Rifampicin-moxifloxacin interaction in tuberculosis treatment: a real-life study.

SETTING: Rifampicin (RMP) has been reported to reduce moxifloxacin (MFX) levels, which may interfere with the effectiveness of MFX in treating tuberculosis (TB). OBJECTIVE: To study the MFX-RMP interaction in patients receiving MFX with or without RMP as part of their anti-tuberculosis treatment regimen. DESIGN: Patients with pulmonary TB followed up by the Tuberculosis Out-patient Clinic of the Pulmonary Department, Aristotle University of Thessaloniki, Greece, who underwent treatment with MFX during the periods 1 May 2012-30 April 2014 and 1 January-31 March 2015, were included in the study. MFX levels were compared between 12 patients who were receiving RMP (Group 1) and 10 who were not (Group 2). RESULTS: The participants did not significantly differ in body mass index, days of MFX treatment or MFX dose/kg. Neither the peak concentration (Cmax) nor the 24 h area under the curve (AUC24) differed significantly between the two groups (Group 1, Cmax median 3.9 [range 1.9-4.5] mg/l; AUC24 29.1 [10-47.4] mg·h/l and Group 2, Cmax 4.1 [2-6.4] mg/l; AUC24 36.5 [14.6-54.2] mg·h/l). CONCLUSION: Although a decrease in MFX exposure was observed in the RMP-treated group, the effect was lower than previously reported in a real-life setting. The large variability observed in MFX pharmacokinetics in both groups may suggest the need for dose readjustment in some patients, regardless of RMP co-administration.

Intratumoral gene therapy versus intravenous gene therapy for distant metastasis control with 2-diethylaminoethyl-dextran methyl methacrylate copolymer non-viral vector-p53.

Lung cancer still remains to be challenged by novel treatment modalities. Novel locally targeted routes of administration are a methodology to enhance treatment and reduce side effects. Intratumoral gene therapy is a method for local treatment and could be used either in early-stage lung cancer before surgery or at advanced stages as palliative care. Novel non-viral vectors are also in demand for efficient gene transfection to target local cancer tissue and at the same time protect the normal tissue. In the current study, C57BL/6 mice were divided into three groups: (a) control, (b) intravenous and (c) intatumoral gene therapy. The novel 2-Diethylaminoethyl-Dextran Methyl Methacrylate Copolymer Non-Viral Vector (Ryujyu Science Corporation) was conjugated with plasmid pSicop53 from the company Addgene for the first time. The aim of the study was to evaluate the safety and efficacy of targeted gene therapy in a Lewis lung cancer model. Indeed, although the pharmacokinetics of the different administration modalities differs, the intratumoral administration presented increased survival and decreased distant metastasis. Intratumoral gene therapy could be considered as an efficient local therapy for lung cancer.

2-diethylaminoethyl-dextran methyl methacrylate copolymer nonviral vector: still a long way toward the safety of aerosol gene therapy.

Revealing the lung tumor genome has directed the current treatment strategies toward targeted therapy. First line treatments targeting the genome of lung tumor cells have been approved and are on the market. However, they are limited by the small number of patients with the current investigated genetic mutations. Novel treatment administration modalities have been also investigated in an effort to increase the local drug deposition and disease control. In the current study, we investigated the safety of the new nonviral vector 2-diethylaminoethyl-dextran methyl methacrylate copolymer (DDMC; Ryujyu Science), which belongs to the 2-diethylaminoethyl-dextran family by aerosol administration. Thirty male BALBC mice, 2 month old, were included and divided into three groups. However, pathological findings indicated severe emphysema within three aerosol sessions. In addition, the CytoViva technique was applied for the first time to display the nonviral particles within the pulmonary tissue and emphysema lesions, and a spectral library of the nonviral vector was also established. Although our results in BALBC mice prevented us from further investigation of the DDMC nonviral vector as a vehicle for gene therapy, further investigation in animals with larger airways is warranted to properly evaluate the safety of the vector.

Multidrug-resistant tuberculosis in an adult with cystic fibrosis.

