Sestamibi SPECT in the detection of myocardial viability in patients with chronic ischemic left ventricular dysfunction: Comparison between visual and quantitative analysis

BACKGROUND: Technetium 99m sestamibi cardiac scintigraphy is widely used as a means of predicting myocardial viability in patients with chronic ischemic left ventricular (LV) dysfunction. No data are available comparing the results of visual and quantitative analysis of tomographic imaging in the assessment of myocardial viability. The aim of this study was to directly compare visual and quantitative analysis of resting sestamibi single photon emission computed tomography in the identification of viable myocardium in patients with chronic LV dysfunction. METHODS AND RESULTS: Sixty-five patients with an earlier myocardial infarction and LV dysfunction that had occurred within 1 week underwent echocardiography and resting sestamibi SPECT. In each patient, regional tracer distribution was visually assessed and quantitatively measured in 13 segments. Regional LV function was evaluated in corresponding segments by means of echocardiography. All patients underwent revascularization, and echocardiography was repeated 12 months later as a means of assessing the recovery of regional LV function. Among all akinetic or dyskinetic revascularized segments, 66 of 112 viable segments (59%) and 85 of 100 nonviable segments (81%) were identified by means of visual analysis. Eighty-two of 112 viable segments (73%; P<.05 vs. visual analysis) and 74 of 100 nonviable segments (74%; P = .3 vs. visual analysis) were identified by means of quantitative analysis, with a threshold of 55%. Receiver operating characteristic curve areas constructed by using visual and quantitative analyses for the detection of myocardial viability in all 212 akinetic or dyskinetic segments were 0.79+/-0.04 and 0.81+/-0.03, respectively (P = not significant). Overall concordance in the detection of myocardial viability between visual and quantitative analysis was observed in 165 of akinetic or dyskinetic dysfunctional segments (78%), with a kappa value of 0.6. CONCLUSIONS: The results of this study demonstrate that, in patients with chronic myocardial infarction and LV dysfunction, visual and quantitative analysis of sestamibi tomographic images at rest have similar overall accuracy in predicting the recovery of LV function after coronary revascularization procedures.     

Non-THC cannabinoids inhibit prostate carcinoma growth in vitro and in vivo: pro-apoptotic effects and underlying mechanisms

BACKGROUND AND PURPOSE

Cannabinoid receptor activation induces prostate carcinoma cell (PCC) apoptosis, but cannabinoids other than Δ⁹-tetrahydrocannabinol (THC), which lack potency at cannabinoid receptors, have not been investigated. Some of these compounds antagonize transient receptor potential melastatin type-8 (TRPM8) channels, the expression of which is necessary for androgen receptor (AR)-dependent PCC survival.

EXPERIMENTAL APPROACH

We tested pure cannabinoids and extracts from Cannabis strains enriched in particular cannabinoids (BDS), on AR-positive (LNCaP and 22RV1) and -negative (DU-145 and PC-3) cells, by evaluating cell viability (MTT test), cell cycle arrest and apoptosis induction, by FACS scans, caspase 3/7 assays, DNA fragmentation and TUNEL, and size of xenograft tumours induced by LNCaP and DU-145 cells.

KEY RESULTS

Cannabidiol (CBD) significantly inhibited cell viability. Other compounds became effective in cells deprived of serum for 24 h. Several BDS were more potent than the pure compounds in the presence of serum. CBD-BDS (i.p.) potentiated the effects of bicalutamide and docetaxel against LNCaP and DU-145 xenograft tumours and, given alone, reduced LNCaP xenograft size. CBD (1–10 µM) induced apoptosis and induced markers of intrinsic apoptotic pathways (PUMA and CHOP expression and intracellular Ca²⁺). In LNCaP cells, the pro-apoptotic effect of CBD was only partly due to TRPM8 antagonism and was accompanied by down-regulation of AR, p53 activation and elevation of reactive oxygen species. LNCaP cells differentiated to androgen-insensitive neuroendocrine-like cells were more sensitive to CBD-induced apoptosis.

CONCLUSIONS AND IMPLICATIONS

These data support the clinical testing of CBD against prostate carcinoma.

