Oxidative Stress, Inflammatory, Angiogenic, and Apoptotic molecules in Proliferative Diabetic Retinopathy and Diabetic Macular Edema Patients.

The aim of this study is to evaluate molecules involved in oxidative stress (OS), inflammation, angiogenesis, and apoptosis, and discern which of these are more likely to be implicated in proliferative diabetic retinopathy (PDR) and diabetic macular edema (DME) by investigating the correlation between them in the plasma (PLS) and vitreous body (VIT), as well as examining data obtained from ophthalmological examinations. Type 2 diabetic (T2DM) patients with PDR/DME (PDRG/DMEG; n = 112) and non-DM subjects as the surrogate controls (SCG n = 48) were selected according to the inclusion/exclusion criteria and programming for vitrectomy, either due to having PDR/DME or macular hole (MH)/epiretinal membrane (ERM)/rhegmatogenous retinal detachment. Blood samples were collected and processed to determine the glycemic profile, total cholesterol, and C reactive protein, as well as the malondialdehyde (MDA), 4-hydroxynonenal (4HNE), superoxide dismutase (SOD), and catalase (CAT) levels and total antioxidant capacity (TAC). In addition, interleukin 6 (IL6), vascular endothelial growth factor (VEGF), and caspase 3 (CAS3) were assayed. The VITs were collected and processed to measure the expression levels of all the abovementioned molecules. Statistical analyses were conducted using the R Core Team (2022) program, including group comparisons and correlation analyses. Compared with the SCG, our findings support the presence of molecules involved in OS, inflammation, angiogenesis, and apoptosis in the PLS and VIT samples from T2DM. In PLS from PDRG, there was a decrease in the antioxidant load (p < 0.001) and an increase in pro-angiogenic molecules (p < 0.001), but an increase in pro-oxidants (p < 0.001) and a decline in antioxidants (p < 0.001) intravitreally. In PLS from DMEG, pro-oxidants and pro-inflammatory molecules were augmented (p < 0.001) and the antioxidant capacity diminished (p < 0.001), but the pro-oxidants increased (p < 0.001) and antioxidants decreased (p < 0.001) intravitreally. Furthermore, we found a positive correlation between the PLS-CAT and the VIT-SOD levels (rho = 0.5; p < 0.01) in PDRG, and a negative correlation between the PSD-4HNE and the VIT-TAC levels (rho = 0.5; p < 0.01) in DMEG. Integrative data of retinal imaging variables showed a positive correlation between the central subfield foveal thickness (CSFT) and the VIT-SOD levels (rho = 0.5; p < 0.01), and a negative correlation between the CSFT and the VIT-4HNE levels (rho = 0.4; p < 0.01) in PDRG. In DMEG, the CSFT displayed a negative correlation with the VIT-CAT (rho = 0.5; p < 0.01). Exploring the relationship of the abovementioned potential biomarkers between PLS and VIT may help detecting early molecular changes in PDR/DME, which can be used to identify patients at high risk of progression, as well as to monitor therapeutic outcomes in the diabetic retina.

Mesenchymal stem cells provide paracrine neuroprotective resources that delay degeneration of co-cultured organotypic neuroretinal cultures.

