Unravelling the diagnostic pathology and molecular biomarkers in lung cancer.

The progress in lung cancer treatment is closely interlinked with the progress in diagnostic methods. There are four steps before commencing lung cancer treatment: estimation of the patient's performance status, assessment of disease stage (tumour, node, metastasis), recognition of histological subtype, and detection of biomarkers. The resection rate in lung cancer is <30% and >70% of patients need systemic therapy, which is individually adjusted. Accurate histological diagnosis is very important and it is the basis of further molecular diagnosis. In many cases only small biopsy samples are available and the rules for their assessment are defined in this review. The use of immunochemistry with at least thyroid transcription factor 1 (TTF1) and p40 is decisive in distinction between lung adenocarcinoma and squamous cell carcinoma. Molecular diagnosis and detection of known driver mutations is necessary for introducing targeted therapy and use of multiplex gene panel assays using next-generation sequencing is recommended. Immunotherapy with checkpoint inhibitors is the second promising method of systemic therapy with best results in tumours with high programmed death-ligand 1 (PD-L1) expression on cancer cells. Finally, the determination of a full tumour pattern will be possible using artificial intelligence in the near future.

The Role of Biomarkers in Lung Cancer Screening.

BACKGROUND: Lung Cancer Screening (LCS) is an evolving field with variations in its implementation in various countries. There are only scarce data from National LCS programs. AIM: We aim to provide an up-to-date overview of the current evidence regarding the use of biomarkers in LCS. MATERIALS AND METHODS: A multidisciplinary Task Force experts' panel collaborated and conducted a systematic literature search, followed by screening, review and synthesis of available evidence. RESULTS: Biomarkers in LCS could be used to improve risk stratification in high-risk participants, improve clarification regarding indeterminate lung nodules and avoid overdiagnosis in suspicious lung findings. Currently, there seem to be promising biomarkers (blood/serum/breath) that have been studied in various trials; however, there is still a lack of solid evidence in clinical validation that would pave the way for their integration into LCS programs. CONCLUSIONS: Biomarkers are the next logical step in improving the LCS pathway and its efficiency by playing an adjuvant role in a minimally invasive way. National LCS programs and pilot studies should integrate biomarkers to validate their accuracy in real-life LCS participants.

Prognostic Value of KRAS Mutations in Relation to PDL1 Expression and Immunotherapy Treatment in Adenocarcinoma and Squamous Cell Carcinoma Patients: A Greek Cohort Study.

BACKGROUND: Factors that could predict which patients will benefit from Immune Checkpoint Inhibitors (ICIs) are not fully understood. This study aimed to investigate the prognostic value of KRAS biomarker in patients with advanced non-small cell lung cancer (NSCLC) in relation to clinical characteristics, treatment response and PDL1 expression. PATIENTS AND METHODS: The study included 100 patients with NSCLC who received immunotherapy with or without chemotherapy as 1st line treatment. In biopsy samples, the PDL1 biomarker expression rate and somatic mutations of KRAS gene were determined. RESULTS: The mean age of the patients was 67 ± 8 years. Patients were all male and 66% were found with adenocarcinoma whereas 34% with squamous cell carcinoma. The KRAS G12C mutation was found with the highest percentage (73%). In the Kaplan-Meier survival analysis, patients with PDL1 > 49% in combination with a negative KRAS result had a median overall survival of 40 months compared to patients with a positive KRAS result (9 months, p < 0.05). In addition, patients diagnosed with adenocarcinoma, PDL1 < 49% and negative KRAS result had a median overall survival of 39 months compared to patients with a positive result (28 months, p < 0.05). CONCLUSIONS: Our study suggests that the presence of KRAS mutations in advanced NSCLC patients has a poor prognostic value, regardless of their PDL1 expression values, after receiving immunotherapy as first-line treatment.

Predictive Value of 99MTC-hynic-toc Scintigraphy in Lung Neuroendocrine Tumor Diagnosis.

