Neoadjuvant and Adjuvant Immunotherapy in Resectable NSCLC.

Non-small cell lung cancer, even when diagnosed in early stages, has been linked with poor survival rates and distant recurrence patterns. Novel therapeutic approaches harnessing the immune system have been implemented in early stages, following the designated steps of advanced NSCLC treatment strategies. Immune-checkpoint inhibitor (ICI) regimens as monotherapy, combinational, or alongside chemotherapy have been intensely investigated as adjuvant, neoadjuvant, and, more recently, perioperative therapeutic strategies, representing pivotal milestones in the evolution of early lung cancer management while holding great potential for the future. The subject of current ongoing research is optimizing treatment outcomes for patient subsets with different needs and identifying biomarkers that could be predictive of response while translating the trials' endpoints to survival rates. The aim of this review is to discuss all current treatment options with the pros and cons of each, persistent challenges, and future perspectives on immunotherapy as illuminating the path to a new era for resectable NSCLC.

A retrospective multicentric cohort study of checkpoint inhibitors-induced pruritus with focus on management.

BACKGROUND: Limited data on immune checkpoint inhibitor (ICI)-induced pruritus per se and efficacy of different therapeutic modalities in its management exist. OBJECTIVE: To study the quantitative and qualitative characteristics of ICI-induced pruritus per se and to assess the efficacy of the therapeutic modalities usually applied. METHODS: We retrospectively reviewed the records of 91 patients who were under treatment with ICIs for any kind of neoplasia and developed pruritus during treatment. RESULTS: Twenty out of 91 individuals (22.0%) with ICI-induced pruritus had pruritus as the only symptom, while 71/91 (78.0%) presented with pruritus coexisting with an additional cutaneous toxicity. Pruritus was treated with antihistamines (18/20, 90.0%) and/or topical regimens, as first-line choice. In resistant cases, as a second therapeutic intervention, narrow-band UVB (NBUVB), oral steroids and GABA analogs were added (70.0%). Statistical analysis revealed a significant difference in mean pruritus Numerical Rating Scale (NRS) scores between baseline and sequential visits. Moreover, subgroup analysis revealed a significant reduction in mean NRS scores in those treated with phototherapy. LIMITATIONS: Retrospective design, low number of patients and survivorship bias. CONCLUSION: Pruritus per se was present in a substantial portion of our cohort (22.0%). Our study confirms the efficacy of current treatment strategies and suggests NBUVB as a potential steroid-sparing therapeutic alternative.

Safety, Antitumor Activity, and T-cell Responses in a Dose-Ranging Phase I Trial of the Oncolytic Peptide LTX-315 in Patients with Solid Tumors.

PURPOSE: LTX-315 is a first-in-class, 9-mer membranolytic peptide that has shown potent immunomodulatory properties in preclinical models. We conducted a phase I dose-escalating study of intratumoral LTX-315 administration in patients with advanced solid tumors. PATIENTS AND METHODS: Thirty-nine patients were enrolled, receiving LTX-315 injections into accessible tumors. The primary objective was to assess the safety and tolerability of this approach, with antitumor and immunomodulatory activity as secondary objectives. Tumor biopsies were collected at baseline and posttreatment for analysis of immunologic parameters. RESULTS: The most common treatment-related grade 1-2 adverse events were vascular disorders including transient hypotension (18 patients, 46%), flushing (11 patients, 28%), and injection site reactions in 38% of patients. The most common grade 3 LTX-315-related toxicities were hypersensitivity or anaphylaxis (4 patients, 10%). Analysis of immune endpoints in serial biopsies indicated that LTX-315 induces necrosis and CD8+ T-cell infiltration into the tumor microenvironment. Sequencing of the T-cell receptor repertoire in peripheral blood identified significant expansion of T-cell clones after treatment, of which 49% were present in available tumor biopsies after treatment, suggesting that they were tumor associated. Substantial volume reduction (≥30%) of injected tumors occurred in 29% of the patients, and 86% (12/14 biopsies) had an increase in intralesional CD8+ T cells posttreatment. No partial responses by immune-related response criteria were seen, but evidence of abscopal effect was demonstrated following treatment with LTX-315. CONCLUSIONS: LTX-315 has an acceptable safety profile, is clinically active, induces changes in the tumor microenvironment and contributes to immune-mediated anticancer activity.

Evaluation of the Insulin-like Growth Factor Receptor Pathway in Patients with Advanced Breast Cancer Treated with Trastuzumab.

