Aurelio Ariza

A Randomized Trial Comparing Preoperative Chemotherapy Plus Surgery with Surgery Alone in Patients with Non-Small-Cell Lung Cancer

BACKGROUND The efficacy of surgery for patients with non-small-cell lung cancer is limited, although recent studies suggest that preoperative chemotherapy may improve survival. We conducted a randomized trial to examine the possible benefit of preoperative chemotherapy and surgery for the treatment of patients with non-small-cell lung cancer. METHODS We studied 60 patients (59 men and 1 woman) with stage IIIA non-small-cell lung cancer. The patients were randomly assigned to receive either surgery alone or three courses of chemotherapy (6 mg of mitomycin per square meter of body-surface area, 3 g of ifosfamide per square meter, and 50 mg of cisplatin per square meter) given intravenously at three-week intervals and followed by surgery. All patients received mediastinal radiation after surgery. The resected tumors were evaluated by means of K-ras oncogene analysis and flow cytometry. RESULTS The median period of survival was 26 months in the patients treated with chemotherapy plus surgery, as compared with 8 months in the patients treated with surgery alone (P < 0.001); the median period of disease-free survival was 20 months in the former group, as compared with 5 months in the latter (P < 0.001). The rate of recurrence was 56 percent in the group treated with chemotherapy plus surgery and 74 percent in the group treated with surgery alone. The prevalence of mutated K-ras oncogenes was 15 percent among the patients receiving preoperative chemotherapy and 42 percent among those treated with surgery alone (P = 0.05). Most of the patients treated with chemotherapy plus surgery had tumors that consisted of diploid cells, whereas the patients treated with surgery alone had tumors with aneuploid cells. CONCLUSIONS Preoperative chemotherapy increases the median survival in patients with non-small-cell lung cancer.

Pretreatment EGFR T790M Mutation and BRCA1 mRNA Expression in Erlotinib-Treated Advanced Non–Small-Cell Lung Cancer Patients with EGFR Mutations

Purpose: Advanced non–small-cell lung cancer (NSCLC) patients harboring epidermal growth factor receptor (EGFR) mutations (deletion in exon 19 or L858R) show an impressive progression-free survival of 14 months when treated with erlotinib. However, the presence of EGFR mutations can only imperfectly predict outcome. We hypothesized that progression-free survival could be influenced both by the pretreatment EGFR T790M mutation and by components of DNA repair pathways. Experimental Design: We assessed the T790M mutation in pretreatment diagnostic specimens from 129 erlotinib-treated advanced NSCLC patients with EGFR mutations. The expression of eight genes and two proteins involved in DNA repair and four receptor tyrosine kinases was also examined. Results: The EGFR T790M mutation was observed in 45 of 129 patients (35%). Progression-free survival was 12 months in patients with and 18 months in patients without the T790M mutation (P = 0.05). Progression-free survival was 27 months in patients with low BRCA1 mRNA levels, 18 months in those with intermediate levels, and 10 months in those with high levels (P = 0.02). In the multivariate analysis, the presence of the T790M mutation (HR, 4.35; P = 0.001), intermediate BRCA1 levels (HR, 8.19; P < 0.0001), and high BRCA1 levels (HR, 8.46; P < 0.0001) emerged as markers of shorter progression-free survival. Conclusions: Low BRCA1 levels neutralized the negative effect of the T790M mutation and were associated with longer progression-free survival to erlotinib. We advocate baseline assessment of the T790M mutation and BRCA1 expression to predict outcome and provide alternative individualized treatment to patients based on T790M mutations and BRCA1 expression. Clin Cancer Res; 17(5); 1–9. ©2011 AACR.

Gastrointestinal Involvement in Mantle Cell Lymphoma: A Prospective Clinic, Endoscopic, and Pathologic Study

The frequency of gastrointestinal (GI) tract involvement in mantle cell lymphoma (MCL) at diagnosis is reported to be below 30%. To investigate the actual frequency of GI involvement by MCL, upper and lower endoscopy was prospectively performed on 13 untreated MCL patients at diagnosis. Multiple biopsies from endoscopically normal and abnormal gastric and colonic mucosa were studied with immunohistochemistry (IHC) for CD20, CD5, and cyclin D1, as well as fluorescence in situ hybridization (FISH) for t(11;14) and polymerase chain reaction (PCR) for immunoglobulin heavy chain gene. Abnormal mucosa was identified in 38% of cases by upper endoscopy (mainly mild nonspecific gastritis) and in 54% of cases by lower endoscopy (mostly micropolyps). Histologically, infiltration by MCL was demonstrated in the stomach in 77% of cases and in the colon in 77% of cases. As a whole, 92% of patients showed upper or lower GI tract infiltration by MCL. Histologic evidence of MCL involvement was present in all cases with endoscopically abnormal mucosa, but it was also observed in two-thirds of cases with endoscopically unremarkable mucosa. Positive cyclin D1 IHC was seen in all instances displaying CD20 and CD5-positive lymphoid infiltrates, whereas t(11;14) was demonstrated by FISH in 63.5% and PCR was clonal in 64% of those instances. In conclusion, the great majority of MCL patients showed GI tract involvement at the time of diagnosis, not uncommonly in the form of minute lymphoid infiltrates. IHC for cyclin D1 was significantly more sensitive than FISH t(11;14) or PCR for immunoglobulin heavy chain gene to confirm MCL in this setting.

