Effective elimination of high-dose methotrexate by repeated hemodiafiltration and high-flux hemodialysis in patients with acute kidney injury.

INTRODUCTION: Acute kidney injury (AKI) after high dose methotrexate (HD-MTX) is associated with delayed MTX-excretion and life-threatening toxicity. Glucapridase, the recommended therapy, is expensive and not always available. CASE SERIES: We describe 3 cases (69, 67, 73 years) with diffuse large B-cell lymphoma who developed AKI and early-onset severely delayed MTX elimination after HD-MTX. MTX serum concentrations were 101 and 69 µmol/L at 24 h after administration in two patients and 34 µmol/L at 32 h in the third. MANAGEMENT AND OUTCOME: Since glucarpidase was unavailable, we performed daily high-flux hemodialysis (HF-HD) or online hemodiafiltration (HDF) sessions (median duration, 6 h). The median serum MTX elimination half-life during HDF/HF-HD sessions was similar in all patients (median, 4.4 h; IQR, 3.8-5.3 h), but serum MTX concentrations rebounded after each dialysis by a median of 40% of the trough concentrations. The three patients underwent multiple dialysis sessions, until MTX serum concentrations remained sufficiently low to be neutralized by leucovorin. Only 1 patient developed severe pancytopenia, and renal function normalized in all patients after 3-6 weeks. DISCUSSION: In conclusion, when glucarpidase is unavailable or delayed, early, repeated and prolonged HDF/HF-HD effectively enhance MTX elimination and prevent toxicity in patients with AKI and severely delayed MTX elimination after HD-MTX.

Chromatin occupancy and epigenetic analysis reveal new insights into the function of the GATA1 N terminus in erythropoiesis.

Mutations in GATA1, which lead to expression of the GATA1s isoform that lacks the GATA1 N terminus, are seen in patients with Diamond-Blackfan anemia (DBA). In our efforts to better understand the connection between GATA1s and DBA, we comprehensively studied erythropoiesis in Gata1s mice. Defects in yolks sac and fetal liver hematopoiesis included impaired terminal maturation and reduced numbers of erythroid progenitors. RNA-sequencing revealed that both erythroid and megakaryocytic gene expression patterns were altered by the loss of the N terminus, including aberrant upregulation of Gata2 and Runx1. Dysregulation of global H3K27 methylation was found in the erythroid progenitors upon loss of N terminus of GATA1. Chromatin-binding assays revealed that, despite similar occupancy of GATA1 and GATA1s, there was a striking reduction of H3K27me3 at regulatory elements of the Gata2 and Runx1 genes. Consistent with the observation that overexpression of GATA2 has been reported to impair erythropoiesis, we found that haploinsufficiency of Gata2 rescued the erythroid defects of Gata1s fetuses. Together, our integrated genomic analysis of transcriptomic and epigenetic signatures reveals that, Gata1 mice provide novel insights into the role of the N terminus of GATA1 in transcriptional regulation and red blood cell maturation which may potentially be useful for DBA patients.

Single-Cell RNA Sequencing Reveals mRNA Splice Isoform Switching during Kidney Development.

BACKGROUND: During mammalian kidney development, nephron progenitors undergo a mesenchymal-to-epithelial transition and eventually differentiate into the various tubular segments of the nephron. Recently, Drop-seq single-cell RNA sequencing technology for measuring gene expression from thousands of individual cells identified the different cell types in the developing kidney. However, that analysis did not include the additional layer of heterogeneity that alternative mRNA splicing creates. METHODS: Full transcript length single-cell RNA sequencing characterized the transcriptomes of 544 individual cells from mouse embryonic kidneys. RESULTS: Gene expression levels measured with full transcript length single-cell RNA sequencing identified each cell type. Further analysis comprehensively characterized splice isoform switching during the transition between mesenchymal and epithelial cellular states, which is a key transitional process in kidney development. The study also identified several putative splicing regulators, including the genes Esrp1/2 and Rbfox1/2. CONCLUSIONS: Discovery of the sets of genes that are alternatively spliced as the fetal kidney mesenchyme differentiates into tubular epithelium will improve our understanding of the molecular mechanisms that drive kidney development.