Mycobacterium tuberculosis infection in patients with cystic fibrosis (CF) is rare. We report a 22-year-old CF patient with high fever, dyspnea and weight loss that progressively worsened over 2 weeks before admission. The patient suffered from liver cirrhosis, was colonized with Pseudomonas aeruginosa and had been repeatedly hospitalized for pulmonary infections. The patient was treated initially as for an exacerbation of P. aeruginosa infection, but tuberculosis (TBC) was suspected due to lack of improvement. A CT of the chest revealed enlarged bilateral cavities in the upper and middle lobes. A tuberculin skin test was positive, and M. tuberculosis nucleic acid was isolated from sputum samples. After receiving first-line anti-TBC drugs for 1 month, the patient's condition continued to worsen so molecular drug susceptibility testing was performed. Multidrug-resistant TBC was discovered, leading to a change in regimen. The patient was treated with ethionamide, moxifloxacin, linezolid, amikacin, imipenem/cilastatin and rifabutin and showed a remarkable clinical improvement. Although nontuberculous mycobacteria are more common in CF, the possibility of TBC should not be ignored. In that setting, early suspicion of infection due to resistant M. tuberculosis can be life saving.

Management of malignant pleural effusion by suicide gene therapy in advanced stage lung cancer: a case series and literature review.

Gene therapy can be defined as the transfer of genetic material into a cell for therapeutic purposes. Cytosine deaminase (CD) transferred into tumor cells by an adenoviral vector (Ad.CD), can convert the antifungal drug fluorocytosine (5-FC) to the antimetabolite 5-fluorouracil (5-FU), which kills not only the transfected tumor cells but also their neighbors by the so-called 'bystander effect'. After testing a protocol for Ad.CD transfer and lung tumor burden control in a Lewis mouse model, we used this technique in the management of lung cancer patients with malignant pleural effusion (MPE): two cases are presented investigating the possible enhancement of anticancer effect in both non-small-cell lung cancer (NSCLC) and small-cell lung cancer (SCLC) by local activation of the pro-drug 5-FC. Results were discussed in parallel to a literature review on the topic. 5-FC and Ad.CD were administered intratumorally to Lewis mouse lung carcinoma and the effect was monitored by tumor size and electromicroscopy. Two patients with advanced stage lung cancer (1SCLC, 1NSCLC), which developed MPE during first-line treatment were administered 10(12) plaque-forming unit (pfu) Ad.CD by intrapleural instillation, in two doses (day 1 and day 7). Instillation was performed when the pleural fluid was ≤200 ml. In addition, they received 5-FC 500 mg four times daily for 14 days. Lung tumor regression and successful transfer of adenoviral particles were observed in treated animals. Patients presented complete regression of pleural effusion as monitored by computerized tomography scan. Neutrapenia and anemia were the most severe adverse effect presented (grade III/grade IV 100%). The increased toxicity followed by the intrapleural gene therapy indicates the augmentation of anticancer effect of transformed pro-drug 5-FC to active 5-FU. The obtained data indicate that intrapleural gene therapy may be a useful tool, adjunct to chemotherapy, in the management of MPE related to lung cancer.

Long acting somatostatin analogues in combination to antineoplastic agents in the treatment of small cell lung cancer patients.

BACKGROUND: Long acting somatostatin analogues combined with platinum analogues have demonstrated an antiproliferative effect on growth of human SCLC xenographs. METHOD: 130 previously untreated SCLC patients--54 with limited disease (LD) and positive somatostatin receptors were included in the study. All patients performed 111In-Octreotide scanning before chemotherapy (CHT), every 3 months and up to 4 times. All patients were treated with paclitaxel 190 mg/m2+carboplatin AUC=5.5 for up to 6 cycles. 47/130 patients (Group A, control group) received only CHT. Forty eight hours after each CHT 43/130 patients (Group B) were also administered 30 mg somatuline® (lanreotide) by a single subcutaneous (s.c.) injection to stimulate somatostatin receptors (SSTRS) for 2 weeks. 40/130 patients (Group C) received 60 mg somatuline® autogel to stimulate SSTRS for 4 weeks. Patients in Groups A and B after the completion of the CHT continued maintenance therapy with somatuline. NSE, IGF1, VEGFA, VEGFC, VEGFR2, HER2 levels were monitored. In histological samples Bcl-2 and VEGF were also explored by immunohistochemistry. RESULTS: No statistically significant differences were observed between the 3 Groups regarding LD and extensive disease (ED) patient ratios, age and PS. Group B had a survival benefit in comparison to Groups A and C (p=0.029). LD patients of Group B had a significant benefit compared to Groups A and C (p=0.012, Breslow test). In LD Group B had a significant longer TTP (p=0.02) in comparison to Groups A and C. Adverse effects had no statistically significant difference between the Groups and toxicity was well managed. INTERPRETATION: Long acting somatostatin analogues could be used as an additive therapy in combination to antineoplastic agents in patients positive for somatostatin receptors. A dose of 30 mg improved survival only in LD SCLC patients.