BACKGROUND: Νeuroendocrine tumors of the lungs are rare arising in the thymus and gastro-entero-pancreatic tract and belonging to foregut of neuroendocrine tumors. The aim of the present prospective study was to estimate the potential impact of single-photon emission computed tomography somatostatin receptor scintigraphy using 99mTc-Tektrotyd on diagnosis, treatment response, and prognosis in patients with neuroendocrine tumors of the lungs. METHODS: Thirty-six patients with neuroendocrine tumors of the lungs were evaluated by using 99mTc-HYNIC-TOC scintigraphy. The scintigraphic results were compared to liver tissue uptake (Krenning score). Likewise, the functional imaging results were compared with biochemical indices including chromogranin A, neuroendocrine-specific enolase, and insulin-like growth factor 1 at the time of diagnosis (baseline) and disease progression. RESULTS: The number of somatostatin receptors, expressed with Krenning score, did not show any correlation with the survival of patients both at baseline ( P = .08) and at disease progression ( P = .24), and scintigraphy results did not relate significantly to progression-free survival. Comparing the results of 99mTc-HYNIC-TOC scintigraphy according to the response of patients in the initial treatment, a statistically significant negative correlation was observed both in the first and in the second scintigraphy with patients' response ( P = .001 and P < .001, respectively). The concentrations of biochemical markers were in accordance with scintigraphy results in the diagnosis. CONCLUSION: This study indicates that 99mTc-HYNIC-TOC scintigraphy appears to be a reliable, noninvasive technique for detection of primary neuroendocrine tumors and their locoregional or distant metastases, although it cannot be used as a neuroendocrine tumors of the lungs predictive technique.

Tumour necrosis factor, interferon-gamma and interleukins as predictive markers of antiprogrammed cell-death protein-1 treatment in advanced non-small cell lung cancer: a pragmatic approach in clinical practice.

BACKGROUND: The emergence of novel antiprogrammed cell death protein-1 (PD-1) inhibitors in non-small cell lung cancers (NSCLC) has revolutionized the therapeutic landscape of this disease. Although overall survival (OS) has improved in the first- and second-line therapy settings for advanced NSCLC, the benefit is not universal. In a climate of global scrutiny for healthcare costs and potential for toxicities related to immunotherapy, appropriate patient selection is crucial. The aim of this study was to evaluate potential prognostic and predictive biomarkers interferon-gamma (IFN-γ), tumour necrosis factor-alpha (TNF-α) and a panel of interleukins (ILs) in the peripheral blood, and assess any correlation with response to anti-PD-1 inhibition, progression-free survival and OS in NSCLC patients. METHODS: We prospectively studied 26 NSCLC patients that received immunotherapy (either pembrolizumab or nivolumab). IFN-γ, TNF-α, IL-1ß, IL-2, IL-4, IL-5, IL-6, IL-8, IL-10 and IL-12 were analyzed by flow cytometry at the time of diagnosis and at 3 months after initiation of anti-PD-1 inhibition. RESULTS: Increased cytokine values (IFN-γ, TNF-α, IL-1ß, IL-2, IL-4, IL-6 and IL-8) at the time of diagnosis and at 3 months after initiation of treatment were significantly correlated with improved response to immunotherapy and prolonged OS. There was no correlation between cytokine levels and programmed cell death ligand-1 (PD-L1) expression. CONCLUSIONS: Increased IFN-γ, TNF-α, IL-1ß, IL-2, IL-4, IL-5, IL-6, IL-8, IL-10 and IL-12 levels resulted in better response to NSCLC anti-PD-1 inhibition and longer survival, and this could potentially play an important role in selecting patients that would benefit from anti-PD-1 inhibitors.

The role of second-line chemotherapy in small cell lung cancer: a retrospective analysis.

BACKGROUND: To evaluate the benefit of second-line chemotherapy with platinum-based treatment in patients with recurrent small cell lung cancer (SCLC). PATIENTS AND METHODS: A total of 535 patients continued with follow-up or best supportive care if needed, and 229 patients who progressed after the completion of first-line chemotherapy were treated with second-line chemotherapy at the time of progression. In total, 103/229 patients received paclitaxel 190 mg/m(2) and carboplatin 5.5 area under the curve while 126/229 patients received etoposide 200 mg/m(2) and carboplatin 5.5 area under the curve every 28 days. RESULTS: Patients administered second-line chemotherapy lived significantly longer, with a median survival of 422 days compared to 228 days in patients with best supportive care alone (P<0.001). Patients who received paclitaxel as second-line chemotherapy lived for an average of 462 days (95% confidence interval: 409-514), versus 405 days in the etoposide group (95% confidence interval: 371-438), which was not statistically significant (P=0.086). The overall response rate was 8% for the paclitaxel group and 6% for the etoposide group. Patients with progression of the disease in more than 3 months had significantly better survival compared with those that progressed in less than 3 months (P<0.001). CONCLUSION: Continuation with carboplatin/paclitaxel or carboplatin/etoposide as second-line chemotherapy has no significant survival impact, and it did not improve response rates.

Treatment of non-small cell lung cancer (NSCLC).