BACKGROUND: Trastuzumab is a monoclonal antibody against HER2-positive breast cancer. Despite improving the natural history of the disease, there is a number of patients who are resistant to it, whereas all patients will eventually develop resistance and disease will progress. Inconsistent preclinical data show that the IGF-R pathway may contribute to either de novo or acquired resistance to trastuzumab. MATERIALS AND METHODS: In total, 227 trastuzumab-treated metastatic breast cancer patients were evaluated for IGF-1, IGF-1R, GLP-1R, Akt1, Akt2 Akt3 mRNA expression, and IGF-1Rα, IGF-1Rß, IGF-2R protein expression. RESULTS: Only 139 patients were truly HER2-positive by central assessment. Among HER2-positive patients, high Akt2 and GLP-1R mRNA expression showed a trend towards higher and lower risk of progression, respectively (HR=1.83, 95%CI=0.90-3.72, p=0.094 and HR=0.62, 95%CI=0.36-1.06, p=0.079), while high Akt1 and GLP-1R mRNA expression presented a trend towards unfavorable survival (HR=1.67, 95%CI=0.93-2.99, p=0.086 and HR=1.67, 95%CI=0.94-2.96, p=0.080). Among HER2-negative patients, high GLP-1R mRNA expression and negative stromal IGF-1Rß protein expression showed a trend towards worse survival (HR=2.31, 95%CI=0.87-6.13, p=0.094 and HR=2.03, 95%CI=0.94-4.35, p=0.071, respectively). In the multivariate analyses, HER2-positive patients with high Akt1 and GLP-1R mRNA expression had a worse survival (HR=1.86, 95%CI=1.01-3.43, p=0.045 and HR=1.83, 95%CI=0.99-3.41, p=0.055, respectively). CONCLUSION: This study revealed a crosstalk between the IGF-R pathway and HER2. There was evidence that high Akt1 and GLP-1R mRNA expression might affect survival among HER2-positive metastatic breast cancer patients treated with trastuzumab.

Targeted Lung Cancer Treatments and Eye Metastasis.

Lung cancer remains the leading cause of death due to cancer. We do not have effective tools for the early detection of lung cancer, so patients are usually diagnosed at an advanced stage. However, novel therapies based on molecular pathways (such as those involving the epidermal growth factor receptor, anaplastic lymphoma kinase, serine/threonine-protein kinase B-Raf, proto-oncogene tyrosine-protein kinase ROS, c-Met proto-oncogene protein, and RET proto-oncogene protein) are now commonly used in the treatment of lung cancer. In particular, these therapies are considered as first-line treatments for non-small-cell lung cancer. This manuscript outlines previous research on these targeted treatments, focusing on whether they are effective against eye metastasis.

Progressive dyspnea due to pulmonary carcinoid tumorlets.

This is a case description of a female patient, 77 years-old, who presented with progressive dyspnea and cough. She had a mild hypoxemia in the arterial blood gases (PaO2 72 mmHg) and normal spirometry. The chest computer tomography revealed diffuse "ground glass" opacities, segmental alveolitis, bronchiectasis, fibrotic lesions and numerous micronodules. A thoracoscopy was performed and the obtained biopsy showed carcinoid tumorlets, with positive CK8/18, CD56, TTF-1 and synaptophysin immunohistochemical markers. Pulmonary carcinoid tumorlets are rare, benign lesions and individuals with tumorlets are typically asymptomatic. Our report presents a symptomatic clinical case of carcinoid tumorlet.

Fine-needle aspiration of skin metastasis in ovarian cancer-report of two cases and review of the literature.

Ovarian cancer is known to be the first cause of death of gynecological malignancy in Europe and United States. Skin metastases consist of an unusual event during the course of ovarian carcinoma and occur in 2-3.5% of the patients. We report two interested cases of patient with skin metastases, due to ovarian carcinoma, diagnosed by fine-needle aspiration (FNA). The clinical information, cytologic findings and immunocytochemical profile are described and further discussed, according to the relevant bibliographic data. The combination of FNA and thin layer cytology contribute to the accurate clarification of metastatic tumors with a known or unknown origin. It known that skin metastasis tend occurs in most ovarian carcinomas at a late stage course of the disease and it is usually associated with poor prognosis, in some cases the survival can be prolonged with appropriate therapy. So, an accurate cyto-immunodiagnosis is crucial for the best management of these patients.

The impact of paclitaxel and carboplatin chemotherapy on the autonomous nervous system of patients with ovarian cancer.

