KRAS G12C mutation and risk of disease recurrence in stage I surgically resected lung adenocarcinoma.

KRAS G12C mutations are found in about 12-13% of LUAD samples and it is unclear whether they are associated with worse survival outcomes in resected, stage I LUAD. We assessed whether KRAS-G12C mutated tumours had worse DFS when compared to KRAS-nonG12C mutated tumours and to KRAS wild-type tumours in a cohort of resected, stage I LUAD (IRE cohort). We then leveraged on publicly available datasets (TCGA-LUAD, MSK-LUAD604) to further test the hypothesis in external cohorts. In the stage I IRE cohort we found a significant association between the KRAS-G12C mutation and worse DFS in multivariable analysis (HR: 2.47). In the TCGA-LUAD stage I cohort we did not find statistically significant associations between the KRAS-G12C mutation and DFS. In the MSK-LUAD604 stage I cohort we found that KRAS-G12C mutated tumours had worse RFS when compared to KRAS-nonG12C mutated tumours in univariable analysis (HR 3.5). In the pooled stage I cohort we found that KRAS-G12C mutated tumours had worse DFS when compared to KRAS-nonG12C mutated tumours (HR 2.6), to KRAS wild-type tumours (HR 1.6) and to any other tumours (HR 1.8); in multivariable analysis, the KRAS-G12C mutation was associated with worse DFS (HR 1.61). Our results suggest that patients with resected, stage I LUAD with a KRAS-G12C mutation may have inferior survival outcomes..

Social distress among medical oncologists and other healthcare professionals during the first wave of COVID-19 pandemic in Italy.

BACKGROUND: Coronavirus disease 2019 (COVID-19) has rapidly spread to every country around the world taking on pandemic proportions. Since 8 March 2020, the Italian government ordered a nationwide lockdown with unavoidable social isolation. Healthcare professionals (HCPs) represent the most physically and emotionally involved category. The aim of this study is to assess the social distress among HCPs in Italy. PATIENTS AND METHODS: In this online, totally anonymous survey, 24 multiple choice questions were posed to medical staff employed in the Italian Healthcare System during the COVID-19 pandemic. Data collection was performed from 30 March to 24 April 2020. RESULTS: A total of 600 HCPs completed the questionnaire. The majority of respondents expressed the fear of being at higher risk of contagion than the general population (83.3%) and the weighty concern of infecting their families (72.5%). An insufficient supply of personal protective equipment (PPE; P = 0.0003) and inadequate training about procedures to follow (P = 0.0092) were seen to significantly coincide with these worries. More than two-thirds declared a change in family organisation, which showed a significant correlation with the concern of infecting their relatives (P < 0.0001). CONCLUSIONS: This is the first Italian survey on social distress among HCPs during the COVID-19 pandemic. The unavailability of PPE, screening procedures and adequate training strongly affected HCPs' emotional status. Although there was a predominance of oncologists (especially from the North of Italy), which impairs the generalisation of our findings, this survey underlined the social impact that this health emergency has had on HCPs.

Single-arm, open label prospective trial to assess prediction of the role of ERCC1/XPF complex in the response of advanced NSCLC patients to platinum-based chemotherapy.

BACKGROUND: Platinum-based therapy, combined or not with immune checkpoint inhibitors, represents a front-line choice for patients with non-small-cell lung cancer (NSCLC). Despite the improved outcomes in the last years for this malignancy, only a sub-group of patients have long-term benefit. Excision repair cross-complementation group 1 (ERCC1) has been considered a potential biomarker to predict the outcome of platinum-based chemotherapy in NSCLC. However, the ERCC1 gene is transcribed in four splice variants where the isoform 202 was described as the only one active and able to complex Xeroderma pigmentosum group F-complementing protein (XPF). Here, we prospectively investigated if the active form of ERCC1, as assessed by the ERCC1/XPF complex (ERCC1/XPF), could predict the sensitivity to platinum compounds. PATIENTS AND METHODS: Prospectively enrolled, patients with advanced NSCLC treated with a first-line regimen containing platinum were centrally evaluated for ERCC1/XPF by a proximity ligation assay. Overall survival (OS), progression-free survival (PFS) and objective response rate (ORR) were analyzed. RESULTS: The absence of the ERCC1/XPF in the tumor suggested a trend of worst outcomes in terms of both OS [hazard ratio (HR) 1.41, 95% confidence interval (CI) 0.67-2.94, P = 0.373] and PFS (HR 1.61, 95% CI 0.88-3.03, P = 0.123). ORR was marginally influenced in ERCC1/XPF-negative and -positive groups [odds ratio (stable disease + progressive disease versus complete response + partial response) 0.87, 95% CI 0.25-3.07, P = 0.832]. CONCLUSION: The lack of ERCC1/XPF complex in NSCLC tumor cells might delineate a group of patients with poor outcomes when treated with platinum compounds. ERCC1/XPF absence might well identify patients for whom a different therapeutic approach could be necessary.