Through the paracrine effects of stem cells, including the secretion of neurotrophic, immunomodulatory, and anti-apoptotic factors, cell-based therapies offer a new all-encompassing approach to treatment of neurodegenerative diseases. In this study, we used physically separated co-cultures of porcine neuroretina (NR) and human mesenchymal stem cells (MSC) to evaluate the MSC paracrine neuroprotective effects on NR degeneration. NR explants were obtained from porcine eyes and cultured alone or co-cultured with commercially available MSCs from Valladolid (MSCV; Citospin S.L.; Valladolid, Spain), currently used for several approved treatments. Cultures were maintained for 72 h. MSC surface markers were evaluated before and after co-culture with NRs. Culture supernatants were collected and the concentration of brain-derived neurotrophic factor (BDNF), ciliary neurotrophic factor (CNTF), and glial-derived neurotrophic factor (GDNF) were determined by enzyme-linked immunosorbent assays. NR sections were stained by haematoxylin/eosin or immunostained for terminal deoxynucleotidyl transferase dUTP nick end labelling (TUNEL), glial fibrillary acidic protein, ß-tubulin III, and neuronal nuclei marker. NR morphology, morphometry, nuclei count, apoptosis rate, retinal ganglion cells, and glial cell activation were evaluated. Treatment effects were statistically analysed by parametric or non-parametric tests. The MSCs retained stem cell surface markers after co-culture with NR. BDNF and CNTF concentrations in NR-MSCV co-cultures were higher than other experimental conditions at 72 h (p < 0.05), but no GDNF was detected. NR general morphology, total thickness, and cell counts were broadly preserved in co-cultures, and the apoptosis rate determined by TUNEL assay was lower than for NR monocultures (all p < 0.05). Co-cultures with MSCV also protected retinal ganglion cells from degenerative changes and reduced reactive gliosis (both p < 0.05). In this in vitro model of spontaneous NR degeneration, the presence of co-cultured MSCs retarded neuroglial degeneration. This effect was associated with elevated concentrations of the neurotrophic factors BDNF and CNTF. Our data suggest that the paracrine secretion of these, and possibly other molecules, are a potential resource for the treatment of several neuroretinal diseases.

Four lines of anaplastic lymphoma kinase inhibitors and brain radiotherapy in a long-surviving non-small-cell lung cancer anaplastic lymphoma kinase-positive patient with leptomeningeal carcinomatosis.

Lung cancer is the most common tumor and the leading cause of cancer-related death worldwide. Approximately 6.7% of non-small-cell lung cancers (NSCLCs) show anaplastic lymphoma kinase (ALK) rearrangement and could benefit from ALK-targeted treatment. Various anti-ALK drugs have been developed during the past years, but it is actually controversial which sequence and which ALK inhibitor is recommended for a single patient. Leptomeningeal carcinomatosis (LC) is associated with a poor prognosis, with an overall survival of 2-4 months for treated patients. The data about LC management derive mainly from retrospective studies, being an exclusion criterion for most trials. Intrathecal chemotherapy and whole-brain radiotherapy (WBRT), associated with a systemic treatment, are the most commonly used approach. Here we present a case of NSCLC harboring an ALK translocation treated with four lines of ALK inhibitors and receiving WBRT for LC, showing an overall survival of ∼5 years from the diagnosis of metastatic disease. This case report focuses mainly on several controversial clinical aspects, that is, the sequence of treatment in ALK-positive NSCLC, the ALK inhibitors' efficacy on brain disease and beyond progression, the management of LC, and the role of WBRT despite the risk of cognitive impairment.

Molecular Detection of EMT Markers in Circulating Tumor Cells from Metastatic Non-Small Cell Lung Cancer Patients: Potential Role in Clinical Practice.

BACKGROUND: Non-small cell lung cancer (NSCLC) is the most common cause of cancer-related mortality; nevertheless, there are few data regarding detection of circulating tumor cells (CTCs) in NSCLC, compared to other kinds of cancers in which their prognostic roles have already been defined. This difference is likely due to detection methods based on the epithelial marker expression which ignore CTCs undergoing epithelial-mesenchymal transition (CTCsEMT). METHODS: After optimization of the test with spiking experiments of A549 cells undergoing TGF-ß1-induced EMT (A549EMT), the CTCsEMT were enriched by immunomagnetic depletion of leukocytes and then characterized by a RT-PCR assay based on the retrieval of epithelial and EMT-related genes. Blood samples from ten metastatic NSCLC patients before starting treatment and during chemotherapy were used to test this approach by longitudinal monitoring. Ten age- and sex-matched healthy subjects were also enrolled as controls. RESULTS: Recovery experiments of spiked A549EMT cells showed that the RT-PCR assay is a reliable method for detection of CTCsEMT. CTCsEMT were detected in three patients at baseline and in six patients after four cycles of cysplatin-based chemotherapy. Longitudinal monitoring of three patients showed that the CTCsEMT detection is related to poor therapeutic response. CONCLUSIONS: The RT-PCR-based approach for the evaluation of CTCsEMT phenotype could be a promising and inexpensive tool to predict the prognosis and the therapeutic response in NSCLC patients.