BACKGROUND: Paclitaxel-based regimens are frequently associated with the development of peripheral neuropathy. The autonomous nervous system (ANS) effects, however, of this chemotherapeutic agent remain unexplored. METHODS: We investigated a group of 31 female patients with ovarian cancer receiving treatment with paclitaxel and carboplatin, as well as a group of 16 healthy age- and gender-matched healthy volunteers. All study participants completed a questionnaire and were assessed neurophysiologically at three time points (baseline, 3-4 months and 6-8 months following the onset of chemotherapy). The evaluation of the ANS included assessment of the adrenergic cardiovascular function (orthostatic hypotension-OH), parasympathetic heart innervation (30/15 ratio) and sympathetic skin response (SSR). RESULTS: At the 3-4 months ANS assessment, 19.2 % of the patients had systolic OH and the same percentage had diastolic OH, but at the 6-8 months evaluation no patient had systolic OH and only 13.8 % had diastolic OH. The values of the 30/15 ratio were significantly reduced at both time points, whereas the SSR was not affected. CONCLUSIONS: Combined paclitaxel and carboplatin chemotherapy is associated with significant effects on the parasympathetic heart innervation and occasionally with effects on the adrenergic cardiovascular reaction. The SSR remained unaffected. Physicians should be alert to the possibility of these treatment-emergent side effects, so as to monitor ANS parameters and introduce treatment modifications accordingly. Our findings however, should be validated in larger cohorts.

Prognostic factors for long term survival in patients with advanced non-small cell lung cancer.

BACKGROUND: Non-small cell lung cancer (NSCLC) represents 85% of all lung cancers. It is estimated that 60% of patients with NSCLC at time of diagnosis have advanced disease. The aim of this study was to investigate clinical and demographic prognostic factors of long term survival in patients with unresectable NSCLC. METHODS: We retrospectively reviewed data of 1,156 patients with NSCLC stage IIIB or IV who survived more than 60 days from the time of diagnosis and treated from August 1987 until March 2013 in the Oncology Department of Pulmonary Clinic of the General Hospital Papanikolaou. Initially univariate analysis using the log-rank test was conducted and then multivariate analysis using the proportional hazards model of Cox. Also Kaplan Meier curves were used to describe the distribution of survival times of patients. The level of significance was set at 0.05. RESULTS: The mean age at diagnosis was 62 years. About 11.9% of patients were women and 88.1% were male. The majority of cases were adenocarcinomas (42.2%), followed squamous (33%) and finally the large cell (6%). Unlike men, most common histological type among women was adenocarcinoma rather than squamous (63% vs. 10.9%). In univariate analysis statistically significant factors in the progression free survival (PFS) and overall survival (OS) were: weight loss ≥5%, histological type, line 1 drugs, line 1 combination, line 1 cycles and radio lung. Specifically radio lung gives clear survival benefit in the PFS and OS in stage IIIB (P=0.002) and IV (P<0.001). On the other hand, the number of distant metastases in stage IV patients did not affect OS, neither PFS. In addition patients who received platinum and taxane had better PFS (P=0.001) and OS (P<0.001) than those who received platinum without taxane. Also the third drug administration proved futile, since survival (682.06±34.9) (P=0.023) and PFS (434.93±26.93) (P=0.012) of patients who received less than three drugs was significantly larger. Finally, large cell carcinoma recorded the shortest OS and PFS compared with adenocarcinoma (P=0.043 and P=0.016 respectively) and squamous cell carcinoma (P=0.021 and P=0.004 respectively). In multivariate analysis the same predictors were statistically significant except for line 1 drugs. CONCLUSIONS: This study confirms the increased incidence of adenocarcinoma in women than in men and the aggressiveness of large cell carcinoma. It also underlines the vitality of factors such as weight loss, radio lung and doublet platinum-based. On the other hand, it excludes significant factors such as gender, age and smoking.

Tyrosine Kinase Inhibitors for Non-Small Cell Lung Cancer and Eye Metastasis: Disease Relapse or a New Entity?

Lung cancer is still diagnosed during the advanced stage of the disease and most patients do not have the opportunity for surgical treatment, despite the new diagnostic equipment that has been made available in recent years, such as the radial and linear endobronchial ultrasound (EBUS) and electromagnetic fiberoptic bronchoscopy. However, novel targeted therapies with second generation tyrosine kinase inhibitors and immunotherapy are available. In this commentary, we will focus on eye metastasis after initiation of tyrosine kinase inhibitors due to epidermal growth factor mutation of lung cancer adenocarcinoma.