Desmin myopathy: a multisystem disorder involving skeletal, cardiac, and smooth muscle

Myopathy associated with desmin-type intermediate filaments is an uncommon disorder of skeletal and/or cardiac muscle. The present study focuses on a 28-year-old man with generalized muscular atrophy, cardiomyopathy, and intestinal malabsorption and pseudo-obstruction. Abundant sarcoplasmic granular and filamentous aggregates that were ultrastructurally continuous with Z lines or dense bodies and exhibited intense immunostaining for desmin were present throughout the skeletal musculature, myocardium, and smooth muscle of the intestine. Moreover, neurofilament-immunoreactive axonal spheroids were identified in the spinal cord and roots. These widely distributed findings illustrate the multisystemic character of desmin myopathy, which in this instance first adds intestinal smooth muscle involvement to its already known skeletal and cardiac muscle manifestations. The additional presence of neurofilament aggregates in the spinal cord and roots constitutes an extremely rare conjunction of intermediate filament pathology of the neuromuscular system.

Antimalarial myopathy: an underdiagnosed complication? Prospective longitudinal study of 119 patients

Objectives: To evaluate the prevalence and incidence of antimalarial myopathy in patients with rheumatic diseases treated with antimalarial drugs. Methods: Over a three year period, all patients with rheumatic diseases who were taking antimalarial drugs were studied. Serum muscle enzymes were assessed at the time of inclusion and every six months thereafter. Muscle strength, electromyography (EMG), and muscle biopsy were assessed in patients with a persistent muscle enzyme disturbances. Results: 119 patients were included (111 chloroquine, eight hydroxychloroquine). Of these, 22 (18.5%) had a persistent muscle enzyme disturbance: lactate dehydrogenase 19/22 (86%); creatine kinase 7/22 (32%), and aldolase 3/22 (14%). Findings of antimalarial myopathy were detected in 3/15 biopsied patients (20%) by light microscopy and in all 15 by electron microscopy. Eleven patients had myopathy at the time of inclusion (prevalence 9.2%) and four patients developed muscle injury during follow up (annual incidence 1.2%). Muscle weakness was observed in 8 of 15 patients with biopsy proven myopathy, giving a prevalence of clinical antimalarial myopathy of 6.7%. All these patients also had a myopathic pattern on electromyography. Conclusions: The prevalence of antimalarial myopathy is higher than previously recognised when muscle enzyme determination is used as a screening method. When a persistent muscle enzyme disturbance is observed, clinical and electromyographic studies should be undertaken periodically to detect the development of clinical myopathy. In cases of clinical myopathy, an anatomical-pathological tissue study, including an ultrastructural study, is mandatory to confirm the diagnosis.

Widespread Bronchogenic Dissemination Makes DBA/2 Mice More Susceptible than C57BL/6 Mice to Experimental Aerosol Infection with Mycobacterium tuberculosis

ABSTRACT We have used the murine model of aerosol-induced experimental tuberculosis to assess the effects of four clinical isolates and a reference strain of Mycobacterium tuberculosis on resistant C57BL/6 mice and susceptible DBA/2 mice. Histological studies and detection of 25 cytokines potentially involved in the infection were carried out. DBA/2 mice showed higher concentrations of bacilli in bronchoalveolar lavage fluid and lung tissue. Furthermore, these mice evidenced a larger granulomatous infiltration in the parenchyma due to an increased rate of emigration of infected foamy macrophages from the granulomas to the neighboring pulmonary alveolar spaces. The better control of bacillary concentrations and pulmonary infiltration observed in C57BL/6 mice from week 3 postinfection could result from their higher RANTES, ICAM-1, and gamma interferon (IFN-γ) mRNA levels. On the other hand, the higher MIP-2 and MCP-3 mRNA levels seen in DBA/2 mice would result in stronger lung recruitment of macrophages and neutrophils. Additionally, DBA/2 mice showed increased inducible nitric oxide synthase expression, induced by the larger number of foamy macrophages, at weeks 18 and 22. This increment was a consequence of phagocytosed bacillary debris, was independent of IFN-γ expression, and could exert only a bacteriostatic effect. The results of the study suggest that DBA/2 mice are more susceptible than C57BL/6 mice to M. tuberculosis infection due to a higher bronchial dissemination of bacilli inside poorly activated foamy macrophages.