Macrolides: from in vitro anti-inflammatory and immunomodulatory properties to clinical practice in respiratory diseases.

BACKGROUND: Macrolides have long been recognised to exert immunomodulary and anti-inflammatory actions. They are able to suppress the "cytokine storm" of inflammation and to confer an additional clinical benefit through their immunomodulatory properties. METHODS: A search of electronic journal articles was performed using combinations of the following keywords: macrolides, COPD, asthma, bronchitis, bronchiolitis obliterans, cystic fibrosis, immunomodulation, anti-inflammatory effect, diabetes, side effects and systemic diseases. RESULTS: Macrolide effects are time- and dose-dependent, and the mechanisms underlying these effects remain incompletely understood. Both in vitro and in vivo studies have provided ample evidence of their immunomodulary and anti-inflammatory actions. Importantly, this class of antibiotics is efficacious with respect to controlling exacerbations of underlying respiratory problems, such as cystic fibrosis, asthma, bronchiectasis, panbrochiolitis and cryptogenic organising pneumonia. Macrolides have also been reported to reduce airway hyper-responsiveness and improve pulmonary function. CONCLUSION: This review provides an overview on the properties of macrolides (erythromycin, clarithromycin, roxithromycin, azithromycin), their efficacy in various respiratory diseases and their adverse effects.

A 26-year-old male with mesothelioma due to asbestos exposure.

Mesothelioma is a malignancy with poor prognosis, with an average 5-year survival rate being less than 9%. This type of cancer is almost exclusively caused by exposure to asbestos. A long exposure can cause mesothelioma and so can short ones, as each exposure is cumulative. We report a case of a 26-year-old male who was exposed to asbestos during his primary school years from the age of 6 to 12. Although the tumor mainly affects older men who in their youth were occupationally exposed to asbestos, malignant mesothelioma can also occur in young adults. A medical history was carefully taken and asbestos exposure was immediately mentioned by the patient. We conducted biopsy on the right supraclavicular lymph node. The patient was not a candidate for surgery, and chemotherapy treatment was initiated. While patient's chemotherapy is still ongoing, no other similar cases of students or teachers have been traced up to date from his school. The school building was demolished in January 2009.

Acute respiratory distress due to thymoma in a patient treated with TK inhibitor: a case report and review of the current treatment options.

Thymic malignancies are rare intrathoracic tumors that may be aggressive and difficult to treat in advanced stage. Surgery is the cornerstone of the management of thymomas: it is significant for the definite histopathological diagnosis and staging, and in most cases, it constitutes the first step of the treatment strategy. For patients with primary unresectable thymomas, the multimodal treatment schedule nowadays includes neoadjuvant chemotherapy, extensive surgery, adjuvant radiotherapy, and in some cases, adjuvant chemotherapy. A patient with a history of stage III COPD and an undiagnosed thoracic mass was admitted to the intensive care unit with acute respiratory distress. A radiologic evaluation by CT scan revealed a mass of 13 cm in diameter at the mediastinum. Fine needle aspiration was performed and revealed a thymoma. Due to poor performance status, the patient was not able to undergo surgery. He refused to be treated with neither chemotherapy nor radiotherapy, but due to EGFR overexpression, treatment with TK inhibitor was suggested. Fine needle aspiration biopsy is commonly used to identify metastasis to the mediastinum. However, it is less often employed as a primary diagnostic tool for tumors, particularly thymic neoplasms. The use of targeted therapies for the treatment of thymic malignancies has been described in the literature. Over the past years, significant efforts have been made to dissect the molecular pathways involved in the carcinogenesis of these tumors. Insights have been obtained following anecdotal clinical responses to targeted therapies, and large-scale genomic analyses have been conducted.