Defining the role of tyrosine kinase inhibitors in early stage non-small cell lung cancer.

Historical, the non-small cell lung cancer (NSCLC) was as a united disease entity and the chemotherapy to the metastatic cancer had limited results. Recent studies for the metastatic non-small cell lung cancer led to the ascertainment that the NSCLC does not constitute exclusively a disease entity, but different neoplasms guided from different molecular paths, different biological behavior and at extension requires different confrontation. Thus the new direction for the therapeutic approach of NSCLC is henceforth the most individualized approach based on the activated molecular paths of tumor. Distinct subtypes of NSCLC are driven by a specific genetic alteration, like EGFR, ALK, ROS1 or BRAF mutations, and these genetic alterations are sensitized to the inhibition of specific oncogenic pathways. The benefit from the use of tyrosine kinase inhibitors in patients with EGFR mutations it was confirmed by six randomized studies of phase III that investigated the role of gefitinib, erlotinib and afatinib. In these studies the response rates vary in the impressive percentages from 55% to 86% and were connected with a remarkable median progression free survival of approximately 8 to 13 months, and with better quality of life compared to that of chemotherapy. In early stages NSCLC is needed the individualization of systemic treatment in order to reduce toxicity that is observed in the classic chemotherapy and to impact outcome. The role of EGFR TKI's has been evaluated in the adjuvant chemotherapy in early stage resected NSCLC. The data from these studies suggest that adjuvant TKI therapy might not increase the overall survival, but delay the recurrences. Prospective trials restricted to EGFR or ALK driven NSCLC subsets potentially offering the opportunity for a definitive answer in early disease adjuvant setting (ALCHEMIST) or as induction treatment before stage III chemo-radiotherapy (RTOG 1210/Alliance 31101), are ongoing. Ongoing prospective trials may offer the opportunity for a definitive answer of the role of tyrosine kinase inhibitors in induction treatment before chemo-radiotherapy or in early disease adjuvant therapy.

Pneumothorax: an up to date "introduction".

The pneumothorax is an abnormal collection of air or gas in the pleural space that separates the lung from the chest wall. Like pleural effusion where a large abnormal concentration of fluid (>100 mL) is liquid buildup in that space, pneumothorax may interfere with normal breathing. A medical term that it is used is the collapsed lung, although that term may also refer to atelectasis. There are two major types of pneumothorax; there is one that occurs without an apparent cause and in the absence of significant lung disease, while the so called; "secondary" pneumothorax occurs in the presence of existing lung pathology. In a minority of cases, the amount of air in the chest increases markedly when a one-way valve is formed by an area of damaged tissue, leading to a third type of pneumothorax, called "tensioned".

Heimlich valve and pneumothorax.

The Heimlich valve is a small one-way valve used for chest drainage that empties into a flexible collection device and prevents return of gases or fluids into the pleural space. The Heimlich valve is less than 13 cm (5 inches) long and facilitates patient ambulation. Currently there are several systems in the market. It can be used in many patients instead of a traditional water seal drainage system. The Heimlich chest drainage valve was developed so that the process of draining the pleural cavity could be accomplished in a safe, relatively simple, and efficient manner. This valve system has replaced the cumbersome underwater drainage bottle system. Moreover; the Heimlich valve system connects to chest tubing and allows fluid and air to pass in one direction only. This system functions in any position, and it does not ever need to be clamped, a regulated suction can be attached to it if necessary. The valve drains into a plastic bag that can be held at any level, allowing the patient undergoing chest drainage to be ambulatory simply by carrying the bag. In the current mini review we will present the Heimlich valve system and method of insertion.

Prophylactic antibiotic administration for post cardiothoracic surgery sternal wounds: a retrospective study.

BACKGROUND: Cardiothoracic surgery sternal infections are difficult to treat situations. Until now there are no clear guidelines which or if an antibiotic could be used as prophylactic treatment. PATIENTS AND METHODS: We collected retrospectively data from 535 patients from our hospital which underwent cardiothoracic surgery and recorded several biological parameters and technical aspects of the surgery. RESULTS: It was observed that patients to whom vancomycin was administered had less post surgery infection than those to whom begalin was administered. Male who were treated with vancomycin it was observed that they had 1.67 chances to be treated properly than female. Patients which were hospitalized for more than 7 days before surgery had 62.6% higher chances for post surgery infection. CONCLUSIONS: It was observed that vancomycin can be used as a prophylactic treatment for cardiothoracic surgeries acting efficiently against sternal wounds.

