Pretreatment HIV-1 drug resistance in Argentina: results from a surveillance study performed according to WHO-proposed new methodology in 2014-15.

BACKGROUND: In Argentina, current national guidelines recommend starting with NNRTI-based regimens. Recently, there have been some local reports regarding concerning levels of NNRTI-transmitted resistance, but surveillance has never been carried out at a national level. OBJECTIVES: To determine the prevalence of HIV drug resistance in people starting ART in Argentina using a WHO-proposed methodology. METHODS: This was a cross-sectional, nationally representative study. Twenty-five antiretroviral-dispensing sites throughout the country were randomly chosen to enrol at least 330 persons starting ART, to generate a point prevalence estimate of resistance-associated mutations (RAMs) with a 5% CI (for the total population and for those without antiretroviral exposure). All consecutive patients older than 18 years starting or restarting ART in the chosen clinics were eligible. Samples were processed with Trugene and analysed using the Stanford algorithm. RESULTS: Between August 2014 and March 2015, we obtained 330 samples from people starting ART. The mean ±â€ŠSD age was 35 ±â€Š11 years, 63.4% were male, 16.6% had prior antiretroviral exposure and the median (IQR) CD4 count was 275 cells/mm3 (106-461). The prevalence of RAMs found was 14% (±4%) for the whole population (3% NRTI-RAMs; 11% NNRTI-RAMs and 2% PI-RAMs) and 13% (±4%) for those without prior antiretroviral exposure (3%, 10% and 2%, respectively). The most common mutation was K103N. CONCLUSIONS: This surveillance study showed concerning levels of HIV drug resistance in Argentina, especially to NNRTIs. Due to this finding, Argentina's Ministry of Health guidelines will change, recommending performing a resistance test for everyone before starting ART. If this is taken up properly, it also might function as a continuing surveillance tool.

Comparison of glomerular filtration rate estimates vs. 24-h creatinine clearance in HIV-positive patients.

BACKGROUND: Guidelines for kidney function monitoring and antiretroviral drug dosing are available and respectively refer to glomerular filtration rate and creatinine clearance (CrCl). OBJECTIVE: The aim of the study was to compare kidney function estimates vs. measured 24-h CrCl in HIV-infected subjects. METHODS: A cross-sectional design was used, with comparison of Cockcroft-Gault (CG), original and simplified modification of diet in renal disease (MDRD) equations vs. measured 24-h CrCl. Subjects were HIV-infected, 18-70 years old, without pre-existing kidney disease. RESULTS: Results are presented as mean (+/-standard deviation), unless otherwise stated. The study population consisted of 90 patients, of whom 71% were male, with a mean age of 45 years (+/-6.5 years). At the time of evaluation, the mean body mass index was 23 (+/-3.3); mean serum creatinine was 0.91 mg/dL (+/-0.2 mg/dL); and mean blood urea nitrogen (BUN) was 34.7 mg/dL (+/-10.6 mg/dL). Differences between paired methods were all significant (P<0.00001), except between CG and simplified MDRD (P=0.21; Pearson r=0.81). In univariate analysis, male gender, CD4 nadir, hepatitis B virus coinfection, BUN and current CD4 cell count showed a significant positive correlation (P<0.2) with the difference between measured 24-h CrCl and either CG or simplified MDRD estimates. In multivariate analysis, only BUN showed a significant positive correlation (P<0.05). CONCLUSIONS: Estimates were lower than the measurements of 24-h CrCl. Original MDRD estimates were lower than those with other equations. CG and simplified MDRD estimates showed a satisfactory correlation.

Differential diagnosis and management of focal ground-glass opacities.