Circulating heparan sulfate chains and body weight contribute to anti-Xa levels in cancer patients using the prophylactic dose of enoxaparin.

Hospitalized cancer patients are at increased risk of thrombosis and prophylaxis with heparin is recommended. Heparanase is a protein capable of degrading heparan sulfate (HS) chains. The first objective of the study was to examine the effects of weight on anti-Xa levels in cancer patients treated with a fixed dose of enoxaparin as thromboprophylaxis. The second aim was to assess a potential correlation between plasma pre-treatment coagulation parameters and anti-Xa levels in an assumption that heparanase degradation activity towards heparins and HS chains could affect anti-Xa levels. Two blood samples (prior to and 3 h after drug injection) of 76 cancer patients with an indication for prophylaxis with enoxaparin (40 mg) were evaluated for coagulation markers. Sub-prophylactic levels of anti-Xa (< 0.2 U/ml) were found in 16/76 (21%) patients; in 13/76 (13%) patients the values were supra-prophylactic (> 0.5 U/ml). In the subgroup of patients weighing > 80 kg, 7/14 (50%) individuals had a sub-prophylactic level. Overall, anti-Xa levels appeared to correlate with patient's weight (r = - 0.48, p < 0.0001), pre-treatment partial thromboplastin time (PTT), D-dimer, HS, heparanase levels and procoagulant activity. We concluded that plasma anti-Xa levels correlated with patient's weight. A substantial portion of cancer patients receiving enoxaparin prophylaxis was undertreated. For patients > 80 kg, a weight-adjusted prophylactic dose of enoxaparin could be considered. Elevated enoxaparin anti-Xa levels correlated with pre-treatment parameters of coagulation system activation. High pre-treatment HS and elevated plasma anti-Xa levels may potentially serve as biomarkers for the identification of patients at increased thrombosis risk.

Successful desensitization protocol for hypersensitivity reaction probably caused by dabrafenib in a patient with metastatic melanoma.

Vemurafenib and dabrafenib are both orally bioavailable small molecule agents that block mitogen activated protein kinase signalling in patients with melanoma and BRAF(V600E) mutation. Generalized hypersensitivity reactions to vemurafenib or dabrafenib have not been described. Continuing vemurafenib or dabrafenib therapy despite hypersensitivity reaction is especially important in patients with melanoma and BRAF(V600E) mutation, in whom this mutation plays a critical role in tumour growth. Desensitization protocols to overcome hypersensitivity reactions by gradual reintroduction of small amounts of the offending drug up to full therapeutic doses are available for many anti-cancer agents, including vemurafenib but, to the best of our knowledge, have not been reported for dabrafenib. We describe a patient with metastatic melanoma who developed Type I hypersensitivity reaction to vemurafenib and to subsequent treatment with dabrafenib, and who was successfully treated by drug desensitization which allowed safe prolonged continuation of dabrafenib. The development of hypersensitivity reactions for both dabrafenib and vemurafinib in the current case could be because these drugs have a similar chemical structure and cause a cross-reactivity. However, hypersensitivity reaction to a non-medicinal ingredient shared by the two drugs is also possible. Oral desensitization appears to be an option for patients with hypersensitivity Type I to dabrafenib. This approach may permit clinicians to safely administer dabrafenib to patients who experience hypersensitivity reactions to this life-prolonging medication.

Increase in triglyceride blood level in patients treated with capecitabine: a retrospective survey.