Radical surgery is the standard of care for fit stage I non-small cell lung cancer (NSCLC) patients. Adjuvant treatment should be offered only as part of an investigation trial. Stage II and IIIA adjuvant cisplatin-based chemotherapy remains the gold standard for completely resected NSCLC tumors. Additionally radiotherapy should be offered in patients with N2 lymph nodes. In advanced stage IIIB/IV or inoperable NSCLC pts, a multidisciplinary treatment should be offered consisted of 4 cycles of cisplatin-based chemotherapy plus a 3(rd) generation cytotoxic agent or a cytostatic (anti-EGFR, anti-VEGFR) drug.

Malignant pleural mesothelioma: current and future perspectives.

Mesothelioma still remains an occupational related cancer with severe outcome. It is usually diagnosed at advanced stage since it does not demonstrate early symptoms. Several efforts have been made towards removing all materials inducing mesothelioma in the work setting and new work protection measures have been applied. Although we have new targeted treatments and radical surgery as arrows in the quiver, the type of mesothelioma and early diagnosis still remain the best treatment approach. Novel treatment modalities have been explored and several others are already on the way. In the current review we will present current data for mesothelioma and future perspectives.

Immunomodifiers in combination with conventional chemotherapy in small cell lung cancer: a phase II, randomized study.

PURPOSE: To evaluate the effect of immunotherapy on response, survival, and certain immune markers in patients with small cell lung cancer (SCLC) who are receiving chemotherapy. PATIENTS AND METHODS: Patients with SCLC (n = 164) were assigned to receive either chemotherapy alone (group A) or a combination of chemotherapy and immunotherapy as follows: interferon α (IFN-α; 3 million IU) 3 times per week (group B); IFN-γ (3 million IU) 3 times per week (group C); and IFN-α and IFN-γ (1.5 million IU of each) 3 times per week (group D). Chemotherapy was the same for all groups and consisted of eight cycles with carboplatin 5.5 mg/m(2) intravenously on day 1, ifosfamide 3.5 mg/m(2) intravenously on day 1, and etoposide 200 mg/m(2) total dose taken orally on days 1 through 3, every 28 days. Patients completing chemotherapy were restaged, and those who were found to have limited disease received primary site and prophylactic cranial irradiation. Immunotherapy was continued throughout these treatments and during the follow-up period. Blood was taken before each course of chemotherapy and during follow-up to measure CD3+ lymphocytes, CD3+CD4+ lymphocytes, CD3+CD8+ lymphocytes, natural killer cells, and natural killer T cells. RESULTS: Differences in response and survival were not significantly different when all patients were considered. However, among patients with limited disease, Kaplan-Meier analysis disclosed a survival benefit for group B (P , 0.05). The analysis of immunologic measurements revealed that the improvement of immune markers was always accompanied by clinical improvement, whereas deterioration of all markers was accompanied by disease progression (result not statistically significant except for group C; P , 0.05). CONCLUSION: Among cytokines used in the study, only IFN-α seems to confer a survival benefit to patients with SCLC with limited disease. However, immunotherapy remains a challenge in the treatment of lung neoplasms and should be further explored.

New dilemmas in small-cell lung cancer TNM clinical staging.

BACKGROUND: Many patients with limited disease (LD) behave similarly to those with extensive disease (ED) from a prognostic point of view. On the other hand, a proportion of patients with ED small-cell lung cancer (SCLC) behave similarly to those with LD. PATIENTS AND METHODS: In this retrospective study analysis, 764 patients with proven SCLC were included and managed with the same therapeutic protocols. Of these patients, 278 (36.4%) had LD, while 486 (63.6%) had ED. RESULTS: No statistically significant difference was observed for survival for IA and IB disease stages (P = 0.254) and between IIA and IIB stages (P = 0.256) according to the new tumor, node, metastasis (TNM) staging classification classification. In addition, no statistical significant difference was observed for survival between patients with (IIA + IIB) and IIIA (P = 0.951), (IIA + IIIA, P = 0.658), and (IIB + IIIA, P = 0.573) stages. Statistical significant difference was observed for survival among the LD SCLC patients with (IA + IB), (IIA + IIB + IIIA), and IIIB stages (P < 0.001). Similarly, statistical significance was observed for ED SCLC patients with (IIA + IIB + IIIA), IIIB, and IV stages (P < 0.001). CONCLUSIONS: Although stratification of SCLC patients in LD and ED is generally satisfactory, the TNM staging system is recommended for more detailed prognostic information and treatment evaluation in these patients.