Focal pulmonary ground-glass opacities (GGOs) can be associated with bronchioloalveolar carcinoma. The present retrospective study aimed to test the validity of a multistep approach to discriminate malignant from benign localised (focal) GGOs, identifies useful diagnostic features on computed tomography (CT), and suggests appropriate management guidelines. A stepwise approach, including oral antibiotics, follow-up high-resolution CT (HRCT) 40-60 days later and CT-guided core biopsy, was used. All cases with localised GGOs detected since 2001 were reviewed. CT features were described according to a structured scheme. In total, 40 patients were evaluated. Of these, 11 patients were diagnosed with benign GGOs, 19 patients had lung cancer and 10 were undetermined. Nonpolygonal shape, apparent radial growth and clear-cut margins were associated with a malignant histology. The specificity of CT findings was low. Diagnostic accuracy increased after oral antibiotics, follow-up HRCT and percutaneous core biopsy. Overall, 18 patients underwent surgery for lung cancer. In conclusion, malignant ground-glass opacities have a fairly typical appearance, but some benign lesions closely mimic their malignant counterparts. The stepwise approach adopted in the present study increased the diagnostic specificity and reduced time to definitive diagnosis. Segmentectomy might be the ideal resection volume for such tumours.

Effectiveness of stereotactic body radiotherapy in the treatment of inoperable early-stage lung cancer.

BACKGROUND: Non-small cell lung cancer (NSCLC) is the leading cause of cancer death worldwide. Stereotactic body irradiation offers a non-invasive treatment modality for patients with early stage NSCLC who are not amenable to surgery or other invasive approaches because of their poor medical condition. PATIENTS AND METHODS: Forty-three inoperable patients with NSCLC were treated with SBRT at our institution. A mean total dose of 30.5 Gy in 1-4 fractions was applied. The median follow-up duration was 14 months (range 6-36 months). RESULTS: The actuarial survival at two years was 53%: two patients died from cancer progression whereas a further 8 patients died from comorbidities. Acute toxicity was practically absent, with 7 (16.3%) patients suffering from grade 1 symptoms and two from (4.6%) grade II effects. At the time of this report, only 1 patient had grade II and 6 patients (13.9%) grade I chronic symptoms. CONCLUSION: Our results compare favourably with recently published studies and confirm that stereotactic radiotherapy has the potential to produce high local control rates with a low risk of lung toxicity in patients not amenable to curative resection. The low grade of side-effects is encouraging for shortening the treatment using a greater dose per fraction.

[Chest wall and vertebral en-bloc resection for sarcoma: ten-year experience]. / Toracectomia e vertebrectomia per sarcoma: dieci anni di esperienza.

AIM: We reviewed our ten-year experience with surgical en-bloc chest wall and vertebral resection for sarcoma invading the spine, and verified five-year survival and feasibility of this aggressive surgery. METHODS: From 1994 to 1999, 13 patients underwent surgical en-bloc resection for primary sarcoma of the chest wall involving the spine. Concurrent pulmonary resection was performed in 12 cases. A single hemi-vertebrectomy was performed in 2 patients, a triple hemi-vertebrectomy in 2, a complete vertebrectomy in 4, a triple complete vertebrectomy in 5. RESULTS: Significative morbidity occurred in 1 patient who had lower limbs paralysis (9%). Perioperative mortality occurred in 2 patients (15.4%): 1 operative death for bleeding and 1 patients for a adult respiratory distress syndrome (ARDS). The overall five-year survival was 30.8%, excluding the 2 perioperative deaths the five-year survival resulted 36.4%. CONCLUSIONS: In spite of the limited number of patients, the morbidity and mortality outcome and the five-year survival leads us to think that surgery is the main therapy for primary chest wall sarcomas involving the spine. En-bloc chest wall and vertebral resection is a safe and effective treatment.

K-ras and p16(INK4A)alterations in sputum of NSCLC patients and in heavy asymptomatic chronic smokers.

