Resistance to osimertinib in advanced EGFR-mutated NSCLC: a prospective study of molecular genotyping on tissue and liquid biopsies.

BACKGROUND: Resistance to osimertinib in advanced EGFR-mutated non-small cell lung cancer (NSCLC) constitutes a significant challenge for clinicians either in terms of molecular diagnosis and subsequent therapeutic implications. METHODS: This is a prospective single-centre study with the primary objective of characterising resistance mechanisms to osimertinib in advanced EGFR-mutated NSCLC patients treated both in first- and in second-line. Next-Generation Sequencing analysis was conducted on paired tissue biopsies and plasma samples. A concordance analysis between tissue and plasma was performed. RESULTS: Sixty-five advanced EGFR-mutated NSCLC patients treated with osimertinib in first- (n = 56) or in second-line (n = 9) were included. We managed to perform tissue and liquid biopsies in 65.5% and 89.7% of patients who experienced osimertinib progression, respectively. Acquired resistance mechanisms were identified in 80% of 25 patients with post-progression samples, with MET amplification (n = 8), EGFR C797S (n = 3), and SCLC transformation (n = 2) the most frequently identified. The mean concordance rates between tissue and plasma for the EGFR activating mutation and for the molecular resistance mechanisms were 87.5% and 22.7%, respectively. CONCLUSIONS: Resistance to osimertinib demonstrated to be highly heterogeneous, with MET amplification the main mechanism. Plasma genotyping is a relevant complementary tool which might integrate tissue analysis for the study of resistance mechanisms.

Soluble PD-L1 and Circulating CD8+PD-1+ and NK Cells Enclose a Prognostic and Predictive Immune Effector Score in Immunotherapy Treated NSCLC patients.

INTRODUCTION: Upfront criteria to foresee immune checkpoint inhibitors (ICIs) efficacy are far from being identified. Thus, we integrated blood descriptors of pro-inflammatory/immunosuppressive or effective anti-tumor response to non-invasively define predictive immune profiles in ICI-treated advanced non-small cell lung cancer (NSCLC). METHODS: Peripheral blood (PB) was prospectively collected at baseline from 109 consecutive NSCLC patients undergoing ICIs as first or more line treatment. Soluble PD-L1 (sPD-L1) (immunoassay), CD8+PD-1+ and NK (FACS) cells were assessed and interlaced to generate an Immune effector Score (IeffS). Lung Immune Prognostic Index (LIPI) was computed by LDH levels and derived Neutrophil-to-Lymphocyte Ratio (dNLR). All these parameters were correlated with survival outcome and treatment response. RESULTS: High sPD-L1 and low CD8+PD-1+ and NK number had negative impact on PFS (P < 0.001), OS (P < 0.01) and ICI-response (P < 0.05). Thus, sPD-L1high, CD8+PD-1+low and NKlow were considered as risk factors encompassing IeffS, whose prognostic power outperformed that of individual features and slightly exceeded that of LIPI. Accordingly, the absence of these risk factors portrayed a favorable IeffS characterizing patients with significantly (P < 0.001) prolonged PFS (median NR vs 2.3 months) and OS (median NR vs 4.1) and greater benefit from ICIs (P < 0.01). We then combined each risk parameter composing IeffS and LIPI (LDHhigh, dNLRhigh), thus defining three distinct prognostic classes. A remarkable impact of IeffS-LIPI integration was documented on survival outcome (PFS, HR = 4.61; 95%CI = 2.32-9.18; P < 0.001; OS, HR=4.03; 95%CI=1.91-8.67; P < 0.001) and ICI-response (AUC=0.90, 95%CI=0.81-0.97, P < 0.001). CONCLUSION: Composite risk models based on blood parameters featuring the tumor-host interaction might provide accurate prognostic scores able to predict ICI benefit in NSCLC patients.

[Total gastrectomy for gastric cancer: can the type of lymphadenectomy condition the long-term results?]. / Gastrectomia totale per cancro gastrico: può il tipo di linfadenectomia condizionare i risultati a distanza?

