Druggable targets meet oncogenic drivers: opportunities and limitations of target-based classification of tumors and the role of Molecular Tumor Boards.

The therapeutic landscape of cancer is changing rapidly due to the growing number of approved drugs capable of targeting specific genetic alterations. This aspect, together with the development of noninvasive methods for the assessment of somatic mutations in the peripheral blood of patients, generated a growing interest toward a new tumor-agnostic classification system based on 'predictive' biomarkers. The current review article discusses this emerging alternative approach to the classification of cancer and its implications for the selection of treatments. It is suggested that different types of cancers sharing the same molecular profiles could benefit from the same targeted drugs. Although recent clinical trials have demonstrated that this approach cannot be generalized, there are also specific examples that demonstrate the clinical utility of this alternative vision. In this rapidly evolving scenario, a multidisciplinary approach managed by institutional Molecular Tumor Boards is fundamental to interpret the biological and clinical relevance of genetic alterations and the complexity of their relationship with treatment response.

Immunotherapy in small-cell lung cancer: from molecular promises to clinical challenges.

Management of small cell lung cancer (SCLC) has not changed over the last decades. In more recent years, alterations of DNA repair machinery and other molecular pathways have been identified in SCLC and preclinical data suggest that dysregulation of these pathways might offer new therapeutic opportunities.While immune checkpoint inhibitors (ICIs) have had a major impact on the clinical outcome of several solid tumors, including non-small cell lung cancer, the potential role of ICIs is currently under investigation in SCLC and some promising data are available. However, several clinical and biological hurdles have to be overcome and predictive markers are still eagerly needed. Knowledge of molecular pathways specifically involved in SCLC growth and treatment resistance is essential for a more rational planning of new combinations including ICIs.The present manuscript summarizes the current clinical evidence on immunotherapy in SCLC, describes the molecular bases underlying treatment resistance and discusses the potentialities and the rationale of different therapeutic combinations.

The role of immune microenvironment in small-cell lung cancer: Distribution of PD-L1 expression and prognostic role of FOXP3-positive tumour infiltrating lymphocytes.

INTRODUCTION: The prognosis of small-cell lung cancer (SCLC) is dismal and new effective therapies are needed. Immunotherapy looks promising, but no molecular predictive markers are currently available, and data on immune microenvironment are very limited. METHODS: We retrospectively analysed 104 SCLC cases. Immunohistochemistry evaluation of PD-L1 was performed both on tumour cells (TCs) and on tumour-infiltrating immune cells (TIICs) by using anti-PD-L1 22C3 antibody (DAKO) and categorised by using 1% as cut-off point. Tumour-infiltrating lymphocytes (TILs) were characterised by using anti-CD8 and anti-FOXP3 antibodies. Semi-quantitative score was used and categorised as positive versus negative/low. The relation of molecular markers with prognosis and with clinical variables was evaluated. RESULTS: The analysis included 66 stage I-III patients (48 surgically resected, 18 treated with radical-intent chemoradiotherapy) and 38 metastatic cases. In the overall study population, PD-L1 was expressed on TCs and TIICs in 25% and 40% of cases, respectively. The proportion of PD-L1-positive cases was significantly higher in stage I-III versus metastatic patients (32% versus 13%, p: 0.034 for TCs; 51.5% versus 21% for TIICs, p: 0.002). CD8- and FOXP3-positive TILs were present in 59% and 72% of samples, respectively. The presence of FOXP3-TILs was associated with improved prognosis among non-metastatic patients, with a hazard ratio for survival of 0.32 (95% confidence interval [CI]: 0.16-0.7, p: 0.006) for univariate analysis, and 0.37 (95% CI: 0.17-0.81, p: 0.013) for multivariate analysis. CONCLUSIONS: Immune contexture of SCLC may differ according to stage. The presence of FOXP3-positive TILs is a potential prognostic marker for stage I-III SCLCs and warrants further investigation.

Olfactory event-related potentials: a new approach for the evaluation of olfaction in nasopharyngeal carcinoma patients treated with chemo-radiotherapy.

OBJECTIVE: Olfactory dysfunction is a possible side effect of chemo-radiotherapy performed in patients affected by nasopharyngeal carcinoma. Self-rating measurements and olfactory event-related potentials were used and compared in order to evaluate the impact of this treatment on the olfactory system. METHODS: Nine patients underwent subjective evaluation of olfactory function (using visual analogue scales for olfactory symptoms and quality of life, and a six-item Hyposmia Rating Scale), and a quantitative and objective measurement (olfactory event-related potentials). RESULTS: Spearman's rank correlation analyses highlighted significant relationships between the clinical scales and olfactory event-related potentials. Inter-group analyses showed significant differences in the latency and in the amplitude of olfactory event-related potentials between patients and controls. CONCLUSION: Taking into account the small sample size and the lack of pre-treatment assessment, olfactory event-related potentials seemed to allow a more objective diagnosis of unilateral and bilateral olfactory loss. Moreover, olfactory event-related potentials and subjective scales results were concordant.