Actinic keratosis with atypical basal cells (AK I) is the most common lesion associated with invasive squamous cell carcinoma of the skin

Progression from actinic keratosis (AK) to invasive squamous cell carcinoma (iSCC) of the skin is thought to occur after the development of full thickness epidermal neoplasia, as in the classic pathway of cervical cancer. Nevertheless, cutaneous iSCC may also directly arise from a proliferation of atypical basaloid cells limited mostly to the epidermal basal layer (AK I), akin to what happens in the ‘differentiated pathway’ of iSCC of the vulva, oral cavity and other locations.

Expression profiles associated with aggressive behavior in Merkel cell carcinoma

Primary neuroendocrine carcinoma of the skin, or Merkel cell carcinoma, is the most aggressive cutaneous neoplasm. In spite of its similarities to small cell carcinomas from other locations, Merkel cell carcinoma shows many peculiarities probably related to its epidermal origin and the etiologic role of UV radiation. We have immunohistochemically investigated 43 markers on a tissue microarray in which 31 surgically resected Merkel cell carcinomas were represented. Of these, 15 patients remained free of disease after removal, whereas 16 developed metastases. Immunoreactivity was scored according to staining intensity and the percentage of positive cells. We found statistically significant correlations between metastatic tumor spread and overexpression of matrix metalloproteinase (MMP) 7, MMP10/2, tissue inhibitor of metalloproteinase 3, vascular endothelial growth factor (VEGF), P38, stromal NF-kappaB, and synaptophysin. Also detected were statistically significant correlations between the expression levels of MMP7 and VEGF, MMP7 and P21, MMP7 and P38, MMP10/2 and VEGF, P38 and synaptophysin, P38 and P53, and P21 and stromal NF-kappaB. These findings may be helpful in predicting the clinical course of Merkel cell carcinoma and are potentially useful for the development of targeted therapies.

Neuroendocrine differentiation as a prognostic factor in non-small cell lung cancer

The prognostic value of clinical and pathological factors in 97 patients with non-small cell lung cancer (NSCLC), were analyzed through immunohistochemical methods. The impact on response rate and survival of age, Karnofsky performance status (PS), sex, NSCLC subtype and grade, extent of disease, objective chemotherapy response, LDH values, metastatic sites involved and immunohistochemical markers of neuroendocrine differentiation (neuron specific enolase (NSE), synaptophysin (Sy 38), chromogranin (Chr A) and Leu-7) were analyzed. Median age was 61 years and seven patients were women. Histologically, 58 had squamous cell carcinoma, 28 adenocarcinoma and 11 large cell undifferentiated carcinoma. One patient had Stage II, 35 Stage IIIa, 19 Stage IIIb and 42 Stage IV. Six patients achieved complete response, 18 partial response, 34 stable disease and 39 progressive disease. NSE was negative in 54.3% of cases as was Sy 38 (77.4%), Chr A (97.8%) and Leu-7 (95.8%). We have found correlation between neuroendocrine differentiation and absence of P-Glycoprotein expression; patients included in this subset had a higher response rate but no evidence of longer survival. The univariate analysis showed that four parameters had significant adverse effect on survival: non-responders, poor PS, abnormal LDH value and absence of NSE expression. Multivariate analysis showed that the best combination of independent prognostic factors in predicting survival was: PS and NSE expression by immunohistochemical methods.

Alpha-Synuclein Posttranslational Modification and Alternative Splicing as a Trigger for Neurodegeneration

Lewy body diseases include Parkinson disease and dementia with Lewy bodies and are characterized by the widespread distribution of Lewy bodies in virtually every brain area. The main component of Lewy bodies is alpha-synuclein (AS). Accumulating evidence suggests that AS oligomerization and aggregation are strongly associated with the pathogenesis of Lewy body diseases. AS is a small soluble protein with aggregation-prone properties under certain conditions. These properties are enhanced by posttranslational modifications such as phosphorylation, ubiquitination, nitration, and truncation. Accordingly, Lewy bodies contain abundant phosphorylated, nitrated, and monoubiquitinated AS. However, alternative splicing of the AS gene is also known to modify AS aggregation propensities. Splicing gives rise to four related forms of the protein, the main transcript and those that lack exon 4, exon 6, or both. Since AS structure and properties have been extensively studied, it is possible to predict the consequences of the splicing out of the two aforesaid exons. The present review discusses the latest insights on the mechanisms of AS posttranslational modifications and intends to depict their role in the pathogenesis of Lewy body diseases. The implications of deregulated alternative splicing are examined as well, and a hypothesis for the development of the pure form of dementia with Lewy bodies is proposed.