INTRODUCTION: Gastric cancer is the second tumor for frequency in the world. Surgery is still the only curative treatment. Good results in terms of long distance survival, postoperative morbidity and mortality have been achieved in the last years. The extension of lymphadenectomy is an important and discussed matter and it is not clear if lymphadenectomy may contribute to improve the surgical results. The Japanese surgeons were the first ones, in the 60's, to introduce a D2-D3 extended lymphadenectomy, but the real benefits of this technique are still being discussed. Indeed lymphonodal metastasis seem to be one of the most important prognostic factors in the gastric cancer and the level and the number of metastatic nodes are useful to predict the patients' survival. The aim of this study is to value the D2 lymphadenectomy in the patients who were treated with total gastrectomy for gastric adenocarcinoma, comparing the results both with the D1 lymphadenectomy and the D3-D4, paying attention to the survival rates related with the lymphonodal dissection. PATIENTS AND METHOD: From 1998 to 2004, we studied 87 patients with gastric cancer. Out of 78 patients treated surgically, 9 were judged unresectable. Out of 69 patients treated surgically, one died before surgery and so he was put away by this study. All the patients were treated with total gastrectomy and a GI tract reconstruction by Roux's Y termino-lateral esophageal-jejunal anastomosis. In 20 patients we also made a splenectomy. We followed the Japanese Research Society for Gastric Cancer guidelines, according to which nodes are gathered into 16 levels and divided in 4 groups (N1-N4) depending on the cancer localization. The extension of the lymphadenectomy has been classified according to the level of the removed nods. The patients were divided into 3 groups. First group: patients undergone a total gastrectomy with D1 lymphadenectomy. Second group: patients undergone D2 lymphadenectomy. Third group: patients undergone D3 and D4 lymphadenectomy. The data we obtained let us value the survival rate. RESULTS: Out of the 78 patients treated, 69 were resected with a 88.5% resection rate (69/78). Perioperatory mortality was 1.4% (1/69). Global survival was 53.8% (44/68). The 5 years survival for the Ia stage was 82.6%, 89.3% for the Ib stage, 67.8% for the II stage, 56.6% for the IIIa, 16.8% for the IIIb and 0% for the IV stage. In addition the 5 years survival in the patients without lymphnodal metastasis was 79%, much higher than the 30.6% obtained in the patients with lymphonodal metastasis (p <0.0001). In the patients who underwent D1 lymphadenectomy, survival was 73.4%, while we obtained a result of 70.4% and 13.8% respectively in the D2 and D3-D4 (p <0.05). In the advanced stages (IIIa, IIIb, IV), the survival rate in the patients with lymphadenectomy D2 vs D1 vs D3-D4 was 38.9% vs 0% vs 36.3% (p <0.0001). The survival rate based on the extension of the lymphadenectomy in the patients with lymphonodal metastasis resulted to be much higher in those patients who underwent a D2 lymphadenectomy (43.5% in 5 years) compared both to D1 (0% in 6 months) and (29.5% in 5 years) D3-D4 lymphadenectomy. CONCLUSIONS: The relation between long distance survival and extension of the lymphadenectomy in the patients with gastric adenocarcinoma is still being discussed. Different studies show the importance of a careful lymphadenectomy as the main mean for a better long distance survival in the patients with gastric cancer. Other studies showed a link between gastric cancer prognosis and number of positive nodes. If more than 7-8 nodes are affected with metastasis, prognosis is usually poor. Therefore the presence of nod metastasis has a negative influence in the prognosis of this tumor; for this reason D2 lymphadenectomy is the technique to be used for the treatment of the gastric adenocarcinoma, both for a good staging and a better long distance survival, but particularly in the advanced cancers which are, at the moment, the highest number of cases that reach the surgeon's attention.

Gastric cancer in the elderly patient.

The incidence of gastric cancer is increasing in elderly patients, unlike what it's being observed in the younger patients. The aim of this study is to evaluate the impact of the age on the resecability, resection type (R0-R1-2), morbidity, mortality and survival rate. The higher mortality observed in the elderly patients, the discussed role of an extended lymphadenectomy and the poor survival rate, would lead to a surgical approach which mostly tends to the palliation of the symptoms than the obtainment of a curative resection. But, on the other hand, the impossibility of making chemotherapy in most of the over 75 year old patients, lead us to a R0 surgery treatment.

CO2 laser subtotal arytenoidectomy and posterior true and false cordotomy in the treatment of post-thyroidectomy bilateral laryngeal fixation in adduction.

A total of 39 patients with bilateral post-thyroidectomy vocal cord paralysis in adduction underwent CO2 laser subtotal arytenoidectomies with removal of the posterior third of the false and true vocal cords. Total airway resistance (Rtot) evaluated before and 4-10 months after surgery showed marked preoperative impairment before and significant improvement after surgery (P < 0.05). In five patients revision surgery was performed due to a progressive impairment of respiratory function. A variable degree of voice breathiness was observed after surgery; the maximum phonation time mean values were lower than normal and peak sound pressure levels 63 +/- 5 dB. In three cases aspiration was present in the first postoperative days, but swallowing dysfunctions disappeared within 1 week. Subtotal arytenoidectomy with removal of the posterior third of the true and false vocal folds was found to be a satisfactory surgical treatment for bilateral vocal cord paralysis in adduction. However, further research is still needed to define the surgical procedure able to balance respiratory, phonatory and sphincteric functions optimally.

[Current views and controversies about reconstruction after esophagectomy]. / Attualità e controversie nelle ricostruzioni dopo esofagectomia.

The Authors examine the reconstructive procedures following total or partial esophagectomy, reporting advantages and disadvantages related to stomach, colon or jejunum transposition. The stomach is certainly the organ most widely employed for its adaptability and excellent vascularization; furthermore, only one anastomosis is needed. After a short note on pathophysiology of the most common complications, the Authors point out the advantages of using stapling devices, with special attention to the low incidence of anastomotic dehiscence.