A phase II study of erlotinib in combination with bevacizumab versus chemotherapy plus bevacizumab in the first-line treatment of advanced non-squamous non-small cell lung cancer.

BACKGROUND: Molecularly targeted agents for non-small cell lung cancer (NSCLC) can provide similar efficacy to chemotherapy without chemotherapy-associated toxicities. Combining two agents with different modes of action could further increase the efficacy of these therapies. The TASK study evaluated the efficacy and safety of the epidermal growth factor receptor tyrosine kinase inhibitor erlotinib in combination with the anti-angiogenic agent bevacizumab as first-line therapy in unselected, advanced non-squamous NSCLC patients. METHODS: Patients were recruited from December 2007 to September 2008. Planned sample size was 200 patients, a total of 124 patients were randomized. Patients were randomized using a minimization algorithm 1:1 to receive bevacizumab (iv 15 mg/kg day 1 of each 21-day cycle) plus chemotherapy (gemcitabine/cisplatin or carboplatin/paclitaxel standard doses, 4-6 cycles) (BC arm) or bevacizumab plus erlotinib (p.o. 150 mg/day; BE arm) until disease progression or unacceptable toxicity. The primary endpoint was progression-free survival (PFS). If the hazard ratio (HR) of PFS for BE relative to BC was above 1.25 at the pre-planned interim analysis in favor of BC, the study would be re-evaluated. Secondary endpoints included overall survival, response rate and safety. RESULTS: All randomized patients (n = 63 BE; n = 61 BC) were evaluated for the efficacy analyses. At the updated interim analysis, median PFS was 18.4 weeks (95% confidence interval [CI] 17.0-25.1) versus 25.0 weeks (95% CI 20.6-[not reached]) for BE versus BC, respectively (HR for death or disease progression, BE relative to BC, 2.05, p = 0.0183). The incidence of death was 19% for BE treatment compared with 11.5% for BC treatment. The HR for PFS at the updated interim analysis was above 1.25, therefore patients on the BE arm were permitted to change arms or switch to another drug and the study was terminated. Adverse events reported were as expected. CONCLUSIONS: The TASK study did not show a benefit in terms of PFS for the combination of erlotinib with bevacizumab in unselected first-line advanced non-squamous NSCLC compared with chemotherapy plus bevacizumab.

Right- and left-subclavian vein port-a-cath systems: comparison of complications.

BACKGROUND: Central venous access systems are frequently used for delivery of medications; however, few studies have compared surgical and postoperative complications of right versus left access via the subclavian vein (SCV). The aim of this study was to compare the surgical and postoperative complications associated with Port-A-Cath system insertion via the right and left SCV. METHODS: The medical records of patients who received Port-A-Cath insertion via the SCV for parenteral chemotherapy between August 2004 and July 2008 were reviewed. The incidence of surgical and postoperative complications was compared between patients who received right- versus left-SCV Port-A-Cath insertion. RESULTS: A total of 1,848 patients were included in the study. Right-SCV catheterization was attempted in 1,029 (55.7%) patients and was successful in 866 (84.2%). Left-SCV catheterization was attempted in 819 (44.3%) patients and was successful in 651 (79.5%). The mean length of postoperative follow-up was 417.3 ± 401.3 and 396.7 ± 379.9 days for the right- and left-SCV groups, respectively. The incidence of SCV puncture failure was significantly lower in the right-SCV group (12.3%) compared with the left-SCV group (16.8%, p = 0.006). The incidence of catheter knotting at the ipsilateral brachiocephalic vein was also significantly lower in the right-SCV group (0.0%) compared with the left-SCV group (0.5%, p = 0.038), as was the incidence of catheter occlusion (1.0% for right SCV vs. 3.5% for left SCV, p = 0.001). CONCLUSION: These findings suggest that the right-SCV approach is superior to the left-SCV approach for Port-A-Cath insertion.

Aberrant co-expression of CD19 and CD56 as surrogate markers of acute myeloid leukemias with t(8;21) in Taiwan.

Aberrant antigen expression in acute myeloid leukemia (AML) has been extensively studied in the West with limited reports from Taiwan. We carried out this retrospective study to characterize the frequency and significance of aberrant antigen expression of AML in Taiwan. Among 111 cases, 58 (52%) showed aberrant antigen expression, most frequently CD7 (27%) and CD56 (23%). Aberrant CD7 expression was observed in all non-AML-M3 subtypes, most frequently in AML-M7 (4/6, 67%); while CD19 expression was only observed in AML-M2 (5/36, 14%). CD56 expression was most common in AML-M5 (4/8, 50%). The relative frequency of CD19 and CD56 expression in AML with t(8;21) was higher than those with other chromosomal abnormalities or normal karyotype (P = 0.011 and 0.005, respectively). In non-M3 AML, aberrant antigen expression was identified in 56/96 (58%) cases, in contrast to 2/15 (13%) AML-M3 cases (P = 0.001). CD7, CD19 and CD56 expression was not correlated with remission rate. We concluded that aberrant immunophenotype was more frequent in non-M3 leukemias in Taiwan. The relative frequency of CD19 and/or CD56 expression in AML with t(8;21) was significantly higher than those without this translocation and co-expression of these two antigens may serve as the surrogate markers for AML with t(8;21).