Exophthalmos as a first manifestation of small cell lung cancer: a long-term follow-up.

Small cell lung cancer is characterized by rapid growth and early metastasis. Despite its sensitivity to cytotoxic therapy, until now treatments have failed to control or cure this disease in most patients. Orbital metastases are a rare manifestation of systemic malignancies. Breast and lung cancers represent more than two thirds of the primary cancer sites. Metastases to the eye and orbit develop in approximately 0.7-12% of patients with lung cancer. Here, we report a rare case of exophthalmos as the first manifestation of a metastatic carcinoma due to small cell lung cancer, and a 6-months follow-up with complete exophthalmic response to chemotherapy.

The role of surgery in the management of malignant pleural mesothelioma.

Malignant pleural mesothelioma (MPM) is a relatively rare multifocal pleural tumor with low metastatic potential. Surgery can be used in MPM for diagnostic and therapeutic purposes. Thoracoscopy is a useful tool to obtain tissue biopsy to establish a definitive diagnosis and to perform talc poudrage of the pleural cavity in order to prevent reaccumulation of fluid. Cytoreductive procedures, such as pleurectomy/ decortication (PD) and extrapleural pneumonectomy (EPP) are also used in multimodal treatment protocols. The available evidence until now suggests that EPP offers better palliation of dyspnea and orthopnea due to a trapped lung and ventilation perfusion mismatch and better adjuvant radiation therapy planning when compared to PD. Better local disease control and obvious survival benefit by using EPP instead of PD are at the moment unproven. However, EPP is connected with high mortality and morbidity rates, especially if performed in centers without expertise with this complex procedure. EPP and thoracoscopic parietal pleurectomy are now tested in two ongoing prospective randomized trials for their efficacy in the treatment of this disease. In the absence of any controlled randomized trial, EPP should be considered as part of the treatment of MPM only within the context of a prospective randomized trial or in special centers with expertise in the procedure and always within a tri-modal or four-modal treatment protocol, including also chemotherapy, radiotherapy, intrapleural immunochemotherapy and laser photodynamic therapy.

Topotecan-carboplatin-etoposide combination as 1st line treatment in patients with small cell lung cancer.

PURPOSE: To test toxicity, tolerability, time to progression, survival and response rate in the 3-day administration of topotecan (T) followed by carboplatin (C), and then etoposide (E) in a study for small cell lung cancer (SCLC) treatment. PATIENTS: 44 chemotherapy-naive patients with SCLC (median age 63.5, PS 0-1). ED was present in 28 patients. METHODS: Each treatment cycle consisted of T (0.8 mg/m(2) on days 1-3), C (AUC=5, day 3) and a standard oral dose of E (100mg on days 15-17). Cycles were repeated every 32 days and up to eight were performed. Responders received radiotherapy to the primary site (50 Gy) after the 4th cycle and complete responders also received PCI. RESULTS: Complete response (CR) was achieved in 4 patients, partial response (PR) in 18, stable disease in 10 and PD in 12. Median survival was 280 (+/-36.7) days and median time to progression 137 days. 11 patients developed grade 3/4 neutropenia and 3 patients grade 3/4 anaemia. Non-haematological toxicity was mild. CONCLUSION: In contrast to ORR, PFS and survival were quite similar to those of SCLC patients suffering from ED treated by a platinum-etoposide regimen. The T/C/E combination was well tolerated and with low toxicity, but without improvement in the ORR and survival in comparison to platinum analogue regimes.

Hypoxemia: an early indication of pigeon breeders' disease. Clinical and laboratory findings among pigeon breeders in the Salonica area.