LINKED ARTICLE

This article is commented on by Pacher et al., pp. 76–78 of this issue. To view this commentary visit http://dx.doi.org/10.1111/j.1476-5381.2012.02121.x     

Hypogonadism in HIV-1-infected men is common and does not resolve during antiretroviral therapy

OBJECTIVES: To assess the prevalence of abnormal testosterone and gonadotropin values in HIV-infected men before and after 2 years of combination antiretroviral therapy (cART). DESIGN: Multicentre cohort of HIV-infected adults. METHODS: We identified 139 Caucasian antiretroviral-naive male patients who started zidovudine/ lamivudine-based cART that was virologically successful over a 2 year period. Ninety-seven were randomly chosen and plasma hormone determinations of free testosterone (fT) and luteinizing hormone (LH) at baseline and after 2 years of cART were evaluated. RESULTS: At baseline 68 patients (70%) had subnormal fT levels. In these, LH levels were low in 44%, normal in 47% and high in 9%. There was a trend for an association between lower CD4+ T-cell counts and hypogonadism. Most participants had normal FSH levels. No significant changes of fT, LH and FSH levels were observed after 2 years of cART. CONCLUSIONS: Low fT levels, mainly with normal or low LH levels and thus indicating secondary hypogonadism, are found in the majority of HIV-infected men and do not resolve during 2 years of successful cART.     

Gene Status in HER2 Equivocal Breast Carcinomas: Impact of Distinct Recommendations and Contribution of a Polymerase Chain Reaction‐Based Method

Background.

The primary objectives of this study on carcinomas with equivocal HER2 expression were to assess the impact of distinct recommendations with regard to identifying patients eligible for anti-HER2 agents by fluorescence in situ hybridization (FISH) and to elucidate whether multiplex ligation-dependent probe amplification (MLPA) may be of support in assessing HER2 gene status.

Methods.

A cohort of 957 immunohistochemistry-evaluated HER2-equivocal cases was analyzed by dual-color FISH. The results were assessed according to U.S. Food and Drug Administration (FDA) and European Medicines Agency (EMA) guidelines and American Society of Clinical Oncology (ASCO) and College of American Pathologists (CAP) 2007 and 2013 guidelines for dual- and single-signal in situ hybridization (ISH) assays. A subgroup of 112 cases was subjected to MLPA.

Results.

HER2 amplification varied from 15% (ASCO/CAP 2007 HER2/CEP17 ratio) to 29.5% (FDA/EMA HER2 copy number). According to the ASCO/CAP 2013 interpretation of the dual-signal HER2 assay, ISH-positive carcinomas accounted for 19.7%. In contrast with the ASCO/CAP 2007 ratio, this approach labeled as positive all 32 cases (3.34%) with a HER2/CEP17 ratio <2 and an average HER2 copy number ≥6.0 signals per cell. In contrast, only one case showing a HER2 copy number <4 but a ratio ≥2 was diagnosed as positive. MLPA data correlated poorly with FISH results because of the presence of heterogeneous HER2 amplification in 33.9% of all amplified carcinomas; however, MLPA ruled out HER2 amplification in 75% of ISH-evaluated HER2-equivocal carcinomas.

Conclusion.

The ASCO/CAP 2013 guidelines seem to improve the identification of HER2-positive carcinomas. Polymerase chain reaction-based methods such as MLPA can be of help, provided that heterogeneous amplification has been ruled out by ISH.     

Adenosquamous lung carcinomas: a histologic subtype with poor prognosis

Introduction

The aim of this study is to evaluate the prognostic factors and outcome of patients operated for adenosquamous (ADS) carcinoma of the lung, in comparison with adenocarcinoma (AD) and squamous cell carcinoma (SCC).

Methods

a retrospective review of our thoracic cancer surgical database for patients operated for ADS, SCC and AD between January, 1995 and December, 2009 was done.

Results

Forty-eight patients (39 males, 81.3%) had ADS; complete tumor resection and lymphadenectomy was accomplished in all patients. A higher stage at presentation was observed in ADS, as compared to AD or SCC (p = 0.0001). Three and 5-year survival rates were 25% and 15%. ADS overall survival was worse than AD or SCC (p = 0.0005). Three and 5-year survival rates of ADS Stage I were similar to those of Stage IIIA AD or SCC. More than half ADS patients developed distant metastases (MTS) or local recurrences. Brain MTS were the most frequent. Median survival for those patients was 8 ± 2.3 months. Postoperative platinum-based chemotherapy statistically improved patients survival (p = 0.02). In the multivariate analysis, the presence of MTS (p = 0.001), the tumor perineural invasion (p = 0.01) and the tumor stage (p = 0.0005) were factors associated with poor prognosis. Adjuvant chemotherapy was a significant positive prognostic factor (p = 0.00001).

Conclusions

ADS are uncommon and extremely aggressive lung tumors. Adjuvant chemotherapy should be administered even in Stage I radically resected tumors. A whole brain postoperative prophylactic radiotherapy could be proposed to reduce risk of developing brain MTS.     