Hydroxyurea and splenic irradiation-induced tumour lysis syndrome: a case report and review of the literature.

Therapeutic agents for chronic myeloid leukaemia (CML) in the chronic phase include hydroxyurea, interferon alpha, allogeneic stem cell transplantation and the tyrosine kinase inhibitor imatinib (STI 571, Gleevec). For elderly patients, oral hydroxyurea is suitable for the relief of symptoms caused by hyperleukocytosis, and splenic irradiation would be considered if abdominal discomfort or fullness induced by splenomegaly were present. Tumour lysis syndrome (TLS) is seldom seen in the treatment for CML, and TLS caused by hydroxyurea or splenic irradiation is rarely observed. Herein, we report an elderly CML patient who received treatment with hydroxyurea, allopurinol, hydration and splenic irradiation. After 3 days, acute TLS developed. Aggressive supportive treatment, including haemodialysis, stabilized the condition.

Increase of PTEN gene expression in insulin resistance.

Phosphatase and tensin homologue deleted from chromosome ten (PTEN) has recently been characterized as a regulator of insulin sensitivity in the insulin target tissue. However, whether PTEN gene expression is changed in insulin resistance remains unclear. We observed that both the mRNA and protein level of PTEN in soleus muscle isolated from the obese Zucker rats (Fa/Fa) were increased compared to the age-matched lean group. Similarly, both the mRNA and protein level of PTEN in soleus muscle of the fructose-fed lean Zucker rats (Fa/Fa) showing the higher glucose-insulin index were higher than that of the regular chow fed group. These results suggest that increase of PTEN gene expression seems to be related to the development of insulin resistance.

Rapid engraftment of mast cells of donor origin in a case of acute myeloid leukemia with mast cell leukemia after allogeneic stem cell transplantation.

Mastocytosis is a rare disease characterized by an abnormal increase of mast cells in tissues. We report a case of acute myeloid leukemia (AML) with t(8;21) and mast cell leukemia (MCL) in which the mastocytosis persisted after standard chemotherapy and allogeneic stem cell transplantation, although the myeloid leukemia achieved molecular complete remission soon after induction chemotherapy. Donor-type mast cells were noted on d31 after transplant. No c-kit mutation was found before or after the transplant. This represents the first reported case in which rapid engraftment of mast cells of donor origin was documented. Thus, the possibility that the mast cell originates from a common myeloid precursor cell may be questioned and a reactive process should be considered in some cases of systemic mastocytosis.

Incidence of thrombophilia detected in southern Taiwanese patients with venous thrombosis.

In order to analyze the incidence of thrombophilia in southern Taiwan, we studied the prevalence of antithrombin (AT), protein C (PC), and protein S (PS) deficiencies, the prevalence of factor V Leiden mutation, and the presence of acquired lupus anticoagulant (LA) and anticardiolipin antibody (ACA) in 56 patients < or =65 years old with deep venous thrombosis (DVT). Of 56 patients, 30 were male, 26 female, and the mean age of the patients was 43 years (18-65 years). None had factor V mutation or activated PC resistance; 21 patients (37.5%) showed abnormal results: 4 (7.1%) had AT deficiencies, 6 (10.7%) PC deficiencies, 6 (10.7%) PS deficiencies, 2 (3.6%) a combined PC and PS deficiency, and 3 (5.4%) LA and ACA. Only PC and PS deficiencies were significantly associated with increased risk for the development of thrombosis with an odds ratio of 4.2 (95% confidence interval: 1.2-15.0, P=0.018) and 8.1 (95% confidence interval: 1.6-40.6, P=0.003), respectively. We concluded that the prevalence of heritable thrombophilia (34.0%) in Taiwan is higher than that in Western countries, but that it is lower than previously reported in Hong Kong and Taiwan. We attribute this to selection bias.

Treatment of classical type Kaposi's sarcoma with paclitaxel.

