Tumor biopsy and patient enrollment in clinical trials for advanced hepatocellular carcinoma

Tumor biopsies may help to reliably distinguish hepatocellular carcinoma(HCC) from other tumors, mostly cholangiocarcinoma as well as to identify the patient populations who most benefit from target-driven HCC treatments, in order to improve the success rate of experimental therapies. Clarifying tumor biology may also lead to identify biomarkers with prognostic role and/or enabling to predict response or resistance to therapies. Recently, clinical trials have more efficiently included biomarker endpoints and increasingly collected tumor tissue from enrolled patients. Due to their frail status and sometimes fast-progressing disease, the performance status of patients with HCC progressing on first-line therapy can deteriorate quickly, preventing their enrollment in clinical trials. However, the challenge of identifying the proper patient at the proper time can be overcome by periodic inter-department meetings involving the key specialists taking care of HCC patients, and solid networks between research centers and referring institutions. An early planned biopsy would also facilitate timely inclusion of patients in biology-driven clinical trials. Ultimately, institution of multidisciplinary teams can optimize treatment choice, biopsy timing, and quick enrollment of patients in clinical trials, before their performance status deteriorates.

Simultaneous Diagnosis of Myeloid Sarcoma of the Jaw and Mycobacterium tuberculosis Infection

Granulocytic or myeloid sarcoma (MS) is a rare neoplastic condition consisting of a tumor mass of myeloid blasts with or without maturation occurring at an anatomical site other than the bone marrow the association between tuberculosis and MS is extremely rare. A 21-year-old female patient presented cough, sore throat and a suppurative swollen gum for 10 days prior to hospital admission. Physical examination revealed moderate pallor and swollen inferior gum. CBC revealed Hb6.5 g/dL, hematocrit 18.4% MCV 97 fL MCH 34 pg, WBC 18.5 ′ 109/μL (1 My/3 Bt/69 Sg/1 Eo/0 Ba/20 Ly/6 Mo), Platelets 43 ′ 109/μL. The peripheral blood smear presented with 3% blast cells (type 1) and granulocytic dysplasia. Bone marrow biopsy showed 100% cellularity. 50% of cells were from granulocytic precursors, diagnosis of granulocytic sarcoma. The diagnosis of AML was established: granulocytic sarcoma with massive gum infiltration (immature granulocytic cells) and 10% of blasts in bone marrow. The patient received induction chemotherapy (3 + 7 daunorubicin 90 mg/m2), and gum tissue culture was positive for Mycobacterium tuberculosis. Simultaneously, a qRT- PCR test confirmed the same bacteria in the gum tissue. Patient treated with isoniazid, rifampicin, pyrazinamide and ethambutol ciprofloxacin and amikacin). Remission was achieved and the patient was submitted for consolidation/ intensification (HiDAC x3) schema and referred to allogeneic HSCT. After induction and full hematological recovery there was no further evidence or recurrence of fever and lytic lesions. Currently patient is under CR and ling follow up (48 months) did not show recurrence of either AML or tuberculosis.

Initial Analysis of Lipid Metabolomic Profile Reveals Differential Expression Features in Myeloid Malignancies

The purpose of this preliminary study was to determine the comparative lipid profile of blood plasma samples of healthy individuals and patients with Myeloproliferative Neoplasms. Methods: Untargeted Shotgun MS/MS Analysis was performed to evaluate plasma samples from 153 participants, being 90 of the Control Group, 43 Myeloproliferative Neoplasms (MPN), 11 Myelodysplastic Syndromes (MDS) and 9 Acute Myeloid Leukemias (AML). Lipids were extracted from plasma using the Bligh-Dyer protocol. Data were acquired using the AB-Sciex Analyst TF, processed using the AB-Sciex LipidViewTM and the web-based analytical pipeline MetaboAnalyst 2.0 (www.metaboanalyst.ca). Results: Untargeted analysis identified in negative and positive-modes a total of 658 features at 2 ppm resolution. PCA and PLS-DA analysis revealed clear discrimination among groups, in particular for AML patients. Main lipid groups differentially expressed were: Monoacylglycerols (MAG), Glucosylceramide E (GlcdE), Ethyl Esters (EE), Lysophosphatidic acid (LPA), Sulfoquinovosil diacylglycerols (SQDG), Monoglycerols (MG), Methyl Ethanolamines (ME), Lysophosphatidylcholines (LPC), Dimethyl Phosfatidyletanolamines (DMPE), Monometylphosphatidiletanolamines (MMPE), Ceramide-1-phosphate (CerP), Glicerophosphoglycerols (GP), Lysomonomethyl-Phosphatidylethanolamines (LMMPE), Phosphatidic Acids (PA), Ergosterols (ERG), Glycerophosphoserine (PS), Diacylglycerols (DAG), Hexocylceramides (HexCer) and Lanosterol (Lan). ROC Curve Analysis revealed Total LMMPE as the strongest discriminating marker between Controls from Patients. In addition, these lipids were also able to differentiate MDS and AML from NPM. Conclusions: The Myeloproliferative Neoplasms from the point of view of global plasma lipidomics are accompanied by several modifications. In particular, the Lysomonomethyl-Phosphatidylethanolamines (LMMPE) seems to play important differentiating roles among them.