Spontaneous Splenic Rupture in a Patient with Acute Lymphoblastic Leukemia of Burkitt Type

We describe a case of spontaneous splenic rupture occurred in a patient with acute lymphoblastic leukemia of Burkitt type before starting cytotoxic chemotherapy. Left hypochondrial pain radiating to the homolateral shoulder was the only clinical symptom. Emergency computed tomography showed splenic laceration and hemoperitoneum. The patient underwent immediate laparotomy with splenectomy and experienced an uneventful postoperative recovery. Eight days after surgery, chemotherapy could be administered and complete remission was achieved. Although spontaneous rupture of the spleen is rare in leukemia and related disorders, this diagnosis should be taken in account also when clinical symptoms are mild. Following immediate operative management, patients may completely recover and receive cytotoxic chemotherapy with substantial possibilities of achieving complete remission.     

Primary breast lymphoma: outcome of 7 patients and a review of the literature

Primary breast lymphomas (PBL) are uncommon neoplasms. Seven PBL were diagnosed between March 1993 and October 2002. A lumpectomy (n = 4) or radical mastectomy (n = 3) was performed; 5 patients were in clinical stage (CS) II and 2 in CS IV; 6 patients received the CEOP regimen (cyclophosphamide, vincristine, epirubicin and prednisone) after surgery and 4 also had additional radiotherapy; 1 patient did not receive any treatment after local excision. Five patients (71%) achieved complete remission and 2 (29%) partial remission, with an overall response rate of 100%. All remitter patients are alive and well after a median follow-up of 75 months (range 10 - 121 months). Two patients in partial remission died of progressive disease. After a median follow-up of 99 months (range 84 - 111 months) for surviving patients, the 10 year overall and disease-free survival rates are both 71%, with 5 patients well and still free of disease. We conclude that the optimal sequence of full-dose anthracycline-containing regimens and radiation therapy should be the treatment of choice for patients with PBL.     

Gefitinib (ZD1839): therapy in selected patients with non-small cell lung cancer (NSCLC)?

PURPOSE: To evaluate response rate, toxicity and epidermal growth factor (EGFR) mutations and gene copy number as outcome predictive factors in Italian patients with non-small cell lung cancer (NSCLC) treated with gefitinib (Iressa) in an expanded access program (EAP). PATIENTS AND METHODS: A total of 137 patients with advanced NSCLC received gefitinib as first line treatment or after failure of chemotherapy. In 43 cases, tissue specimens were available for EGFR status evaluation: immunohistochemical (IHC) for EGFR, fluorescence in situ hybridisation (FISH) or Chromogenic in situ hybridisation (CISH)-(ISH) analysis for EGFR and HER2 gene copy number, and PCR-DNA sequencing for mutational analysis of EGFR were performed. RESULTS: In the study population, response rate (PR) was 13%; disease stabilization (DS) 26%; overall disease control rate 39%; median survival 6.3 months and time to progression 2.7 months. Toxicity was mild (G3 skin toxicity in 3% and G3 liver toxicity in 4% of patients). An EGFR-mutation was detected in 9/43 patients: Eight deletions in exon 19 and 1 missense mutation in exon 21. Increased gene copy number for EGFR and/or HER2 was detected in 17/43 patients. Response rate was significantly higher in women, non-smokers, in mutation carriers than in wild type carriers, in EGFR-trisomy/polysomy carriers and HER2-trisomy/polysomy carriers. CONCLUSIONS: In this study, response rate and toxicity to gefitinib treatment were consistent with previously reported data for whites. Female gender, absence of smoking history, EGFR-mutations, EGFR and HER2-polysomy were significantly associated with response to gefitinib therapy in NSCLC patients.     

No longitudinal mitochondrial DNA sequence changes in HIV-infected individuals with and without lipoatrophy

The potential for mitochondrial (mt) DNA mutation accumulation during antiretroviral therapy (ART), and preferential accumulation in patients with lipoatrophy compared with control participants, remains controversial. We sequenced the entire mitochondrial genome, both before ART and after ART exposure, in 29 human immunodeficiency virus (HIV)-infected Swiss HIV Cohort Study participants initiating a first-line thymidine analogue-containing ART regimen. No accumulation of mtDNA mutations or deletions was detected in 13 participants who developed lipoatrophy or in 16 control participants after significant and comparable ART exposure (median duration, 3.3 and 3.7 years, respectively). In HIV-infected persons, the development of lipoatrophy is unlikely to be associated with accumulation of mtDNA mutations detectable in peripheral blood.