Paclitaxel has recently been shown to be effective in treating acquired immunodeficiency syndrome-associated Kaposi's sarcoma. We report good therapeutic effects of paclitaxel in two patients with classical form Kaposi's sarcoma (KS) which had poor or partial response to chemotherapy (vincristine, vinblastine, oncovin, bleomycin, epirubicin, dactinomycin, decarbazine) and interferon alpha-2b. Paclitaxel appears to be active against Kaposi's sarcoma as a single agent. The experience suggests that paclitaxel is an effective alternative in the treatment of classical form Kaposi's sarcoma.

Comparison of in vitro growth-inhibitory activity of carboplatin and cisplatin on leukemic cells and hematopoietic progenitors: the myelosuppressive activity of carboplatin may be greater than its antileukemic effect.

BACKGROUND: Carboplatin [cis-diammine(cyclobutane-1, 1-dicarboxylato)platinum(II)] has been shown to be an active agent for acute myeloid leukemia. This second-generation platinum drug has less nephrotoxicity and ototoxicity but more myelotoxicity than does the first-generation platinum drug cisplatin. The study was designed to elucidate whether their myelosuppressive activities equal their antileukemic effects. METHODS: Cisplatin and carboplatin were used to treat four leukemic cell lines (CEM, HL60, K562 and U937), blast cells from 10 leukemic patients and hematopoietic progenitors from five umbilical cord blood samples. RESULTS: The mean IC50 of leukemic cell lines was 0.4 and 6.2 microg/ml, the mean IC50 of patients' leukemic blasts was 2.0 and 22.4 microg/ml and the mean IC50 of hematopoietic progenitors (BFU-E, CFU-E and CFU-GM) was 1.8 and 1.7 microg/ml for cisplatin and carboplatin, respectively. CONCLUSIONS: Carboplatin required a 10 times higher drug concentration than cisplatin to induce a similar degree of growth inhibition on leukemic cells. However, the hematopoietic progenitors responded equally to cisplatin and carboplatin at the same drug concentration. The results suggest that the myelosuppressive activity of carboplatin is greater than its antileukemic effect.

Epstein-Barr virus-containing T-cell lymphoma and atherosclerotic abdominal aortic aneurysm in a young adult.

Malignant lymphoma infiltrating the abdominal aorta and resulting in an aortic aneurysm has never been documented. We report here a case of angiocentric T-cell lymphoma in a 33-year-old man who for months presented intermittent fever, splenomegaly, and an abdominal pulsatile mass. Angiography revealed extensive aneurysmal dilatation of the infrarenal abdominal aorta, bilateral iliac artery, and right common femoral artery. Splenic abscess and infected abdominal aortic aneurysm were initially suspected. An urgent splenectomy and aneurysmectomy with an aortic bifemoral bypass were performed. Pathological examination of the aortic aneurysm showed extensive necrosis, severe atherosclerosis, and lymphoma cell infiltration of the aortic wall. The lymphoid cells in the aorta and spleen were stained positive for CD45RO, CD56, and CD8, but negative for CD4 and CD19. Double-labeling immunohistochemistry and in situ hybridization using EBER1 for Epstein-Barr virus (EBV) revealed positive nuclear staining in the atypical T-lymphoid cells. This is the first definitive proof of peripheral T-cell lymphoma involving the abdominal aorta. Our evidence also supports that the EBV infection of T cells could be responsible for the atherosclerosis and hypertriglyceridemia, and the angiocentricity of the tumor cells apparently results in the presenting atherosclerotic aortic wall destruction, providing an additional causative concept for abdominal aortic aneurysm.

Leukemia cutis in acute lymphocytic leukemia masquerading as viral exanthem.

Leukemia cutis is a specific skin lesion caused by infiltration of leukemic cells into the skin. It is uncommon in acute lymphocytic leukemia (ALL). It typically manifests as red or violaceous papules, nodules, or plaques, mainly on the face. Leukemia cutis presenting with a generalized viral exanthem-like maculopapular eruption appears to be rare in the English literature. We report such a case. A 19 year-old man presented with a generalized purpuric maculopapular eruption of eight day's duration. Hematologic studies showed changes of acute lymphocytic leukemia, T-cell type. A skin biopsy specimen revealed a cuff-like, dense, perivascular infiltration of atypical lymphocytes in the upper and mid-dermis, consistent with leukemia cutis. The rash resolved in two weeks after chemotherapy. Our case illustrates that leukemia cutis should be considered in the differential diagnosis of a generalized morbilliform viral exanthem-like eruptions. Skin biopsy is important in establishing the diagnosis.

Bone marrow metastasis in nasopharyngeal cancer: early detection using EBER1 in situ hybridization.

