detection of Cancer Using Advanced Computerized Analysis of Infrared Spectra of Peripheral Blood

We have developed a novel approach for detection of cancer based on biochemical analysis of peripheral blood plasma using Fourier transform infrared spectroscopy. This approach has proven to be quick, safe, minimal invasive, and effective. Our approach recognizes any signs of solid tumor presence, regardless of location in the body or cancer type by measuring a spectrum that gives information regarding the total molecular composition and structure of the peripheral blood samples. The analysis includes clinically relevant preprocessing and feature extraction with principal component analysis, and uses Fishers linear discriminant analysis to classify between cancer patients and healthy controls. We evaluated our method with leave-one-out cross validation and were able to establish sensitivity of 93.33%, specificity of 87.8%, and overall accuracy of 90.7%. Using our method for cancer detection should result in fewer unnecessary invasive procedures and yield fast detection of solid tumors.

Rituximab in a Patient with Acute Renal Failure due to B-cell Lymphomatous Infiltration of the Kidneys

Renal failure is known to occur in lymphoproliferative disorders because of ureteral obstruction or parenchymal infiltration by disease. Rituximab is a genetically engineered chimeric murine/human monoclonal antibody directed against the CD20 antigen found on the surface of normal and malignant B-lymphocytes. The pharmacokinetics and metabolism of rituximab is not well established. The extent of renal clearance is not fully known, with little experience reported on the use of rituximab in patients with renal failure. We present a case where rituximab was administered to a patient with acute renal failure due to bilateral kidney infiltration by non-Hodgkins lymphoma (NHL). The patients renal function improved on therapy, with no need for hemodialysis and there were no significant toxicities. Rituximab may be used as a treatment option for NHL patients with impaired renal function.

Low dose palliative radiotherapy for splenomegaly in hematologic disorders

Abstract Splenomegaly (SM) is a common complication in hematologic disorders often associated with hypersplenism, and may cause pain, epigastric discomfort and variable systemic effects due to cytopenias. We retrospectively evaluated the results of palliative splenic irradiation (PSI) in terms of symptomatic relief in patients with hematologic disorders. In 1998–2006, 32 patients with hematologic disorders (median age 57) received 52 courses of PSI for SM. Twenty-one patients (66%) were diagnosed with myeloproliferative disorders (MPD), five patients (16%) had malignant lymphoma (ML), five patients (16%) had chronic lymphocytic leukemia (CLL) and one patient (3%) had hairy cell leukemia. Splenomegaly was accompanied by pain, anemia, thrombocytopenia and cachexia. Radiation therapy to the entire spleen was delivered by two parallel opposed fields using 0.5 Gy daily fractions given 5 days per week to a total dose of 6–10 Gy. PSI resulted in splenic size reduction in 78.8%, improvement of anemia in 75% and improvement of thrombocytopenia in 63.5% of PSI courses. The median survival (MS) of patients with MPD, CLL and ML was 45, 10 and 5 months, respectively. The MS of responders to PSI versus non-responders was 45 and 16 months, respectively (hazard ratio 0.17; p = 0.03; 95% confidence interval 0.035–0.84). In our hands, low dose PSI provided effective palliation for patients with hematologic disorders with SM. Splenic re-irradiation was feasible without excessive toxicity.