NSCLC rates among the most frequent and lethal neoplasm world-wide and a significant decrease in morbidity and mortality relies only upon effective early diagnostic strategies. We investigated K-ras mutations and p16(INK4A) hypermethylation in tumor tissue and sputum of 50 patients with NSCLC and correlated them with sputum cytology and with tumor staging, grading and location, to ascertain, in sputum, their potential diagnostic impact. The same genetic/epigenetic abnormalities and cytological features were also evaluated in sputum from 100 chronic heavy smokers. Genetic analysis identified molecular abnormalities in 64% tumors (14/50 K-ras mutations and 24/50 p16(INK4A) hypermethylation) and in 48% sputum (11/50 K-ras mutations and 16/50 p16(INK4A) hypermethylation). In tumors K-ras mutations and p16(INK4A) hypermethylation were mostly mutually exclusive, being found in the same patients in 3 cases only. Genetic abnormalities in sputum were detected only in molecular abnormal tumors. Molecular changes in sputum had rates of detection similar to cytology (42%) but the cyto-molecular combination increased the diagnostic yield up to 60%. Interestingly, the rate of detection of genetic changes in sputum of tumors at early stage (T1) was not significantly different from that of tumors at more advanced stage (T2-T4). In fact K-ras point mutations were frequently recognised in tumors at early stage while p16(INK4A) inactivation prevailed in tumors at advanced stage ( P=0.0063). As expected, diagnostic cytological findings were more frequently found in tumors at advanced stage (P=0.004). No correlation was found between tumor grading and location (central versus peripheral) and molecular changes. p16(INK4A) hypermethylation, but not K-ras mutations, was documented in sporadic cases of asymptomatic heavy smokers (4%) where it was uncoupled from cytological abnormalities. In conclusion the cyto-molecular diagnostic strategy adopted in this study was able to detect the majority of tumors but in order to be proposed as effective and early diagnostic tool, this molecular panel needs to be tested in prospective studies with adequate follow-up.

Activity of a specific inhibitor, gefitinib (Iressa, ZD1839), of epidermal growth factor receptor in refractory non-small-cell lung cancer.

BACKGROUND: Gefitinib (Iressa(TM), ZD1839) is an orally active, selective epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor. Phase I studies showed that it is well tolerated, with evidence of tumor regression in patients with advanced non-small-cell lung cancer (NSCLC). Therefore, we aimed to assess the antitumor activity and tolerability of gefitinib in a series of patients with previously treated, advanced NSCLC, as a part of a compassionate use program. PATIENTS AND METHODS: To be eligible, all patients were required to have histologically or cytologically proven advanced or metastatic NSCLC, prior chemotherapy with at least one cisplatin-containing chemotherapy regimen or contraindication to cytotoxic drugs, Eastern Cooperative Oncology Group performance status < or =2, and adequate hematological, renal and hepatic parameters. All patients provided signed informed consent. Patient re-evaluation was performed every 4-6 weeks. RESULTS: Seventy-three consecutive patients were enrolled. Response rate, including complete and partial response, was 9.6%; an additional 43.8% of patients achieved stable disease, for an overall disease control of 53.4%. EGFR1 status was evaluated by immunocytochemistry in 25 patients. According to EGFR1 immunoreactivity all responses were observed with medium/strong imunoreactivity while three out of four responses were observed in high expressive patients. Median survival for all patients was 4 months while it reached 6 months for patients with disease control. The 1-year survival rate was 13.1% for the entire series and 23.2% for patients with disease control. Non-hematological toxicity was generally mild. CONCLUSION: Gefitinib has promising activity with a good toxicity profile in patients with progressive NSCLC who have received one or two prior chemotherapy regimens. A possible relationship within response and EGFR1 expression is suggested.

Three-week versus four-week schedule of cisplatin and gemcitabine: results of a randomized phase II study.