BACKGROUND: Previous studies have reported the abundant expression of EBER1 in primary nasopharyngeal carcinoma (NPC) metastatic to lymph nodes and bone marrow (BM). This study was done to research the use of EBER1 in situ hybridization to detect micrometastasis in the marrow of NPC patients. PATIENTS AND METHODS: A total of 41 patients who underwent BM biopsy either for routine pretherapeutic evaluation or suspected bone marrow metastasis were enrolled for study. Thirty-two patients underwent BM biopsy for routine staging examination (Group I) and 10 were examined for unexplained cytopenia, leukoerythroblastosis, disseminated intravascular coagulation, or extensive bone metastasis (Group II). The authors applied EBER1 in situ hybridization to investigate the expression of EBER1 in 42 BM specimens. Examinations were performed on paraffin embedded tissues using polymerase chain reaction-derived, digoxigenin-labeled EBER1 DNA probes. RESULTS: Eight of 42 specimens (19%) were positive for BM metastasis. Just one (3%) had bone marrow involvement in Group I. However, seven (70%) were positive in Group II. All but one of them with bone marrow metastasis showed positive EBER1 in situ hybridization in the BM. Another patient suspected of having BM metastasis was negative for cytokeratin, but was positive for EBER1 in situ hybridization. CONCLUSION: Routine bone marrow study is not recommended in the staging of NPC, since only 3% of patients had BM metastasis. EBER1 in situ hybridization of marrow specimens cannot detect malignant cells earlier in NPC, but can be usefully applied to cases of equivocal marrow metastasis.

Bcl-2 and proliferating cell nuclear antigen (PCNA) expression correlates with subsequent local recurrence in nasopharyngeal carcinomas.

Many anticancer treatments, including radiation therapy, have been demonstrated to work through apoptosis. The treatment of choice on nasopharyngeal carcinoma (NPC), a radiosensitive tumor, is radiotherapy. Apoptosis therefore provides a good model to predict or re-evaluate the therapeutic response in NPC. Cellular genes such as p53 and bcl-2 have been shown to be involved in apoptosis. Proliferating cell nuclear antigen (PCNA) is a useful marker for proliferating cells. This study was designed to investigate whether the expression of p53, bcl-2 and PCNA, evaluated on tumor specimens obtained at diagnosis, is indicative of the subsequent local recurrence and distant metastasis following radiation therapy. We analyzed the expression of p53, bcl-2 and PCNA by immunohistochemical methods from NPC specimens prior to radiation therapy. A total of 63 T3/T4 NPC patients including 10 patients with local relapse (Group I), 19 patients with distant metastasis (Group II), and 34 disease-free patients (Group III) were assessed. Six of the 10 (60%) group I NPC, 4 of the 19 (21.1%) group II NPC, and 13 of the 34 (38.2%) group III NPC exhibited positive p53 expression. For bcl-2 immunostaining, 8 of the 10 (80%) group I NPC, 10 of the 19 (52.6%) group II NPC, and 10 of the 34 (29.4%) group III NPC were positive. High PCNA labelling index was shown in 6 of the 10 (60%) group I NPC, 7 of the 19 (36.8%) group II NPC, and 5 of the 34 (14.7%) group III NPC. The bcl-2 and PCNA reactivity in NPC developing local recurrence after radiation therapy was significantly higher than that in the disease-free NPC (p < 0.05). These findings show that the overexpression of bcl-2 and high PCNA labelling index are probably related to local relapse in NPC patients receiving radiation therapy alone as primary treatment.

Relation of left atrial spontaneous echo contrast with prethrombotic state in atrial fibrillation associated with systemic hypertension, idiopathic dilated cardiomyopathy, or no identifiable cause (lone).

To investigate the association of left atrial (LA) spontaneous echo contrast with the hemostatic state in nonrheumatic atrial fibrillation (AF), we examined the plasma levels of prothrombin fragment 1+2 and fibrinopeptide A in 73 patients with chronic nonrheumatic AF undergoing transesophageal echocardiography and 38 age-matched normal subjects. The results support the theory that LA spontaneous echo contrast in nonrheumatic AF is associated with a hypercoagulable state, especially in patients with marked LA spontaneous echo contrast.

Selective IgA deficiency with recurrent vasculitis of the central nervous system.

We describe an unusual case of selective IgA deficiency complicated by recurrent vasculitis of the central nervous system (CNS). The patient suffered from two episodes of CNS vasculitis, one of which was located in the cerebrum and the other in the cerebellum. The vasculitic process resulted in brain tumor-like lesions shown by computed tomography. There was no evidence of associated connective tissue diseases. Vasculitis in other organs or tissues was not noted. This is the first detailed description in the English literature of pathologically proven CNS vasculitis in a patient with selective IgA deficiency. Our report demonstrates that isolated CNS angiitis can be a rare clinical feature of selective IgA deficiency.