Real-world outcomes according to treatment strategies in ALK-rearranged non-small-cell lung cancer (NSCLC) patients: an Italian retrospective study.

PURPOSE: Anaplastic lymphoma kinase (ALK) rearrangement confers sensitivity to ALK inhibitors (ALKis) in non-small-cell lung cancer (NSCLC). Although several drugs provided an impressive outcome benefit, the most effective sequential strategy is still unknown. We describe outcomes of real-life patients according to the treatment strategy received. PATIENTS: We retrospectively collected 290 ALK rearranged advanced NSCLC diagnosed between 2011 and 2017 in 23 Italian institutions. RESULTS: After a median follow-up of 26 months, PFS for crizotinib and a new generation ALKis were 9.4 [CI 95% 7.9-11.2] and 11.1 months [CI 95% 9.2-13.8], respectively, while TTF were 10.2 [CI 95% 8.5-12.6] and 11.9 months [CI 95% 9.7-17.4], respectively, being consistent across the different settings. The composed outcomes (the sum of PFS or TTF) in patients treated with crizotinib followed by a new generation ALKis were 27.8 months [CI 95% 24.3-33.7] in PFS and 30.4 months [CI 95% 24.7-34.9] in TTF. The median OS from the diagnosis of advanced disease was 39 months [CI 95% 31.8-54.5]. Patients receiving crizotinib followed by a new generation ALKis showed a higher median OS [57 months (CI 95% 42.0-73.8)] compared to those that did not receive crizotinib [38 months (CI 95% 18.6-NR)] and those who performed only crizotinib as target agent [15 months (CI 95% 11.3-34.0)] (P < 0.0001). CONCLUSION: The sequential administration of crizotinib and a new generation ALKis provided a remarkable clinical benefit in this real-life population, being an interesting option to consider in selected patients.

Chemotherapy-induced nausea and vomiting (CINV) in patients with advanced lung cancer during the first-line treatment: assessment by physicians, nurses, and patients from an Italian multicenter survey.

PURPOSE: Chemotherapy-induced nausea and vomiting (CINV) still represents a common side-effect of chemotherapy, and often, its perception differs between patients and healthcare professionals. The aim of this study was to evaluate the agreement on the perception of CINV and other items among clinicians, patients, and nurses. METHODS: This observational prospective study was part of an evaluation program promoted by the Women Against Lung Cancer in Europe (WALCE) Onlus. From August 2015 to February 2016, a survey was administered in 11 oncologic institutions to 188 stage IV lung cancer patients and to their oncologists and nurses during first-line chemotherapy. Our survey investigated 11 aspects: anxiety, mood, weakness, appetite, nausea, vomiting, pain, drowsiness, breath, general condition, and trust in treatments. These items were assessed through Numerical Rating Scale at four consecutive evaluations: at T0 (immediately prior to the first cycle), at T1 (immediately prior to the second cycle), at T2 (immediately prior to the third cycle), and at T3 (immediately prior to the fourth cycle). Clinician versus patient (CvP), nurse versus patient (NvP), and clinician versus nurse (CvN) agreements were estimated applying Weighted Cohen's kappa. A multivariate logistic model and generalized equation estimates were applied to evaluate factors possibly influencing CINV development. RESULTS: The incidence of patients reporting CINV varied from 40% at T0 to 71% at T3. Both CvP and NvP agreement on the investigated items were mainly moderate, slightly increasing over time, and becoming substantial for some items, in particular for NvP. Pre-chemotherapy anxiety in its mild, moderate, and severe manifestations, as well as mild, moderate, and severe anxiety experienced after chemotherapy start, exposed patients to a higher risk of anticipatory and acute/delayed CINV, respectively. CONCLUSIONS: Despite clinical staff awareness of patients' status and perceptions, CINV still represents a clinical problem. This study confirms that particular attention should be paid to anxiety due to its key role in CINV development.