BACKGROUND: The cisplatin and gemcitabine (GC) regimen is usually administered as a 4- or 3-week schedule; however, the best schedule to use is still unclear. We therefore started a randomized phase II trial to compare toxicity and dose intensity (DI) between these two GC schedules. PATIENTS AND METHODS: Ninety-six patients with non-small-cell lung cancer (NSCLC) and an additional 11 patients with an advanced epithelial neoplasm [bladder (n = 5), head and neck (n = 3), cervix (n = 1), esophageal (n = 1) or unknown primary carcinoma (n = 1)] were randomized to receive cisplatin 70 mg/m(2) intravenously on day 2 plus either gemcitabine 1000 mg/m(2) on days 1, 8 and 15 of a 28-day cycle or gemcitabine 1000 mg/m(2) on days 1 and 8 of a 21-day cycle. Planned DI (PDI) for the 4-week schedule was 750 mg/m(2)/week for gemcitabine and 17.5 mg/m(2)/week for cisplatin; for the 3-week regimen PDI was 666 mg/m(2)/week and 23 mg/m(2)/week for gemcitabine and cisplatin, respectively. RESULTS: From July 1998 to March 2000, 107 patients were randomized. Grade 3/4 neutropenia was observed in 27.8% of patients in the 3-week versus 22.5% in the 4-week arm (P = 0.69), while grade 3/4 thrombocytopenia was higher in the 4-week arm (29.5% versus 5.5% of patients; P = 0.14). A total of 398 cycles of therapy were delivered. Overall, 51% of cycles were modified in dose, timing or both in the 4-week arm, and 19% in the 3-week arm. The 21-day schedule of GC leads to a similar received DI of gemcitabine and higher cisplatin DI. Both regimens had activity in NSCLC, with a response rate of 39% (38% for the 4-week arm, and 42% for the 3-week arm). CONCLUSIONS: The 3-week schedule has similar DI to the 4-week schedule. However the 3-week regimen has a better compliance profile and a comparable response rate in NSCLC, supporting the use of such a schedule.

Thoracoscopic resection of an esophageal stromal tumor through the left pleural cavity.

We describe the technique for endoscopic removal of a stromal tumor of the lower third of the esophagus through the left thoracoscopic approach. The tumor resembled a leiomyoma and was classified as a borderline, potentially malignant lesion after thoracoscopic removal. The technique and clinical implications in such cases are discussed on the basis of current knowledge.

Bcl-2 protein and prognosis in patients with potentially curable non-small-cell lung cancer.

The bcl-2 proto-oncogene functions as a cell death suppressor, and its expression prolongs cell survival by blocking apoptosis. Data available on the clinical relevance of bcl-2 protein expression in patients with non-small-cell lung cancer (NSCLC) are controversial. We analysed the role of bcl-2 protein expression on 6-year relapse-free survival in 229 patients with stage I-IIIa NSCLC (101 squamous cell carcinomas and 128 adenocarcinomas) subjected to surgery, with curative intent. Immunohistochemical analysis was performed on archival material by using a monoclonal antibody anti-bcl-2 (clone 124). Bcl-2 protein expression, which was detected in 22% of the cases, was significantly related to stage, histology and grading, and was an indicator of clinical outcome. The probability of relapse-free survival at 6 years was longer for patients with bcl-2-positive tumours (74%) than for those with bcl-2-negative tumours (57%) (P=0.02). This finding was mainly evident for the subgroups of patients with stage IIIa tumours (P=0.05), squamous cell carcinoma (P=0.03) or moderately/poorly differentiated tumours (P=0.02). However, multivariate analysis by Weibull's regression model indicated that bcl-2 protein expression was not an independent prognostic risk factor in patients with curable NSCLC when the information provided by stage was available.

Sternal resection for primary or secondary tumors.

METHODS: From January 1980 to December 1993, 52 patients underwent surgical-resection for tumors involving the sternum. The series included 20 primary malignant tumors, 4 desmoid tumors, 2 malignant tumors infiltrating the sternum from adjacent organs, 19 local recurrences or metastases of breast tumors, and 7 metastases of other tumors. Total sternectomy was performed in 5 patients, subtotal sternal resection in 19, and partial resection (less than 50% of the sternum) in 28. Concurrent en bloc resection included anterior ribs in 37 patients, clavicle in 11, lung in 12 patients, pericardium in 7, and diaphragm in 2. The chest was reconstructed with prosthetic material and a myocutaneous flap in 26 patients (50%), prosthetic material only in 12 patients (23%), a myocutaneous flap in 5 patients (10%), and other techniques in the remaining patients. In 47 patients (90%) the resection was radical, and in the remaining 5 patients it was palliative. RESULTS: No perioperative deaths occurred. After a median follow-up of 39 months, the overall 3-year survival was 58% and the 5-year survival 46%, with a median survival of 50 months. In 24 patients with primary tumor the 5-year survival after radical resection was 63%, and in 23 patients with secondary invasion (direct extension or metastasis) the 5-year survival was 38% (median 35 months). In recurrent breast cancer the 5-year survival was 48% in patients with direct extension to the chest wall and 60% in patients with distant bone metastasis. CONCLUSIONS: Our experience demonstrates that sternal resection is a safe and effective treatment, which may improve the patient's quality of life and achieve a long-term survival not only in primary tumors but also in selected secondary malignant tumors of the sternum.

