Kirsten Rat Sarcoma viral oncogene homolog (KRAS) is the most frequently altered oncogene in Non-Small Cell Lung Cancer (NSCLC). KRAS mutant tumors constitute a heterogeneous group of diseases, different from other oncogene-derived tumors in terms of biology and response to treatment, which hinders the development of effective drugs against KRAS. Therefore, for decades, despite enormous efforts invested in the development of drugs aimed at inhibiting KRAS or its signaling pathways, KRAS was considered to be undruggable. Recently, the discovery of a new pocket under the effector binding switch II region of KRAS G12C has allowed the development of direct KRAS inhibitors such as sotorasib, the first FDA-approved drug targeting KRAS G12C, or adagrasib, initiating a new exciting era. However, treatment with targeted KRAS G12C inhibitors also leads to resistance, and understanding the possible mechanisms of resistance and which drugs could be useful to overcome it is key. Among others, KRAS G12C (ON) tricomplex inhibitors and different combination therapy strategies are being analyzed in clinical trials. Another area of interest is the potential role of co-mutations in treatment selection, particularly immunotherapy. The best first-line strategy remains to be determined and, due to the heterogeneity of KRAS, is likely to be based on combination therapies.

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Anti-Ma2 encephalitis is a rare neurological disorder with a predominant involvement of brainstem, limbic and diencephalic structures. Although an unspecific encephalopathy is the usual form of presentation, acute-onset neurologic symptoms and other atypical manifestations have been described and account for the challenging diagnosis of this entity. Despite being usually detected as a paraneoplastic syndrome in patients with early-stage tumors or without a previous history of malignancy, a growing concern has arisen from several cases reported in metastatic patients under treatment with immune checkpoint inhibitors. We report what to our knowledge is the first known case of anti-Ma2 encephalitis associated to pembrolizumab and presenting as an acute-onset focal neurological syndrome, consisting on acute global aphasia, right upper limb paresia, hypoacusia, sleep disorder, decreased conscious level and a motor focal status that was refractory to anticonvulsant therapy. A brain MRI scan showed a focal alteration of the cortical-subcortical signal on the left parietal lobe. CSF study found a significant hyperproteinorrhachia and electroencephalography showed lateralized periodic discharges (LPDs), suggestive of a diffuse encephalopathy. A positive result for anti-Ma2 antibodies was obtained both in blood and CSF samples through indirect immune-fluorescence (IFI) and later confirmed by western-blot technique. Our patient obtained a mild response to steroid therapy and a significant improvement after the administration of intravenous immunoglobulins. The hypothesis that checkpoint inhibitors may trigger the expression of previously subclinical paraneoplastic events, through the strengthening of cytotoxic T cells-mediated immune response, is supported by our finding of preexisting anti-Ma2 antibodies in preserved blood samples obtained before the initiation of pembrolizumab in our patient. Further research is needed to reveal if the detection of onconeural antibodies prior to a treatment with checkpoint inhibitors may be used as a predictive biomarker of neurologic immune-related high-grade toxicity.

The 2004 discovery of EGFR mutations, followed by ALK rearrangements, ushered in a targeted therapy era for advanced non-small cell lung cancer (NSCLC). Tyrosine kinase inhibitors targeting gene alterations have substantially improved survival and quality of life for patients with NSCLC. In the last decade, rearrangements of the ROS1 oncogene have been incorporated into healthcare practice that are applicable to another small subgroup of patients who benefit from similar targeted strategies. Recent genome studies of lung adenocarcinoma have identified other possible therapeutic targets, including RET , NTRK fusions, c-MET alterations, and activating mutations in KRAS , BRAF , and HER2, all with frequencies greater than 1%. Lung cancers harbouring these genome changes can potentially be treated with agents approved for other indications or under clinical development. This review updates the therapeutic arsenal that especially targets those genes.

rate (ORR), TTP, and OS: RAS (KRAS/NRAS) mutational status, primary tumour location and metastases site, efficacy of first-line treatment, sex, age, body mass index, lactate dehydrogenase (LDH), alkaline phosphatase, CEA, lymphocytes and haemoglobin level at the time of beginning second line treatment. Median follow-up was 35 months. Results: In whole group median TTP was 5.1 months and OS -12.9. Response rates: CR -1%, PR -18%, NC -40%, PD -40%. For patients who achieved ORR (CR or PR) median TTP and OS was 7.8 and 19.3 months while for patients with PD -2.8 and 9.9. Hepatic location of metastases was associated with the highest rate of ORR, while peritoneal with the lowest: 46% and 0% (p ¼ 0.041) respectively. Median TTP for patients who gained CR, PR or NC (DCR -disease control) while first-line treatment was 6.7 compared with 3.3 months for patients with PD (p < 0,0001). TTP under/equal 6 months and PD during first-line treatment were associated with shorter OS: 12.9 vs 15.3 months (p ¼ 0.049) and 9.9 vs 14.2 months (p ¼ 0.007). Age over 70 and BMI !25 were good prognostic factors with OS 19.6 months vs 10.4 (p ¼ 0.01) and 18.4 months vs 9.1 (p ¼ 0.039) respectively. There was no difference between patients in terms of KRAS and NRAS mutational status. For wild type and mutant tumours it was 6.6 months vs 6.1 (p ¼ 0.098) and 17.9 vs 12.9 (p ¼ 0.183) respectively in TTP and OS. Right-side primary tumours were associated with worse DCR, TTP and OS compared to left-side primary; 45%, 2.3 months and 11.2 months vs 61%, 4.9 months and 12.8 months, but the differences were not statistically significant. Other factors did not occur relevant. Sixteen patients (20%) discontinued treatment due to adverse events. There were no toxic deaths. Conclusion: Positive prognostic impact on second-line treatment with bevacizumab and FOLFOX4 in mCRC have: first-line treatment response, hepatic site of metastases, age over 70 and BMI !25. Worse prognosis was observed in group of patients with peritoneal metastases and poor response for first-line chemotherapy. RAS mutational status seemed to not influence prognosis in the analysed cohort. Location of the primary tumour in the right side of the colon was not proven to be a negative prognostic factor. P À 231 Clinical significance of microsatellite instability in Introduction: Colorectal cancer (CRC) with microsatellite instability (MSI) are known to have better prognosis compared to those with microsatellite stable (MSS). Recent studies reported that there are biological differences according to tumor location in CRC. In this study, we aimed to identify the clinical significance of MSI in patients with right-sided CRC. Methods: Between October 2004 and December 2016, medical records from a total of 1,009 patients with CRC were retrospectively reviewed. Patients with MSI testing were included in the analysis. We assessed the long-term outcomes of MSI according to the tumor location using the Kaplan-Meier curves and Cox regression models. Results: The median follow-up duration was 25 ...