Nuclear and cytoplasmic cellular distribution of survivin as survival predictor in resected non-small-cell lung cancer.

AIM: Survivin is a member of the inhibitors of apoptosis (IAP) gene family that acts through pathways different from those involving the bcl-2 family. Largely undetectable in normal adult tissues, survivin is deregulated in most human cancers including non-small-cell lung cancer (NSCLC) and may represent a tumor marker with prognostic and therapeutic implications. Aim of our study was to determine the prognostic role of survivin as an apoptosis-related biomarker in a series of resected NSCLC patients. METHODS: A retrospective series of resected NSCLC patients were retrieved from the files of the Regina Elena National Cancer Institute. Survivin was detected by immunohistochemistry (IHC) using a polyclonal antibody. Survivin displayed two kinds of immunoreactivity: (i) a diffuse cytoplasmic staining and (ii) a distinct nuclear staining. A score-scale to distinguish positive (score 1-2) vs. negative (score 0) pattern was applied. Clinical and biological (nuclear and cytoplasmic survivin staining) covariables were screened for a prognostic relationship with overall survival (OS) and disease-free survival (DFS) into the univariate and multivariate analyses. RESULTS: Data referring to 116 NSCLC patients who underwent surgery for stage I-IIIA NSCLC were collected. Multivariate analyses identified tumor size, nodal status and nuclear, but not cytoplasmic, expression of survivin as significant independent predictors of OS, with a hazard ratio of 2.40 (95% CI 1.44, 3.99, p=0.001), 2.03 (95% CI 1.26, 3.26, p=0.003) and 1.83 (95% CI 1.01, 3.30, p=0.044), respectively. Median OS for nuclear survivin positive (score 1-2) and negative (score 0) patients were 23 months (95% CI 15, 31) and 36 months (95% CI 1, 76), respectively (p=0.01); five-year survival for score 1-2 and score 0 patients were 20% and 44.5%, respectively. Conversely, no significant impact on survival is found when patients are stratified according to cytoplasmic survivin expression. CONCLUSIONS: Data presented herein open the issue that prognosis of stage I-IIIA NSCLC can be linked to the cellular pattern of distribution of survivin.

Gene expression of ERCC1 as a novel prognostic marker in advanced bladder cancer patients receiving cisplatin-based chemotherapy.

BACKGROUND: Customizing chemotherapy on the basis of chemosentitivity prediction may improve outcome in advanced bladder cancer patients. Since DNA damaging agents are the cornerstones of therapy, we hypothesized that levels of DNA repair genes could predict survival. PATIENTS AND METHODS: Messenger RNA expression levels of excision repair cross complementing 1 (ERCC1), breast cancer 1 (BRCA1), ribonucleotide reductase subunit M1 (RRM1) and caveolin-1 were determined by RT-PCR in tumor DNA from 57 advanced and metastatic bladder cancer patients treated with either gemcitabine/cisplatin or gemcitabine/cisplatin/paclitaxel (Taxol). Levels were correlated with survival, time to disease progression and chemotherapy response. RESULTS: Median survival was significantly higher in patients with low ERCC1 levels (25.4 versus 15.4 months; P = 0.03) (median follow-up 19 months). A trend towards longer time to progression was observed in patients with tumors expressing low levels of all markers. Levels of RRM1, BRCA1 and caveolin-1, however, failed to predict the survival and a clear link with chemotherapy response could not be established. On multivariate analysis with pretreatment prognostic factors, ERCC1 emerged as an independent predictive factor for survival. CONCLUSION: The results of the study indicate that ERCC1 may predict survival in bladder cancer treated by platinum-based therapy.

Usefulness of predictive tests for cancer treatment.