The purpose of this study is to identify pathological findings among pigeon breeders in the Salonica area. Fifty-four volunteer breeders with varying intensity of contact with pigeons participated in the study. All the breeders, after filling in a questionnaire that included questions about the existence of conjunctivitis, rhinitis, chronic cough and sputum, were subjected to clinical examination and spirometric, hematological (arterial and venous), radiographic and immunologic tests. Twenty-five point nine percent of the breeders suffered from conjunctivitis, 31.5% from rhinitis and 33.3% from chronic cough and sputum. Fourteen point eight percent of them had class I precipitins, 7.4% had class II, 5.6% had class III and 16.7% had class IV and a positive correlation of precipitin class with the number of pigeons bred was found. Seven breeders (13%) had hypoxemia at rest and other 8 (14.8%) presented with hypoxemia after the exercise testing. Two breeders presented with a combination of findings of allergic alveolitis that satisfied the criteria of the Pigeon Breeders' Disease (PBD). A substantial number of the examined pigeon breeders were sensitized to pigeon serum antigens. Arterial hypoxemia, either at rest and/or after exercise was observed in 27.8% of breeders. Three point seven percent of breeders presented with clinical and laboratory findings consistent with PBD. Chronic cough and sputum in pigeon breeders should be considered as a possible manifestation of PBD.

Thoracic splenosis twenty-nine years after traumatic splenectomy mimicking intrathoracic neoplasm.

Thoracic splenosis refers to a condition of ectopic splenic tissue in the thoracic cavity. It is usually a consequence of splenic tissue seeding in the pleural cavity after thoracoabdominal trauma. A rare case of thoracic splenosis, in a 62-year-old man who had had a traumatic splenectomy due to thoracoabdominal trauma 29 years earlier, is reported. The patient, a heavy smoker, was admitted for evaluation of a left-side thoracic lesion discovered on a plain chest film. Bronchoscopy, CT scan and needle biopsy proved inconclusive for the diagnosis. Exploratory thoracotomy was necessary to establish the diagnosis. During the operation, a thoracic splenosis was confirmed. To date, only 28 cases of thoracic splenosis have been reported in the literature. The purpose of this report is to present a new case of splenosis of the thoracic cavity simulating intrathoracic neoplasm.

Oral vinorelbine in combination with cisplatin: a novel active regimen in advanced non-small-cell lung cancer.

BACKGROUND: A phase II trial of alternating i.v. and oral vinorelbine in combination with cisplatin was designed to determine the response rate, safety profile, progression-free survival, overall survival and quality of life (QoL) in advanced non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Fifty-six chemotherapy-naïve patients received cisplatin 100 mg/m(2) and i.v. vinorelbine 25 mg/m(2) on day 1, followed by oral vinorelbine 60 mg/m(2) on days 8, 15 and 22, every 28 days. RESULTS: After an independent review, the response rate was 33% [95% confidence interval (CI) 20% to 46%]. Median progression-free and overall survival were 5.5 months (95% CI 3.7-6.4) and 8.9 months (95% CI 8.8-11.7), respectively. The most frequent hematological toxicities were neutropenia (grade 3-4 in 73% of patients) and anemia (grade 3-4 in 11% of patients). Grade 3-4 infections and non-hematological toxicities occurred occasionally. QoL for lung cancer related symptoms was stable or improved. CONCLUSIONS: The efficacy and safety of the alternating vinorelbine schedule (i.v. on day 1, oral on days 8, 15 and 22) in combination with cisplatin in advanced NSCLC are similar to those of the standard regimen using exclusively i.v. vinorelbine, whereas ease of administration and patient comfort may favor the novel approach.

A Phase II study of docetaxel and carboplatin in the treatment of non-small cell lung cancer.

We investigated the efficacy of docetaxel (D) in combination with carboplatin (C) in the treatment of non-small cell lung cancer (NSCLC) patients. Since 1996, 123 with inoperable NSCLC were enrolled in the study; 120 (108 males, 12 females; mean age 58.0+/-8.3 years) were evaluated. Of those, 46 patients had squamous carcinoma, 44 adenocarcinoma, 11 large cell carcinoma and 19 undifferentiated tumours. Eligibility criteria included, documented inoperable NSCLC, WHO performance status (PS) 0-1, age up to 70 years, and normal renal and hepatic function. A total of 622 cycles of chemotherapy (CHT) (median 7 (95% CI 6.2-7.47), courses per patient) were administered. Each cycle consisted of 100 mg/m(2) of docetaxel in a 2-h infusion with C at a dose of area under the curve (AUC) of 6 on day 1. This regimen was repeated every 28 days up to eight cycles. Of the patients, five (4%) achieved complete response, 49 (40%) partial response, 47 (39%) had stable disease and 19 (15%) had progressive disease. The median survival was 12 months for all patients, 12 for the four patients with stage IIb disease, 18 for the patients with stage IIIa disease, 20 for the 29 patients with stage IIIb disease, and 11 for the 65 stage IV patients. The median time to progression was 8 months (90 patients). Toxicity was, grade 3/4 neutropenia, 18 patients (15%); grade 3/4 anaemia, 6 patients (5%); and tolerable peripheral neuropathy, 16 patients (13.3%). Responders received radiotherapy (total dose, 50 Gy in 4 weeks) between the 6th and 8th cycle. Among responders with initial stage IIIb disease, 7 (5%) underwent surgical resection. Patients with early progression of the disease received the same dose of radiotherapy between 2nd and 3rd cycle. The study is ongoing, and six patients (5%) are still alive (after 3 years). Preliminary results indicate that the D/C combination is very active in the treatment of NSCLC with tolerable toxicity. It appears that this drug combination is also good as neoadjuvant therapy in inoperable NSCLC patients.