According to registry studies of capecitabine, grade 3-4 hypertriglyceridemia can occur in 0.1-1% of patients, unexplained by the drug's mechanism of action. This retrospective study aimed at estimating the incidence of capecitabine-induced hypertriglyceridemia (CIH) and attempted to identify the risk factors for its occurrence. In a retrospective survey, the files of 289 patients treated with capecitabine as a single agent or combined with other drugs were reviewed. A total of 102 patients without grade 2 or more hypertriglyceridemia at baseline and with at least one test of triglyceride blood level (TGBL) at least 2 months from the start of capecitabine were eligible for the study. The mean TGBL was 149±80 mg/dl at the onset of treatment and the mean maximal level after two or more cycles of capecitabine was 236±137 mg/dl (P<0.001; average increase 93 mg/dl). Nineteen (19%) patients developed grade≥2 CIH, four (4%) of whom had grade 3-4. The median time to developing grade≥2 CIH was 79 days (range, 16-243 days). A high rate of grade≥2 CIH, without statistical significance, was observed on the basis of several risk factors: pre-existing hypertriglyceridemia grade 1 (11/45; 24%), diabetes (7/25; 37%), hypertension (10/60; 17%), and ischemic heart disease (IHD) (5/14; 36%). The only identified risk factor for grade≥3 CIH was IHD (2/14; P=0.02). Increased capecitabine-induced TGBL is common and grade≥2 was detected in 19% of patients in this series. Close monitoring of lipid profile is recommended in patients on capecitabine treatment. IHD may be a risk factor for development of severe hypertriglyceridemia.

Toxicity of induction chemotherapy with docetaxel, cisplatin and 5-fluorouracil for advanced head and neck cancer.

BACKGROUND: The role of induction chemotherapy in advanced squamous cell carcinoma of the head and neck (SCCHN) is under constant debate. Surgery, radiotherapy, chemotherapy, and targeted therapies are part of the treatment strategy in these patients, but their sequence remains to be defined. OBJECTIVES: To evaluate the feasibility of induction chemotherapy with docetaxel-cisplatin-5-flurouracil (TPF) followed by external beam radiotherapy (EBRT) with concomitant chemotherapy or cetuximab (ERT) in the treatment of patients with advanced SCCHN. METHODS: We reviewed the data of all patients with advanced SCCHN, stage III and IV, treated in 2007-2010. Tolerability was assessed and scored according to the proportion of patients completing the planned study protocol. Toxicity was scored using the U.S. National Cancer Institute Common Toxicity Criteria (version 4) for classification of adverse events. RESULTS: The study included 53 patients. TPF was initiated at a reduced dose in 13 patients (25%). Twenty-two patients (41.5%) received primary prophylaxis with granulocyte colony-stimulating factor (GCSF) and 42 (77%) completed treatment according to schedule. During the induction phase one patient (2%) died and 24 (45%) had one or more grade 3-4 complications. The number of patients who developed neutropenia was lower in the group that received primary GCSF prophylaxis. Secondary dose reductions were required in 21% of the patients. CONCLUSIONS: Induction TPF was associated with grade 3-4 toxicity. Prophylaxis with GCSF should be part of the treatment regimen.

Vitamin D deficiency in oncology patients--an ignored condition: impact on hypocalcemia and quality of life.

BACKGROUND: Vitamin D status is not evaluated routinely in cancer patients with bone metastasis who are treated with bisphosphonates. OBJECTIVES: To assess the effect of vitamin D status on risk of hypocalcemia and quality of life in these patients. METHODS: We performed laboratory tests for routine serum biochemistry, 25(OH)D, plasma parathyroid hormone (PTH) and bone turnover markers (CTX, P1NP) in 54 patients aged 57.5 +/- 13 years treated with intravenous bisphosphonates. RESULTS: Most of the patients (n = 44, 77.8%) did not receive calcium and vitamin D supplementation. Their mean serum 25(OH)D levels (12.83 +/- 6.86 ng/ml) correlated with vitamin D daily intake (P = 0.002). In 53 patients (98.1%) 25(OH) D levels were suboptimal (< 30 ng/ml). Albumin-corrected calcium levels correlated with plasma PTH (P = 0.001). No correlation was observed between daily calcium intake and serum calcium (P = 0.45). Hypocalcemia was observed in one patient. Mean plasma PTH was 88.5 - 65 ng/L. Plasma PTH correlated negatively with 25(OH)D serum levels (P = 0.003) and positively with P1NP (P = 0.004). Albumin-corrected calcium correlated negatively with P1NP (mean 126.9 +/- 191 ng/ml) but not with CTX levels (mean 0.265 +/- 0.1 ng/ml) (P < 0.001). There was no correlation among quality of life parameters, yearly sun exposure and 25(OH)D levels (P = 0.99). CONCLUSIONS: Vitamin D deficiency is frequent in oncology patients with bone metastasis treated with bisphosphonates and might increase bone damage. Our results indicate a minor risk for the development of severe hypocalcemia in vitamin D-deficient patients receiving bisphosphonate therapy. Although vitamin D deficiency might have some effect on the quality of life in these patients, it was not proven significant.