This review highlights the numerous molecular biology findings in the field of lung cancer with potential therapeutic impact in both the near and distant future. At least six lines of research have recently emerged as potential contributors to changes in clinical practice. Abundant pre-clinical and clinical data indicate that BRCA1 mRNA expression is a differential modulator of chemotherapy sensitivity. Low levels predict cisplatin sensitivity and antimicrotubule drug resistance, and the opposite occurs with high levels. Secondly, single nucleotide polymorphisms in the ERCC1 gene influence survival and toxicity with cisplatin-based chemotherapy. The main core of recent research has centered on EGFR mutations and gene copy numbers. For the first time, EGFR mutations have been shown to predict dramatic responses in metastatic lung adenocarcinomas, with a threefold increase in time to progression and survival in patients receiving EGFR tyrosine kinase inhibitors. In contrast, K-ras mutations confer a negative effect in these patients. Evidence has also been accumulated on the crosstalk between estrogen and EGFR receptor pathways, paving the way for clinical trials of EGFR tyrosine kinase inhibitors plus aromatase inhibitors. microRNAs control the expression of cognate target genes, and downregulation of Dicer has been shown to be a strong predictor of relapse in surgically resected non-small-cell lung cancer patients. Finally, overexpression of the Wingless-type (Wnt) genes and methylation of Wnt antagonists like WIF and secreted frizzled related proteins have been documented in non-small-cell lung cancer and are believed to be an important mechanism of cancer stem cell maintenance.

Second- and third-generation aromatase inhibitors as first-line endocrine therapy in postmenopausal metastatic breast cancer patients: a pooled analysis of the randomised trials.

The purpose of this study was to estimate in all randomised trials the relative risk of overall response rate (ORR), clinical benefit (CB), time to progression (TTP), overall survival (OS), and toxicity of aromatase inhibitors (AI), compared with tamoxifen (Tam) as first-line endocrine therapy in postmenopausal metastatic breast cancer (PMBC) women. Prospective randomised studies were searched through computerised queries of MEDLINE, EMBASE, and the American Society of Clinical Oncology (ASCO) abstract database. Relative risk, 95% confidence interval, and heterogeneity were derived according to the inverse variance and Mantel-Haenszel method and Q statistics. Six phase III prospective randomised trials including 2787 women were gathered. A significant advantage in ORR (P = 0.042), TTP (P = 0.007), and CB (P = 0.001) in favour of AI over Tam was detected at the fixed effects model. These results were not significant at the random effects model, owing to the significant heterogeneity. On the contrary, no difference was registered for OS (P = 0.743) with no significant heterogeneity. Regarding toxicity, Tam caused more frequently thromboembolic events (P = 0.005) and vaginal bleeding (P = 0.001) compared with AI. Aromatase inhibitors appear to be superior to Tam as first-line endocrine option in PMBC women. Owing to a component of variability between the six studies analysed, the random effects estimates differed from corresponding fixed ones. Investigators should assess heterogeneity of trial results before deriving summary estimates of treatment effect.

Polymorphisms in DNA repair genes modulate survival in cisplatin/gemcitabine-treated non-small-cell lung cancer patients.

BACKGROUND: Impaired DNA repair capacity may favorably affect survival in cisplatin/gemcitabine-treated non-small-cell lung cancer (NSCLC) patients. We investigated the association of survival with genetic polymorphisms in X-ray repair cross-complementing group 1 and group 3 (XRCC3), xeroderma pigmentosum group D (XPD), excision repair cross-complementing group 1, ligase IV, ribonucleotide reductase, TP53, cyclooxygenase-2, interleukin-6, peroxisome proliferator-activated receptor gamma, epidermal growth factor, methylene-tetra-hydrofolate reductase and methionine synthase. PATIENTS AND METHODS: One hundred and thirty-five stage IV or IIIB (with malignant pleural effusion) NSCLC patients treated with cisplatin/gemcitabine from different hospitals of the Spanish Lung Cancer Group were genotyped for 14 different polymorphisms in 13 genes. Polymorphisms were detected by the TaqMan method, using genomic DNA extracted from baseline blood samples. RESULTS: Median survival was significantly increased in patients harboring XRCC3 241 MetMet: 16 months versus 10 months for patients with ThrMet and 14 months for those with ThrThr (P = 0.01). The risk of death ratio was significantly lower for MetMet than for ThrMet patients (hazard ratio, 0.43; P = 0.01). In the multivariate Cox model, XRCC3 241 remained an independent prognostic factor (hazard ratio: XRCC3 241 MetMet, 0.44; P = 0.01), and XPD 751 and XRCC1 399 also emerged as significant prognostic factors (hazard ratios: XPD 751 LysGln, 0.46, P = 0.03; XRCC1 399 ArgGln, 0.61, P = 0.04). No other association was observed between genotype and survival. CONCLUSION: XRCC3 241 MetMet is an independent determinant of favorable survival in NSCLC patients treated with cisplatin/gemcitabine. A simple molecular assay to determine the XRCC3 241 genotype can be useful for customizing chemotherapy.