Biocompatibility of intravitreal injection of human mesenchymal stem cells in immunocompetent rabbits.

PURPOSE: To evaluate the feasibility, safety, and biocompatibility of intravitreal injection of human mesenchymal stem cells (MSCs) in immunocompetent pigmented rabbits. MATERIALS AND METHODS: Thirty-two pigmented rabbits (24 females, 8 males; Chinchilla-New Zealand White) were divided into 8 groups of 4 animals. Commercially prepared human MSCs were injected (0.05 ml) into the post-lens vitreous of the right eyes. Groups 1 and 4 received isotonic medium (Ringer lactate-based), groups 2, 5, 7, and 8 received a low dose of 15 × 106 cells/ml. Groups 3 and 6 received a high dose of 30 × 106 cells/ml. Clinical signs were evaluated and scored before MSCs injection and weekly for 2 or 6 weeks. Animals were sacrificed at 2 or 6 weeks after injection. Eyes, liver, spleen, and gonads were assessed by histology and by fluorescent in situ hybridization to evaluate survival and extraocular migration of MSCs. RESULTS: There were no relevant clinical findings between control and MSC-injected rabbit eyes at any time point. There were also no relevant histological findings between control and MSC-injected rabbits related to ocular, liver, spleen, or gonad tissues modifications. MSCs survived intravitreally for at least 2 weeks after injection. Extraocular migration of MSCs was not detected. CONCLUSIONS: MSCs are safe and well-tolerated when administered intravitreally at a dose of 15 × 106 cells/ml in pigmented rabbits. These findings enable future research to explore the intravitreal use of commercially prepared allogenic human MSCs in clinical trials of retinal diseases.

Crizotinib plus radiotherapy in brain oligoprogressive NSCLC ROS1 rearranged and PD-L1 strong.

ROS1+ patients represent a unique molecular subset of non-small cell lung cancer (NSCLC). Early phase clinical trials have shown a high response rate to crizotinib in these patients. We describe a case of an 18 years old woman, never smoker, with NSCLC ROS1+ and miliary brain metastases treated with crizotinib and radiotherapy. From October 2014 to June 2015 the Patient was treated with crizotinib. The first intracranial time to progression (IT-TTP) occurred after 7 months; the patient underwent stereotactic radiosurgery (SRS) and continued TKI treatment. The second IT-TTP appeared after 16 months. A continued response in the chest was observed for all the 23 months of crizotinib treatment. At the progression, we assessed programmed death ligand 1 (PD-L1) expression by immunohistochemistry, that resulted highly expressed. Our report indicates that the integration of crizotinib with local treatments should be considered in ROS1 NSCLC patients experiencing oligometastatic progression. Moreover, this case is an example of PD-L1 strong in oncogene addicted patients.

Complete Tumor Response with Afatinib 20 mg Daily in EGFR-Mutated Non-small Cell Lung Cancer: A Case Report.

Afatinib, a second-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, is efficacious as first-line treatment in patients with EGFR-mutated non-small cell lung cancer (NSCLC). Dosage reduction is recommended in patients with intolerable adverse events; however, data regarding the efficacy of low-dose afatinib are limited. We report the case of a 71-year-old female patient who was diagnosed with advanced EGFR-mutated NSCLC and started treatment with oral afatinib 40 mg daily. The patient achieved partial tumor response on computed tomography imaging, but developed unacceptable skin-related toxicities requiring dosage reduction to 20 mg daily. The patient subsequently achieved complete tumor response and showed improvements in performance status. These observations suggest that low-dose afatinib is effective in patients with EGFR-mutated NSCLC who require dosage reduction for intolerable adverse events.