Minimally invasive procedures.

Minimally invasive procedures, which include laparoscopic surgery, use state-of-the-art technology to reduce the damage to human tissue when performing surgery. Minimally invasive procedures require small "ports" from which the surgeon inserts thin tubes called trocars. Carbon dioxide gas may be used to inflate the area, creating a space between the internal organs and the skin. Then a miniature camera (usually a laparoscope or endoscope) is placed through one of the trocars so the surgical team can view the procedure as a magnified image on video monitors in the operating room. Specialized equipment is inserted through the trocars based on the type of surgery. There are some advanced minimally invasive surgical procedures that can be performed almost exclusively through a single point of entry-meaning only one small incision, like the "uniport" video-assisted thoracoscopic surgery (VATS). Not only do these procedures usually provide equivalent outcomes to traditional "open" surgery (which sometimes require a large incision), but minimally invasive procedures (using small incisions) may offer significant benefits as well: (I) faster recovery; (II) the patient remains for less days hospitalized; (III) less scarring and (IV) less pain. In our current mini review we will present the minimally invasive procedures for thoracic surgery.

Pneumothorax from diagnosis to treatment, hands on course: Part II.

Pneumothorax is a situation where air is inserted in the pleural space that separates the lung from the chest wall. Pneumothorax can be primary or secondary. There is also a third type called; tensioned. Based on the concentration of air and type of pneumothorax the proper treatment has to be selected. There are cases where the concentration is minimal and observation is enough and more severe cases where surgery is required. Currently there are many techniques used for the biopsy of lung lesions. The bronchoscope (forceps, fine needle aspiration), fine needle aspiration under computed tomography scan and endobronchial ultrasound (EBUS) are commonly used. However, all these techniques have in common a possible side effect; pneumothorax. In our current issue we will focus on the different minimally invasive techniques of pneumothorax management. Moreover, a presentation will be made for several systems that are being used for air or fluid aspiration.

Pacemaker insertion.

A pacemaker (PM) (or artificial PM, so as not to be confused with the heart's natural PM) is a medical device that uses electrical impulses, delivered by electrodes contracting the heart muscles, to regulate the beating of the heart. The primary purpose of this device is to maintain an adequate heart rate, either because the heart's natural PM is not fast enough, or there is a block in the heart's electrical conduction system. Modern PMs are externally programmable and allow the cardiologist to select the optimum pacing modes for individual patients. Some combine a PM and defibrillator in a single implantable device. PMs can be temporary or permanent. Temporary PMs are used to treat short-term heart problems, such as a slow heartbeat that's caused by a heart attack, heart surgery, or an overdose of medicine. Permanent PMs are used to control long-term heart rhythm problems. A PM can relieve some arrhythmia symptoms, such as fatigue and fainting. A PM also can help a person who has abnormal HRs resume a more active lifestyle. In the current mini review we will focus on the insertion of a PM and the possible pneumothorax that can be caused.

Chest drainage systems in use.

A chest tube is a flexible plastic tube that is inserted through the chest wall and into the pleural space or mediastinum. It is used to remove air in the case of pneumothorax or fluid such as in the case of pleural effusion, blood, chyle, or pus when empyema occurs from the intrathoracic space. It is also known as a Bülau drain or an intercostal catheter. Insertion of chest tubes is widely performed by radiologists, pulmonary physicians and thoracic surgeons. Large catheters or small catheters are used based on each situation that the medical doctor encounters. In the current review we will focus on the chest drain systems that are in use.

Thoracocentesis: from bench to bed.

Lung cancer can be diagnosed with minimal interventional procedures such as: bronchoscopy, endobronchial ultrasound (EBUS), fine needle aspiration under CT guidance and esophageal ultrasound. In our current editorial we will provide a definition and current up to date information regarding fine needle aspiration under CT guidance. We will focus on pneumothorax and treatment methods.

Pleura space anatomy.

The pleural cavity is the potential space between the two pleurae (visceral and parietal) of the lungs. The pleurae are serous membranes which fold back onto themselves to form a two-layered membranous structure. The thin space between the two pleural layers is known as the pleural cavity and normally contains a small amount of pleural fluid. There are two layers; the outer pleura (parietal pleura) is attached to the chest wall and the inner pleura (visceral pleura) covers the lungs and adjoining structures, via blood vessels, bronchi and nerves. The parietal pleurae are highly sensitive to pain, while the visceral pleura are not, due to its lack of sensory innervation. In the current review we will present the anatomy of the pleural space.