Increased Risk of Acute Myeloid Leukemia in Patients with CYP1A1 Polymorphisms

Acute Myeloid Leukemia (AML) is a group of genetically diverse hematopoietic malignancies arising from cell progenitors developing in the myeloid pathway or from primitive stem cells. Genetic susceptibility of AML may account for an increased risk of AML due to partial metabolism of or biocativation of carcinogens. Chemical compounds are metabolized by a two-tiered phase detoxifying system. Polymorphisms in these pathways may lead to DNA damage and development of AML. We determined the frequencies of carcinogen metabolism gene polymorphisms (CYP1A1, del{GSTM1} and del{GSTT1}) in a case control-study based on polymorphism analysis. Fifty-eight consecutively AML patients (median age 62 years) and 174 sex and age-matched control group were assessed by a PCR-RFLP assay. There were 51 de novo and 7 secondary AML. CYP1A1*2A and CYP1A1*2C polymorphisms were more frequent in CG than AML p 0.001 and in contrast, CYP1A1*3 and CYP1A1*4 were more frequent in AML than CG p 0.001. There were no differences in del{GSTM1} neither del{GSTT1} between AML and CG (p = 0.999 and p = 0.539). Odds ratio for AML in patients harboring CYP1A1*3 was 2.36 (95% CI 1.2 - 4.5), 2.38 for CYP1A1*4 (95% CI 0.8 - 6.8). Adjusted OR was 2.63 for CYP1A1*3 (95% CI 1.4 - 5.1) and 2.66 for CYP1A1*4 (95% CI 0.9 - 7.8). In the multivariate analysis CYP1A1*3 polymorphism was a risk factor for AML with an OR for 3.99 (95%CI 1.9 - 8.6). To the best of our knowledge this is the first study to show that CYP1A1*3 heterozygous genotypes increase the risk of AML. Our data support that inherited absence of this carcinogen detoxification pathway may be an important determinant of AML.

Time Elapsed from AML Diagnosis to Induction Chemotherapy Affects Overall Survival

We aimed to study the effect of elapsed time from AML diagnosis to treatment (TDT) on OS in a group of patients from public Hospital in Brazil. 41 AML (23 M, 18 F, 41 yrs, 18 - 84 yrs, from 2001 to 2004). There were 38 de novo AML and 3 secondary, median TDT was 6 days (range 1 - 82 d);the young ones?were treated earlier than old ones (TDT 4 days vs 11, p = 0.07). Longer TDT (>10 d) was associated with worse CR rates (p = 0.02) and OS (p = 0.04). When patients were categorized into TDT from 1 - 4 d (I) vs >5 (II), those from I presented better OS than II (p = 0.004). When TDT was longer than 7 days OS decreased even more. Hb was higher in patients with TDT I vs II (8.3 vs 7.5 g/dL, p = 0.03) but WBC (p = 0.34) and platelet count (p = 0.75) were not different. Patients with TDT of 10 d were younger than TDT > 10 d (median age 41 vs 70 yrs, p = 0.001). The OS was 15.1% in 2 yrs and 8.6% in 7 yrs. Our data suggest longer TDT, when analyzed continuously, predicted for lower CR rates and OS rates.

Hepatocellular carcinoma in elderly patients:a concise reviewon systemic therapy with sorafenib

The treatment of hepatocellular carcinoma(HCC)in elderly patients is unclear.In particular,the effi cacy and safety of sorafenib as a systemic treatment in these patients is still under debate.We performed a concise review of sorafenib therapy in this population.However,it is important to make any decisions on treatment for elderly patients with HCC through a multidisciplinary team that includes experts in the liver disease.Patients with good clinical conditions should be treated with sorafenib.