Femoral and sciatic nerves block (BiBlock) in orthopedic traumatologic lower limbs surgery in patients with multiple sclerosis.

Multiple sclerosis is a progressive demyelinating disease which affects large areas of the brain and of the spinal cord. Stressful events, surgical procedures, general anaesthesia and central blocks seem to be responsible for relapses, with worsening of the disease. So, when we scheduled 2 patients with multiple sclerosis for lower limbs orthopedic traumatologic surgery, we decided to use a peripheral block, and in particular a BiBlock. The patients' evaluation in the immediate postoperative course and 30 days after surgery has shown no relapses of the disease. In the literature, however, data about anaesthesia and multiple sclerosis are few and controversial, sometimes in contrast. Anyway, the use of peripheral blocks has neither anatomic, nor metabolic interferences with the lesion sites of multiple sclerosis. In conclusion, peripheral block is safe and it is the technique of choice for this type of patients, when surgery allows it.

Anaestethic problems in Sanfilippo syndrome. A rare case of adult patient.

The authors report the case of a female patient (41 years old) affected by mucopolysaccharidosis type III or Sanfilippo syndrome submitted to a gynecologic surgical procedure and describe the main anesthesiologic problems. A sub-arachnoid anesthesia with hyperbaric Bupivacain 0.5% was used. This technique proved to be safe and convenient without peri- and postoperative complications.

[Meigs' syndrome and "Meigs' pseudo-syndrome." Report of 2 cases]. / Sindrome di Meigs e "pseudo-sindrome di Meigs". Descrizione di due casi.

BACKGROUND: The aim of this study is to investigate similitudis and differences between the Meigs' syndrome and Meigs' pseudosyndrom. The Meigs' syndrome is an uncommon disease that is characterized by benign ovarian tumor, ascites and pleural effusion. The Meigs' pseudosyndrom is a serious disease that is characterized by malignant ovarian tumor, ascites, pleural effusion. METHODS: We have examined two cases: a case of Meigs' syndrome that is characterized by vomit, abdominal pain, ascites, height serum Ca 125 level; a case of Meigs' pseudosyndrom that is characterized by ovarian adenocarcinoma that is diagnosticated owing to ascites and pleural effusion. CONCLUSIONS: This study suggest that the surgical therapy have a very important role for the complete remission of the disease in the Meigs' syndrome and for the remission of ascites and pleural effusion in the Meigs' pseudosyndrom.

[HPV infection. Clinical features and treatment]. / Infezione da HPV. Aspetti clinici e trattamento.

The aspecific and exiguous symptoms and the lacking information are among the reasons of the diffusion of the vulvo-vaginal papillomatosis. We carried out the present study between 1995 and 1999 in the outpatient clinic of cervico-vaginal pathology of the Second University of Naples. 680 patients (aged between 18 and 56 years) underwent vulvoscopic and colposcopic examination. The did not show any relevant symptoms specific for HPV infection. Among the viral strains, HPV-16 and HPV 18 are able to induce a cervical cancer. To eliminate the pathology the primary prevention is necessary: it consist of both an adequate information about the micro-condilomatosis, the role of the activator agent, the modality of the infection, and the annual screening examinations such as pap-test and colposcopy. As first line treatment during secondary prevention, we utilize Roferon A, and perform diathermocoagulation according with the local diffusion and the degree of the disease (mild, moderate, severe). At the end of the therapy with Roferon A we observed that the infective focus was eliminated in about 60% of the cases and, only for moderate and severe micro-condilomatosis a diathermocoagulation was necessary.