Classifications for Proliferative Vitreoretinopathy (PVR): An Analysis of Their Use in Publications over the Last 15 Years.

Purpose. To evaluate the current and suitable use of current proliferative vitreoretinopathy (PVR) classifications in clinical publications related to treatment. Methods. A PubMed search was undertaken using the term "proliferative vitreoretinopathy therapy". Outcome parameters were the reported PVR classification and PVR grades. The way the classifications were used in comparison to the original description was analyzed. Classification errors were also included. It was also noted whether classifications were used for comparison before and after pharmacological or surgical treatment. Results. 138 papers were included. 35 of them (25.4%) presented no classification reference or did not use any one. 103 publications (74.6%) used a standardized classification. The updated Retina Society Classification, the first Retina Society Classification, and the Silicone Study Classification were cited in 56.3%, 33.9%, and 3.8% papers, respectively. Furthermore, 3 authors (2.9%) used modified-customized classifications and 4 (3.8%) classification errors were identified. When the updated Retina Society Classification was used, only 10.4% of authors used a full C grade description. Finally, only 2 authors reported PVR grade before and after treatment. Conclusions. Our findings suggest that current classifications are of limited value in clinical practice due to the inconsistent and limited use and that it may be of benefit to produce a revised classification.

A novel coculture model of porcine central neuroretina explants and retinal pigment epithelium cells.

PURPOSE: To develop and standardize a novel organ culture model using porcine central neuroretina explants and RPE cells separated by a cell culture membrane. METHODS: RPE cells were isolated from porcine eyes, expanded, and seeded on the bottom of cell culture inserts. Neuroretina explants were obtained from the area centralis and cultured alone (controls) on cell culture membranes or supplemented with RPE cells in the same wells but physically separated by the culture membrane. Finally, cellular and tissue specimens were processed for phase contrast, cyto-/histological, and immunochemical evaluation. Neuroretina thickness was also determined. RESULTS: Compared to the neuroretinas cultured alone, the neuroretinas cocultured with RPE cells maintained better tissue structure and cellular organization, displayed better preservation of photoreceptors containing rhodopsin, lower levels of glial fibrillary acidic protein immunoexpression, and preservation of cellular retinaldehyde binding protein both markers of reactive gliosis. Neuroretina thickness was significantly greater in the cocultures. CONCLUSIONS: A coculture model of central porcine neuroretina and RPE cells was successfully developed and standardized. This model mimics a subretinal space and will be useful in studying interactions between the RPE and the neuroretina and to preclinically test potential therapies.

Pulmonary Fibrosis after Pegylated Liposomal Doxorubicin in Elderly Patient with Cutaneous Angiosarcoma.

Introduction. Angiosarcoma is a rare cancer of the inner lining of blood vessels and can arise anywhere in the body, most commonly presenting as cutaneous disease in elderly patient, involving head and neck (H&N), especially the scalp. Pegylated liposomal doxorubicin (PLD) is one of the available treatments in patients with advanced or metastatic disease. Common toxicities are myelosuppression, palmar-plantar erythrodysesthesia, nausea, and stomatitis. Regarding PLD-related pulmonary fibrosis in an uncommon toxicity, there are few cases reported in literature. None of these occurred in angiosarcoma. Methods. This is a case report describing an elderly patient treated with PLD for advanced H&N cutaneous angiosarcoma who developed G5 pulmonary toxicity after the second PLD administration. Results. According to our data and patient clinical outcome, we believe that she passed away from fatal PLD-induced pulmonary fibrosis. This is the first case of fatal interstitial pneumonitis in a 77-year-old woman treated with PLD for angiosarcoma. The case has been reported for its rarity. Conclusions. Pathophysiology of this phenomenon is still unclear and more studies are necessary to understand the true incidence of pulmonary toxicities in patients in treatments with PLD and its mechanism.