Characterization of alternative mRNA splicing in cultured cell populations representing progressive stages of human fetal kidney development.

Nephrons are the functional units of the kidney. During kidney development, cells from the cap mesenchyme-a transient kidney-specific progenitor state-undergo a mesenchymal to epithelial transition (MET) and subsequently differentiate into the various epithelial cell types that create the tubular structures of the nephron. Faults in this transition can lead to a pediatric malignancy of the kidney called Wilms' tumor that mimics normal kidney development. While human kidney development has been characterized at the gene expression level, a comprehensive characterization of alternative splicing is lacking. Therefore, in this study, we performed RNA sequencing on cell populations representing early, intermediate, and late developmental stages of the human fetal kidney, as well as three blastemal-predominant Wilms' tumor patient-derived xenografts. Using this newly generated RNAseq data, we identified a set of transcripts that are alternatively spliced between the different developmental stages. Moreover, we found that cells from the earliest developmental stage have a mesenchymal splice-isoform profile that is similar to that of blastemal-predominant Wilms' tumor xenografts. RNA binding motif enrichment analysis suggests that the mRNA binding proteins ESRP1, ESRP2, RBFOX2, and QKI regulate alternative mRNA splicing during human kidney development. These findings illuminate new molecular mechanisms involved in human kidney development and pediatric kidney cancer.

Successful desensitization protocol for hypersensitivity reaction caused by sunitinib in a patient with a gastrointestinal stromal tumor.

Sunitinib is an orally bioavailable small molecule that inhibits multiple receptor tyrosine kinases. Generalized hypersensitivity reactions (HSR) to sunitinib have not been described. A patient with a gastrointestinal stromal tumor (GIST) who developed a type I HSR to sunitinib and who was successfully treated by drug desensitization is reported. A 51-year-old man with metastatic GIST developed a type I HSR during sunitinib treatment. Four days after treatment initiation, the patient presented to the Emergency Department with acute generalized urticaria and facial and throat swelling. Sunitinib was restarted 1 week later, using a desensitization protocol in which 10 escalating reduced doses, beginning with 0.05 mg, were given following pre-medication with prednisone and promethazine. This protocol was well tolerated and allowed us to continue the treatment, obtaining partial remission of the liver metastasis that was followed by complete resection. Sunitinib was temporarily discontinued before the operation and renewed after surgery by repeating the same desensitization procedure. At the time of this report, sunitinib has been continued for 1 year without evidence of recurrent disease. Oral desensitization appears to be an option for patients with hypersensitivity type I to sunitinib and may permit its safe administration to patients who experience HSR to this life-prolonging medication.

Asymptomatic deep vein thrombosis in advanced cancer patients: the value of venous sonography.

PURPOSE: Although guidelines for venous thromboembolism prevention are available, the implementation of anticoagulant prophylaxis in patients with advanced cancer has yet to be more clearly defined. We aim to determine the incidence of lower extremity deep vein thrombosis (DVT) diagnosed by Doppler sonography (USD) in asymptomatic nonambulatory patients with advanced cancer. METHOD: In a prospective study, 44 nonambulatory cancer patients with grade 3-4 World Health Organization performance status, asymptomatic for lower extremity DVT, underwent bilateral venous USD studies of the lower extremities. Different risk factors and laboratory data were registered and correlated with the incidence of DVT. RESULT: Asymptomatic DVT was detected in 15 of 44 patients (34%, 95% CI, 0.21-0.49). Twenty-three percent of all patients had isolated deep calf vein thrombi and 11% of all patients had thrombi in the proximal veins. The only significant risk factor was the number of metastatic sites. DVT was found in 4 of 23 (17.4%) patients with one metastatic site as opposed to 11 of 21 (52.3%) with two or more sites (p < 0.01). CONCLUSION: USD of the lower extremities detected asymptomatic DVT in 34% of advanced nonambulatory cancer patients and may serve as an additional decision-making tool in the consideration of anticoagulant therapy for this specific population.