[Second-look in ovarian cancer: laparoscopy or laparotomy?]. / Second-look per cancro dell'ovaio: laparoscopia o laparotomia?

BACKGROUND: The aim of the present study was to compare the laparoscopic second-look with laparotomic second-look as regards the consistency of diagnosis of residual tumoral disease after first step treatment in patients affected by ovarian cancer, and to evaluate the feasibility of the laparoscopic second-look. METHODS: Twenty-one patients affected by ovarian cancer underwent laparoscopic second-look followed by laparotomic second-look. Six months after the first surgical intervention all the patients showed no contraindications to laparoscopic second-look. All the surgeries were performed with the same procedure: after the introduction of the trocars the lysis of adherences was carried out, the whole abdominal cavity was explored, 18 abdominal-pelvic sites were examined, direct biopsies were performed and samples for the cyto- and histological analysis were obtained. RESULTS: Positive predictive value for laparoscopy was 100% (6 out of 6 cases), while negative predictive value was 84% (2 false negative cases out of 12). The complete abdominal-pelvic examination was possible in 95% of cases with laparotomy while in 41% of cases with laparoscopy, because of post-operative severe adherences. CONCLUSIONS: Laparoscopic second-look has a good consistency as regards the diagnosis of residual tumoral disease, but its feasibility is lower than laparotomy owing to the presence of severe adherences and the high risk of intra- and post-operative compliances.

Initial development of a system-wide maternal-fetal outcomes assessment program.

OBJECTIVE: This study was undertaken to develop a comprehensive risk-assessment approach capable of evaluating maternal and fetal outcomes. STUDY DESIGN: Data from 10,984 women and 11,066 infants delivered at 79 military treatment facilities in the United States from 1995 to 1997 were used to develop two individual but complementary risk-adjustment models for maternal and, separately, fetal outcomes. A range of maternal and delivery-related risk variables and clinically important outcomes were identified by expert opinion and selected and weighted with ordinal logistic regression analysis. Receiver operating characteristic curves for the maternal and fetal models were determined. Variation across the facilities in risk-adjusted performance was also evaluated. RESULTS: Risk factors and poor outcomes were rare for both mothers and infants, with 96.9% of infants and 97.7% of mothers having good or excellent outcomes (0.7% mortality and 0.01% mortality, respectively). Despite the low frequency of poor outcomes both models performed well, with receiver operating characteristic curves of 0.75 for maternal outcomes and 0.78 for infant outcomes. When the models were applied to the military treatment facilities, there were significant differences among facilities in risk-adjusted outcomes. Twenty-four of the facilities in the study (30%) had outcomes odds ratios that were significantly >1 or significantly <1 (P <.05). There did not appear to be any relationship between the performance of a military treatment facility for maternal outcome and that for infant outcome. CONCLUSION: Complementary risk models for maternal and infant outcomes were developed that had satisfactory discriminatory power across a variety of facilities within a large health system. With further development and refinement this approach holds promise of being able to detect variations in risk-adjusted performance that could be used to identify best practices. The results might also be used to help coordinate and improve the quality of care for the entire conception-to-delivery process.

Stress-induced changes in the functional electromyographic activity of the masticatory muscles.

The present study was undertaken to assess the effect of a non-experimental emotional stress situation on the functional electromyographic (EMG) activity of the masticatory muscles. The material comprised 15 dental students without signs and symptoms of disorders from the temporomandibular system. The activity of the masseter and anterior temporalis muscles was recorded bilaterally by means of surface EMG. The subjective degree of helplessness of the subjects was assessed and related to the EMG activity response, to assess a possible interrelation. The EMG activity during the stress situation was significantly greater than for the non-stress situation. This shift in EMG activity was seen for all the muscles and all the functions analyzed. No significant gender differences were found. When the subjective degree of helplessness is taken into consideration, women showed significantly higher ratings than male subjects. The Helplessness Scale ratings correlated with the changes in EMG activity.