A rare case of palatin tonsillar metastasis from small cell lung cancer.

Tonsillar metastases are absolutely rare. Small cell lung cancer (SCLC) is known to be the most frequent histological type of tonsillar metastases, however the way of tumor cells spreading to tonsil remains controversial. We described a case report of 76-year-old man with SCLC and tonsillar metastases, to highlight the importance of oral cavity evaluation as a part of a clinical exam and to show the rare tumor cells spreading.

Unexpected long survival of brain oligometastatic non-small cell lung cancer (NSCLC) treated with multimodal treatment: a single-center experience and review of the literature.

Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related death worldwide. Fifty percent of the cases are metastatic at diagnosis and about 20% develop brain metastasis. The brain involvement represents a negative prognostic factor. However, some patients could benefit from locoregional treatments of metastatic foci and experience an unexpected long survival or healing. In the previous years some classifications were proposed to identify patients' prognostic category, according to stage of the primary tumor, the timing of metastases occurrence (synchronous or metachronous) and the number of metastatic sites. Several data show a benefit in patients receiving resection of both the primary tumor and brain metastases. Whole brain radiotherapy (WBRT) and stereotactic radiosurgery (SRS) are the selected options in most cases. Overall, literature data showed highly variable outcome, with an overall survival (OS) ranging from 5.9 to 68 months. No data from randomized and homogeneous trials are currently available. Therefore, a growing interest in this field is observed. Different trials investigating the effectiveness of local treatments and studies analyzing biological mechanisms are ongoing. In this report we analyze literature data and we explore the current field of study. Furthermore, we show a single institutional experience of multimodal management of stage IV NSCLC with brain metastases, experiencing an unexpected long survival. We conclude that a better knowledge of this subpopulation of patients and new studies in this field can lead to distinguish the patients who can benefit from local treatment from those with poor prognosis.

Proliferative vitreoretinopathy: A new concept of disease pathogenesis and practical consequences.

During the last four decades, proliferative vitreoretinopathy (PVR) has defied the efforts of many researchers to prevent its occurrence or development. Thus, PVR is still the major complication following retinal detachment (RD) surgery and a bottle-neck for advances in cell therapy that require intraocular surgery. In this review we tried to combine basic and clinical knowledge, as an example of translational research, providing new and practical information for clinicians. PVR was defined as the proliferation of cells after RD. This idea was used for classifying PVR and also for designing experimental models used for testing many drugs, none of which were successful in humans. We summarize current information regarding the pathogenic events that follow any RD because this information may be the key for understanding and treating the earliest stages of PVR. A major focus is made on the intraretinal changes derived mainly from retinal glial cell reactivity. These responses can lead to intraretinal PVR, an entity that has not been clearly recognized. Inflammation is one of the major components of PVR, and we describe new genetic biomarkers that have the potential to predict its development. New treatment approaches are analyzed, especially those directed towards neuroprotection, which can also be useful for preventing visual loss after any RD. We also summarize the results of different surgical techniques and clinical information that is oriented toward the identification of high risk patients. Finally, we provide some recommendations for future classification of PVR and for designing comparable protocols for testing new drugs or techniques.

Safety and Biocompatibility of a New High-Density Polyethylene-Based Spherical Integrated Porous Orbital Implant: An Experimental Study in Rabbits.