Long-term infusion in cancer chemotherapy with the Groshong catheter via the inferior vena cava.

AIMS AND BACKGROUND: Vascular access through a vein draining into the superior vena cava is commonly used for long-term infusion of drugs inr cancer chemotherapy; prolonged cannulation of the inferior vena cava is generally considered as having an excessively high complication rate. METHODS: Prolonged cisplatin infusion via the inferior vena cava by means of a Groshong catheter was evaluated in 20 consecutive patients with thoracic malignancies showing evidence of superior vena cava infiltration or obstruction. RESULTS: We achieved 1,291 catheter days for our survey with a mean duration of vascular access of 64.5 days per patient and a mean duration of infusion time of 40 days. There were 2 complications, a catheter obstruction after a 7-day rest period and an ileo-femoral thrombosis 6 days after catheter placement. CONCLUSIONS: Our experience compared favourably with the results obtained by long-term central venous access via the supraumbilical route, and demonstrated the reliability and safety of this approach in cases where the superior vena cava cannulation is technically difficult or impossible.

P53 expression, DNA ploidy and S-phase cell fraction in operable locally advanced non-small-cell lung cancer.

The identification of biomarkers to complement pathological stage for a more accurate prognosis and help clinicians decide on treatment is still an open problem for patients with lung cancer. Expression of P53 protein was detected by an immunohistochemical approach using the monoclonal antibody PAb1801 on paraffin-embedded sections of tumours obtained surgically from 102 stage II - IIIa patients with non-small-cell lung cancer (52 squamous cell carcinomas, 50 adenocarcinomas). [3H]Thymidine labelling index, an indicator of the S-phase cell fraction, was evaluated on histological sections of [3H]thymidine-labelled tumour samples. DNA ploidy was defined by flow cytometric analysis on frozen tumour tissue. The biomarkers, histology and pathological stage were analysed in relation to relapse-free survival in univariate and multivariate analyses. Stage and interaction between [3H]thymidine labelling index and histology provided significant prognostic information for the overall series. [3H]thymidine labelling index was an independent prognostic indicator of 3 year relapse-free survival in patients with adenocarcinoma. The results indicate the importance of cell proliferation to complement prognostic information provided by pathological stage in patients with stage II-IIIa adenocarcinomas.

Conservative management of esophageal leaks by transluminal endoscopic drainage of the mediastinum or pleural space.

BACKGROUND: The management of postoperative leaks into the mediastinum or pleural cavities after esophageal surgery yields unsatisfactory results. A recently described method, drainage of the mediastinum or pleural cavity through suture line defects, has been used in our department with eight patients. METHODS: A suction tube was advanced over an endoscopically placed guide wire into the abscess from inside the esophagus, and gentle aspiration was used to remove saliva and secretions. Intravenous antibiotics and total parenteral nutrition were also given. RESULTS: The sepsis was rapidly controlled, and the abscess cavity progressively collapsed in all cases. Seven patients recovered and were discharged 34 to 61 days after operation; one died of concomitant complications. CONCLUSIONS: This method seems promising for the management of intrathoracic esophageal leaks.

Ambulatory low-toxicity chemotherapy in non-small-cell lung carcinoma by continuous 28-day infusion of alternating cisplatin and 5-fluorouracil.

BACKGROUND: One regimen consisting of a continuous infusion of cisplatin and fluorouracil was designed to be minimally toxic, and suitable for application with radiotherapy in non-small-cell lung carcinoma (NSCLC). PATIENTS AND METHODS: Forty-four NSCLC patients received daily 8 mg/m2 of cisplatin on days 1-2, 8-9, 15-16, 22-23, and 300 mg/m2 of fluorouracil on days 3-7, 10-14, 17-21, 24-28 (35-day courses). RESULTS: Two patients experienced grade 3-4 toxicities. Eleven achieved objective responses. The median progression-free and observed survival was 22 and 39.5 weeks. CONCLUSIONS: The schedule management was fully ambulatory. Toxicity was negligible. The activity was moderate, but the combination with radiotherapy is advisable due to the radioenhancing properties of both of the drugs.