The Older Adults With Rectal Cancer-Does Age Matter?: A Single-center Experience.

OBJECTIVES: Oncological treatments of older patients have many unresolved questions mainly because of the fact that these patients were not eligible to be included in most clinical trials. The aim of this study was to evaluate the treatment approach to localized rectal cancer in the older population, including complication rates and overall survival in patients treated with curative intent. MATERIALS AND METHODS: A retrospective review of patients older than 80 years old (group A) who were treated for clinical stages II to III rectal cancer. The data collection included demographics, comorbidities, treatment protocols, adverse events, time of death, and a comparison with a group of patients aged 65 to 75 years (group B). RESULTS: A total of 88 patients were included in the analysis (group A, 35; group B, 53). The groups were balanced with regards to sex, comorbidities, pretreatment albumin, and hemoglobin levels (for all categories P>0.05). More patients in group A (25%) received preoperative treatment as in-patients (P=0.022) and were treated with radiation only (P<0.0001) as the initial treatment approach. In group A, in 82% of patients the initial chemotherapy dose was reduced to 75% or less of the calculated dose compared with 7% in group B (P<0.001). Discontinuation of chemotherapy was needed in 55% in group A and 31% in group B (P=0.07). Median overall survival was 33 months in group A and 55 months in group B (P=0.06), 5-year overall survival was 27% and 60%, respectively (P=0.004). CONCLUSIONS: The age has a significant implication on preoperative treatment, chemotherapy dose, hospitalization rates, and survival.

Ex Vivo Expanded 3D Human Kidney Spheres Engraft Long Term and Repair Chronic Renal Injury in Mice.

End-stage renal disease is a worldwide epidemic requiring renal replacement therapy. Harvesting tissue from failing kidneys and autotransplantation of tissue progenitors could theoretically delay the need for dialysis. Here we use healthy and end-stage human adult kidneys to robustly expand proliferative kidney epithelial cells and establish 3D kidney epithelial cultures termed "nephrospheres." Formation of nephrospheres reestablishes renal identity and function in primary cultures. Transplantation into NOD/SCID mice shows that nephrospheres restore self-organogenetic properties lost in monolayer cultures, allowing long-term engraftment as tubular structures, potentially adding nephron segments and demonstrating self-organization as critical to survival. Furthermore, long-term tubular engraftment of nephrospheres is functionally beneficial in murine models of chronic kidney disease. Remarkably, nephrospheres inhibit pro-fibrotic collagen production in cultured fibroblasts via paracrine modulation, while transplanted nephrospheres induce transcriptional signatures of proliferation and release from quiescence, suggesting re-activation of endogenous repair. These data support the use of human nephrospheres for renal cell therapy.

Local recurrence following adjuvant chemotherapy without radiotherapy in completely resected stomach and gastroesophageal junction adenocarcinoma.

BACKGROUND: The gold standard of adjuvant treatment after surgical resection of adenocarcinoma of the stomach or gastroesophageal junction (GEJ) is chemoradiotherapy. We retrospectively evaluated chemotherapy without radiotherapy in stomach and GEJ adenocarcinoma, using a combination of etoposide, adriamycin and cisplatin (modified EAP). PATIENTS AND METHODS: Sixty-five patients with completely resected gastric or GEJ adenocarcinoma and positive regional lymph nodes were treated with modified EAP over an 8-year period. RESULTS: Recurrent disease was diagnosed in 38/58 (69%) patients evaluable for analysis. Only two (5%) had locoregional recurrence. The main toxicity was hematological, with 22 (34%) patients developing neutropenic fever and 12 (18%) anemia requiring blood transfusion. The median survival for the entire group was 20 months, with a median time to recurrence of 11 months. Seventeen (26%) patients are alive for a median of 7+ years, with no evidence of recurrent disease. CONCLUSION: Our data cast doubt on the benefit of radiotherapy adjuvant to chemotherapy.

A pilot study of first-line olaratumab, doxorubicin and ifosfamide in patients with metastatic soft tissue sarcoma.