Purpose. To evaluate clinically and histologically the safety and biocompatibility of a new HDPE-based spherical porous orbital implants in rabbits. Methods. MEDPOR (Porex Surgical, Inc., Fairburn, GA, USA), OCULFIT I, and OCULFIT II (AJL Ophthalmic S.A., Vitoria, Spain) implants were implanted in eviscerated rabbis. Animals were randomly divided into 6 groups (n = 4 each) according to the 3 implant materials tested and 2 follow-up times of 90 or 180 days. Signs of regional pain and presence of eyelid swelling, conjunctival hyperemia, and amount of exudate were semiquantitatively evaluated. After animals sacrifice, the implants and surrounding ocular tissues were processed for histological staining and polarized light evaluation. Statistical study was performed by ANOVA and Kaplan-Meier analysis. Results. No statistically significant differences in regional pain, eyelid swelling, or conjunctival hyperemia were shown between implants and/or time points evaluated. However, amount of exudate differed, with OCULFIT I causing the smallest amount. No remarkable clinical complications were observed. Histological findings were similar in all three types of implants and agree with minor inflammatory response. Conclusions. OCULFIT ophthalmic tolerance and biocompatibility in rabbits were comparable to the clinically used MEDPOR. Clinical studies are needed to determine if OCULFIT is superior to the orbital implants commercially available.

Loss of Visual Acuity after Successful Surgery for Macula-On Rhegmatogenous Retinal Detachment in a Prospective Multicentre Study.

Purpose. To quantify the frequency of visual loss after successful retinal detachment (RD) surgery in macula-on patients in a multicentric, prospective series of RD. Methods. Clinical variables from consecutive macula-on RD patients were collected in a prospective multicentric study. Visual loss was defined as at least a reduction in one line in best corrected visual acuity (VA) with Snellen chart. The series were divided into 4 subgroups: (1) all macula-on eyes (n = 357); (2) macula-on patients with visual loss at the third month of follow-up (n = 53) which were further subdivided in (3) phakic eyes (n = 39); and (4) pseudophakic eyes (n = 14). Results. Fifty-three eyes (14.9%) had visual loss three months after surgery (n = 39 phakic eyes; n = 14 pseudophakic eyes). There were no statistically significant differences between them regarding their clinical characteristics. Pars plana vitrectomy (PPV) was used in 67.2% of cases, scleral buckle in 57.7%, and scleral explant in 11.9% (36.1% were combined procedures). Conclusions. Around 15% of macula-on RD eyes lose VA after successful surgery. Development of cataracts may be one cause in phakic eyes, but vision loss in pseudophakic eyes could have other explanations such as the effect of released factors produced by retinal ischemia on the macula area. Further investigations are necessary to elucidate this hypothesis.

Pharmacogenomics in lung cancer chemotherapy: a review of what the oncologist should know.

Lung cancer is the leading cause of cancer-related death around the world; the addition of chemotherapy to treatment of this disease has been shown to significantly increase progression-free survival and overall survival. Despite newer chemotherapies, it is important to personalize the care (treatment and dose) upon each single patient's susceptibility for controlling and reducing adverse side-effects, at best. The present review describes the current status of pharmacogenomics studies regarding germline DNA variants that may alter response and tolerability to chemotherapeutic agents used to treat lung cancer, including perspective studies.

Triple-layered mixed co-culture model of RPE cells with neuroretina for evaluating the neuroprotective effects of adipose-MSCs.

Mesenchymal stem cell (MSC) therapy is promising for neuroprotection but there is no report of an appropriate in vitro model mimicking the situation of the in vivo retina that is able to test the effect of MSCs in suspension or encapsulated with/without a drug combination. This study aims to establish a viable mixed co-culture model having three layers: neuroretina explants (NRs), retinal pigment epithelium (RPE) cells and adipose tissue-derived MSCs (AT-MSCs) for evaluating adipose-MSC effects. AT-MSCs were grown on the lower surface of a transwell membrane and RPE cells were grown on the bottom of a culture plate as monocultures. A transwell membrane was inserted into a culture plate well. NR was placed as an organotypic culture on the upper surface of the transwell membrane. Thus, a triple-layered co-culture setup was constructed. In double-layered setups, NR were co-cultured with AT-MSCs or RPE cells. Optimum medium, experiment execution period and transwell membrane permeability (TMP) were determined. MSC effects on RPE cell proliferation and NR reactive gliosis were evaluated. Limitations were discussed. Our study shows that neurobasal A with DMEM (1:1) mixed medium was suitable for viability of all three layers. AT-MSC growth decreased TMP significantly, 30-60 % in 3- to 6-day periods. Spontaneous NR reactive gliosis limits the experiment execution period to 6 days. AT-MSCs maintained their undifferentiated nature and showed no or limited neuroprotective effects. In this study, we successfully assembled viable double- and triple-layered co-culture setups for AT-MSCs, RPE and NR, optimised conditions for their survival and explored setup Limitations.