Management of chemotherapy-related anaemia with low-dose recombinant human erythropoietin in patients with small cell lung cancer.

We examined the efficacy of low-dose erythropoietin in the management of chemotherapy-related anaemia in patients with small cell lung cancer (SCLC). We gave recombinant human erythropoietin A (rHuEPO) to 63 SCLC patients, 30 with limited disease (LD) and 33 with extensive disease (ED) who underwent chemotherapy with carboplatin, etoposide and ifosfamide and had previously received blood transfusions for chemotherapy-related anaemia. rHuEPO was given at a dose of 2000 IU subcutaneously three times per week for 2 weeks after every chemotherapy cycle, starting 48 h after the end of chemotherapy. Before the use of rHuEPO, all patients in both groups had to be transfused after a mean of 5.5 CT cycles. In 64 CT cycles following administration of rHuEPO, only 5/30 LD patients (17%) had to be transfused in six cycles (9%). In 88 cycles following the use of rHuEPO, 7/33 ED patients (21%) had to be transfused in 11 cycles (12.5%). Haemoglobin values in patients with ED (but not those with LD) were significantly improved after rHuEPO administration on both day 14 and day 28 after chemotherapy. No adverse effects were recorded. rHuEPO considerably decreased the degree of anaemia and the need for blood transfusion at doses markedly lower (25-30 IU/kg body weight) than those reported in the literature so far (150 IU/kg body weight), without toxicity.

Interferon alpha-2a and combined chemotherapy as first line treatment in SCLC patients: a randomized trial.

BACKGROUND: Interferons (IFNs) are known to act synergistically with antineoplastic agents when applied to SCLC cell cultures. This study was conducted in order to detect the clinical benefits, if any, of the addition of IFN-alpha in the induction chemotherapy (CT) of SCLC patients. PATIENTS AND METHODS: Ninety previously untreated patients with SCLC were randomly assigned to receive either CT alone (arm A) or CT plus IFN alpha-2a in a dose of 3 MU/m2 twice weekly (arm B). CT for both arms consisted of carboplatin 420 mg/m2, etoposide 200 mg/m2 and ifosfamide 3.5 g/m2 or epirubicin 80 mg/m2 every 28 days for a total of eight cycles. Responding patients received primary site and prophylactic cranial irradiation and then had maintenance CT with cyclophosphamide 100 mg/m2/day for 20 days every month. Patients in arm B received IFN throughout these treatments. RESULTS: Eighty-one patients were evaluable for response, 39 in arm A and 42 in arm B. Both arms were comparable in terms of age, performance status and extent of disease. Overall response rates were not significantly different between the two arms (90% vs. 86%), although complete response rate was higher in arm B (38% vs. 28%). More importantly, Kaplan-Meier analysis disclosed a clear survival benefit in the arm receiving IFN-alpha (P < 0.05). For limited disease the difference was even more significant (P < 0.0067), while for extensive disease no significant difference was found (P < 0.35). Fever, fatigue and anorexia were more frequent in arm B (P < 0.001), as also leukopenia (P < 0.01). CONCLUSION: The addition of IFN-alpha to induction CT appears to confer a survival benefit to SCLC patients but optimal dosing schedule has yet to be defined.