INTRODUCTION: Olaratumab (O) is a monoclonal antibody that specifically binds PDGFRα. The addition of O to doxorubicin (D) has been approved by the regulatory authorities for metastatic soft tissue sarcoma (MSTS). Since the combination of D + ifosfamide (I) is commonly used in MSTS and is associated with a higher response rate than D alone, it seems reasonable to combine O with the combination of D + I (ODI). We report our preliminary experience with O + D+I in MSTS. METHODS: Between 01/01/2015 and 30/05/2018, 15 patients (pts) with MSTS were treated with ODI as first-line therapy. The treatment protocol consisted of IV D 50 mg/m2 and I 5000 mg/m2, day 1 (3 pts), or D 37.5 mg/m2 and I 3000 mg/m2 days 1-2 (12 pts). O (15 mg/kg) was given IV on days 1, 8, and cycles were repeated every 21 days. RESULTS: With a median follow up of 16 months, 63 cycles of ODI were given. Objective response was achieved in 4 pts (27%) (CR in 3, PR in 1); 5 pts (33%) remained with stable disease for ≥ 5 mo. Median overall survival was 22 months. Major hematological toxicities (grade 3-4) included: neutropenia-7 pts (47%), and neutropenic fever-3 pts (20%). Non-hematological toxicities included grade 3 diarrheas in 2 pts (13%) after the second cycle. There was no treatment-related mortality. CONCLUSION: According to our preliminary experience, adding olaratumab to doxorubicin and ifosfamide is active and its safety profile is comparable to that of doxorubicin and ifosfamide alone in MSTS.

Treatment of patients aged over 50 years with non-osseous Ewing's sarcoma family tumors: five cases and review of literature.

BACKGROUND: Most clinical trials on Ewing's sarcoma family of tumors include pediatric and adolescent populations, whereas clinical data on older patients are limited. PATIENTS AND METHODS: We report on 5 patients older than 50 years with a tumor of the Ewing's sarcoma family treated recently in our department. RESULTS: Myelosuppression and infectious complications were the main toxicity encountered. Major dose reductions and/or treatment delays were required in all 5 patients. One patient died of septic shock. Complete remission was achieved in the remaining 4 patients with the addition of different treatment modalities. One patient had lung metastasis 3 years after starting chemotherapy, and 3 patients have remained without evidence of recurrent disease for 1-6 years from the onset of chemotherapy CONCLUSIONS: There is no definite answer as to whether older age is a poor prognostic factor in patients with a tumor of the Ewing's sarcoma family. In our experience, patients over 50 poorly tolerated the standard chemotherapy protocol used in the pediatric population.

A brief review of single-cell transcriptomic technologies.

In recent years, there has been an effort to develop new technologies for measuring gene expression and sequence information from thousands of individual cells. Large data sets that were obtained using these 'single cell' technologies have allowed scientists to address fundamental questions in biomedicine ranging from stems cells and development to cancer and immunology. Here, we provide a brief review of recent developments in single-cell technology. Our intention is to provide a quick background for newcomers to the field as well as a deeper description of some of the leading technologies to date.

Epiphora (excessive tearing) and other ocular manifestations related to weekly docetaxel: underestimated dose-limiting toxicity.

PURPOSE: Epiphora due to canalicular stenosis is a recently described side effect of weekly docetaxel. We prospectively evaluated the incidence of this complication and other ocular manifestations in patients treated at our medical center. PATIENTS AND METHODS: Twenty-one consecutive patients (breast cancer: 14; metastatic non-small cell lung cancer: 6; metastatic nasopharyngeal carcinoma: 1) (female/male: 14/7; age range: 34-78 yr) were treated with weekly docetaxel (35 mg/m2/wk iv for 6 wk, cycles repeated every 49 d). A standard questionnaire regarding epiphora was completed before each dose of docetaxel. Patients who complained of excessive tearing underwent a thorough ophthalmologic evaluation before receiving the next dose. RESULTS: Epiphora due to stenosis of the lacrimal puncti and canaliculi developed in seven (33%) patients following a cumulative dose of 208-645 mg/m2 (median: 400 mg/m2). Two patients developed complete canalicular stenosis requiring surgery. Epiphora was accompanied by madarosis and ectodermalization of the palpebral and bulbar conjunctiva, complete in five patients. Treatment was discontinued due to epiphora in two (10%) patients. After a median follow-up of 11 mo, four patients still had epiphora. CONCLUSION: Epiphora due to canalicular stenosis is a frequent complication of weekly docetaxel and might be dose limiting. Irreversible damage requiring surgical intervention may develop despite close monitoring.