A Synchronous Pancreatic Metastasis from Renal Clear Cell Carcinoma, with Unusual CT Characteristics, Completely Regressed after Therapy with Sunitinib.

We present a case report of a 75-years-old woman affected by renal clear cell carcinoma with a synchronous pancreatic metastasis and a metachronous lung metastasis. This case has two peculiarities. First the pancreatic metastasis was treated just with medical therapy, that is, Sunitinib, instead of the surgical therapy that is mostly considered. Secondly, the pancreatic lesion showed different characteristics on the computed tomography scan compared to the usual pancreatic metastases from renal clear cell carcinoma. The pancreatic metastasis totally regressed after medical treatment and nowadays, four years after the diagnosis, the patient is disease-free.

The use of bevacizumab in non-small cell lung cancer: an update.

Lung cancer is the leading cause of cancer-related death worldwide, with approximately 1.2 million deaths annually. The standard-of-care in patients with advanced disease is platinum-based doublet chemotherapy. Recent advances in the understanding of biological mechanisms of tumor growth have allowed for identification of some molecular targets for cancer treatment, such as vascular endothelial growth factor (VEGF) and epidermal growth factor receptor (EGFR). VEGF is a pro-angiogenetic factor, which binds membrane receptors, and whose intra-cytoplasmatic domain presents tyrosine kinase activity. Pathological angiogenesis promotes tumor growth and metastasis. Targeted action against angiogenesis can lead to regression or normalization of neovascular structures and to inhibition of new blood vessel growth. The most commonly used mechanism is mediated by bevacizumab, a monoclonal antibody that selectively binds to VEGF and prevents interaction with its receptor. Currently bevacizumab is the only anti-angiogenic agent approved for the first-line treatment of non-small cell lung cancer (NSCLC) in selected patients. In the present review, we discuss the most important trials that demonstrate the efficacy and safety of bevacizumab. We also present an overview of the types of patients eligible for this treatment and a cost-effectiveness analysis. In conclusion, the possibility of administering a treatment with bevacizumab must be carefully analyzed case by case. It is important to identify those patients who can really benefit from the use of this drug, through the identification of specific response markers.

Esophageal stenosis: a differential diagnosis between esophageal cancer and metastasis from other neoplasia.

BACKGROUND: The occurrence of radiological mediastinal lymphadenopathy as the only evidence of tumor recurrence of cervical carcinoma is very rare. We report on such a case with stenosis of the esophagus. CASE REPORT: A 36-year-old Caucasian woman, without any relevant history of gynecological cancer, underwent a trans-vaginal ultrasound with evidence of any cervical lesion locally extended. After histologically-proven diagnosis of squamous cell carcinoma of the cervix uterine, the patient was treated by neoadjuvant chemoradiation, followed by total abdominal hysterectomy with bilateral salpingoophorectomy. A subsequent close follow-up was negative for recurrence of disease until December 2008, two years after diagnosis. At that period, the patient experienced cough and severe dysphagia and for this reason she underwent several examinations including esophagogastroduodenoscopy, whole-body computed tomographic scan and bronchoscopy with transbronchial needle aspiration. Histology led to diagnosis of recurrence of cervical cancer, HPV31-positive, in multiple mediastinal lymphnodes, with infiltration of the esophageal mucosa. CONCLUSION: Mediastinal lymphade-nopathy in patients with a history of cervical carcinoma should be suspicious of metastatic disease, even if there is no radiological evidence of distant metastases.