A summary of the Milan experience with multimodality therapies in patients with small cell lung cancer: attempts to improve long-term outcome.

From February 1985 to June 1993, 173 consecutive, previously untreated patients with small cell lung cancer received individualized treatment tailored to disease extent. Almost all patients (14 of 16) with stage I and II disease and 30 patients with operable stage III disease were submitted to surgery preceded or followed by chemotherapy. Chest irradiation and prophylactic brain radiotherapy (in complete responders) were administered at the end of treatment in 42 of 44 cases. Patients with inoperable limited disease received chemotherapy followed by radiotherapy in 67 of 71 cases, while chemotherapy alone or followed by radiotherapy in sites of either initially bulky or residual disease was administered to 58 patients with extensive disease. The overall response rate was 77% (complete response, 45%; partial response, 32%). Complete responses were documented more frequently in limited disease than in extensive disease (57% v 22%; P < .001). The 2- and 5-year freedom from progression rates (24% and 16%, respectively), as well as overall survival rates (31% and 16%, respectively) were significantly affected by disease extent. No patient with extensive disease was progression free and alive at 2 years, while more than half of stage I and II patients were disease free and alive at 5 years. This retrospective analysis performed on a large number of consecutive, nonrandomized patients suggests that, at least in patients with limited disease, it is possible to achieve favorable long-term results using treatment tailored to disease extent. Nonetheless, the disappointing results commonly achieved in the treatment of small cell lung cancer strongly support the need for either prospective, randomized studies to confirm recently reported improved results or new pilot studies with investigation of entirely innovative approaches.

Determination of platinum in plasma of patients affected by inoperable lung carcinoma treated with radiotherapy and concurrent low-dose continuous infusion of cis-dichlorodiammine platinum(II).

Platinum microquantities were determined in plasma of patients affected by lung carcinoma during treatment with radiotherapy (RT) and concurrent low-dose continuous infusion of cis-dichlorodiammineplatinum(II) (CDDP). RT was given at 50 Gy in continuous course; CDDP was continuously infused at 4 mg/m2 daily for 100 h/week for 5 weeks, and the infusions were separated by 68 h of rest. The percentage of free drug versus total drug in plasma was about 3%. It did not vary with therapy duration and was not significantly different from that found in 5-day continuous infusions at much higher daily doses. Nevertheless, maximal values of free Pt in plasma were very low and agreed with the low level of CDDP toxicity encountered on the present administration schedule.

Cyfra 21-1 - a new tumor-marker for lung-cancer.

Among 20 known cytokeratins, cytokeratin fragment 19 is a 40 kD acidic molecule whose distibution is restricted to simple or pseudo-stratified epitelia, such as the epithelial layer of the bronchial tree. An immunoradiometric assay, CYFRA 21-1, was used to detect a fragment of cytokeratin 19 in the serum of 90 subjects and compared with serum levels of CEA, NSE and TPA. Sixty-seven consecutive patients with lung cancer and 23 healthy subjects were tested. Cut-off values for tumor markers were considered as the 95% of specificity versus controls. There were 32 adenocarcinomas, 29 squamous carcinomas and 6 other tumors. Increased serum levels of CYFRA 21-1 were found in lung cancer patients compared to controls [1.6 (0.2-3.2) versus 0.5 (0.2-1.8): p<0.001]. In our study TPA was more sensitive than CYFRA 21-1: 49% versus 40%; when we combined both markers the sensitivity increased to 63%. Significant difference in values were found before and after surgery in serum levels of 34 operated patients: p<0.01. We found higher levels of soluble cytokeratin 19 in lung cancer patients and in the adenocarcinoma subgroup. This study does not support the exclusive use of soluble cytokeratin 19 as a specific marker of lung cancer and not only in squamous carcinoma subgroup. This suggested that diagnostic and prognostic sensitivity increase when CYFRA 21-1 and TPA or other markers are combined.