Prospective evaluation of patients hospitalized with venous thromboembolism: comparison between cancer and non-cancer patients.

BACKGROUND: Little is known about the epidemiology of venous thromboembolism in hospitalized patients in Israel. Also, a direct comparison of the clinical and laboratory features between cancer and non-cancer patients has not yet been reported. OBJECTIVES: To investigate and compare the epidemiologic, clinical and laboratory characteristics of cancer and non-cancer patients hospitalized with venous thromboembolism in a large referral medical center in Israel. METHODS: Between February 2002 and February 2003, patients diagnosed at the Rambam Medical Center as suffering from VTE (deep vein thrombosis and/or pulmonary embolism), based on diagnostic findings on Doppler ultrasonography, spiral computed tomography scan or lung scan showing high probability for pulmonary embolism, were prospectively identified and evaluated. In addition, at the conclusion of the study period, the reports of spiral chest CT scans, performed during the aforementioned period in this hospital, were retrospectively reviewed to minimize the number of unidentified cases. Blood samples were drawn for evaluation of the coagulation profile. RESULTS: Altogether, 147 patients were identified and 153 VTE events diagnosed, accounting for 0.25% of all hospitalizations during the study period. The cancer group included 63 patients (43%), most of whom had advanced disease (63%). The most common malignancies were cancer of the lung (16%), breast (14%), colon (11%) and pancreas (10%). Of 122 DVT events (with or without pulmonary embolism) there were 14 upper extremity thromboses (12%). The most common risk factors for VTE, except malignancy, were immobilization (33%), surgery/trauma (20%) and congestive heart failure (17%). There was no difference in prevalence of various risk factors between cancer and non-cancer patients. During an acute VTE event, D-dimer levels were higher in cancer patients than non-cancer patients (4.27 +/- 4.04 vs. 2.58 +/- 1.83 mg/L respectively, P = 0.055). Relatively low values of activated protein C sensitivity ratio and normalized protein C activation time were observed in both cancer and non-cancer groups (2.05 +/- 0.23 vs. 2.01 +/- 0.33 and 0.75 +/- 0.17 vs. 0.71 +/- 0.22, respectively). These values did not differ significantly between the groups. CONCLUSION: The proportion of cancer patients among patients suffering from VTE was high. Their demographic, clinical and laboratory characteristics (during an acute event) were not different from those of non-cancer patients, except for higher D-dimer levels.

[Mistletoe (Viscum album) preparations: an optional drug for cancer patients?].

Extracts and preparations from the parasitic plant mistletoe (Viscum album L.) have been used in the treatment of cancer for decades. Mistletoe treatment for cancer was introduced in 1920 by Steiner and Wegman, founders of the Anthroposophical medical method. Today, mistletoe extracts are the most frequently prescribed unconventional cancer therapies in Germany, as in some other European countries. Full clinical data about the efficacy of the mistletoe preparations is still missing. The preparations are usually given as subcutaneous injections, but other routes of administration are also used. Numerous preclinical and in-vitro studies have reported immunostimulatory, cytotoxic and proapoptotic effects. More than 15 prospective clinical trials using mistletoe extracts in patients with different malignancies have been reported. In most of these studies the authors reported that mistletoe extracts had therapeutic benefit in terms of response rate, overall survival, quality of life and reduction in side-effects of the oncological treatment. Unfortunately, almost all of these reported studies had at least one major weakness that questioned their reliability. Side effects of the different mistletoe preparation used in human studies are generally minimal and non-life threatening. In the current review recent studies, including two phase II studies from our center, are included. In the future, data that will be obtained from good quality studies might facilitate reaching firm conclusions regarding the therapeutic benefit of mistletoe preparation for oncological treatment.