[Recanalizing entero-rectal fistula post-colostomy for inoperable rectal cancer]. / Fistola entero-rettale ricanalizzante dopo colostomia sinistra definitiva per tumore del retto inoperabile.

The Authors report a case of a spontaneous intestinal 'recanalization' after 1 year since the palliative surgery (definitive colostomy) for rectal cancer in a 79 years-old patient.

Amyand's hernia: case report and review of the literature.

The authors report a case of gangrenous acute appendicitis in the sac of an inguinal hernia (Amyand's hernia). After a review of the literature, they emphasise the extreme rarity of the case reported, they underline how the clinical picture is highly similar to that of a strangulated inguinal hernia. They affirm that appendicectomy and hernioplasty may be performed at the same time, since the repair of the hernia should be performed without prosthesis implantation due to the contamination of the operating field.

[Surgery of inguinal hernia in the elderly]. / La chirurgia dell'ernia inguinale nel paziente geriatrico.

The authors report their 14 years experiences with inguinal hernia repair in elderly. The result were compared with young (< 75 years old), and confirmed that there were no significant differences between the 2 groups. The study confirmed the safety and effectiveness of the "tension-free" technique under local anaesthesia, which is proposed as the treatment of choice in elderly.

[Indications for preventive tracheostomy in the surgical treatment of non-neoplastic thyroid disease]. / Indicazioni alla tracheostomia precauzionale nella chirurgia delle tireopatie non neoplastiche.

In thyroid surgery, an emergency tracheostomy is mandatory, as is well known, in acute pre- and postoperative asphyxia due to obstruction of the upper airways, especially in cases of malignant tumours. In particular conditions, in the presence of benign thyroid disease and when there is no reduction in the laryngo-tracheal lumen, tracheostomy has an important precautionary function following total thyroidectomy. The authors describe their experience with 6 patients treated by precautionary tracheostomy after total thyroidectomy for benign thyroid disease, analysing the indications and the advantages of this method.

[Incidental diagnosis of seminoma in male infertility: report of a clinical case]. / Diagnosi incidentale di seminoma nell'infertilità maschile: descrizione di un caso clinico.

The aims of the study were to evaluate the association between male infertility and risk of developing testis cancer and to establish guidelines for the early diagnosis of testis neoplasia in subfertile men. 32-year-old infertile man. The patient underwent random testicular biopsy to establish the exact cause of infertility. An incidental diagnosis of seminoma was made and the patient then underwent right testis excision. Anatomopathologic macroscopic examination revealed two nodules, the sizes of which were 0.8 x 0.4 and 0.3 x 0.2 cm, respectively. Histologic examination confirmed the diagnosis of typical seminoma, pT1, with copious lymphocytic struma infiltration. There appears to be a correlation between male infertility and occurrence of seminoma. Diagnosis of testis cancer is often incidental and sometimes occurs in men undergoing testicular biopsy to investigate infertility. Since the biopsy was not specifically targeted in our case, the diagnosis of seminoma was casual. This suggests the need for a careful follow-up, including testicular ultrasonography as a screening test to achieve an early diagnosis of testis cancer in all infertile men, because of their higher risk of developing testis cancer than the normal population.

Hypocalcemia and hypoparathyroidism after total thyroidectomy: a clinical biological study and surgical considerations.

BACKGROUND: Post-operative hypocalcemia is a common and most often transient event afterextensive thyroid surgery. It may be due to iatrogenic injury to the parathyroid glands. AIMS: We carried out a study aimed to evaluate the incidence of hypocalcemia and hypoparathyroidism following extracapsular total thyroidectomy. METHODS: The study was carried out in 312 patients (273 females and 39 males, whose age was between 23 and 76 years, median age 48.61 +/- 14.1) who had undergone total thyroidectomy (TT) in our department from 1995 to 1998 and in 100 patients (72 females and 28 males, whose age was between 24 and 75 years, median age 51.66 +/- 13.4) who had undergone other (non-thyroid) surgery. RESULTS: Post-operative hypocalcemia was observed in 62 patients of the control group (62%) and the decrease of the serum calcium level lasted about 3 days, and went back to normal within the 5th day. In 2 patients undergoing total thyroidectomy, hypocalcemia was considered severe (confirmed for more than 7 days, symptomatic), these had been operated for large multinodular goitre with mediastinal extension. In these patients the symptoms arose acutely about 5 h after the operation. In both cases the clinical and biological aspects went back to normal within 10 days, after a treatment with calcium and vitamin D. Transient asymptomatic hypocalcemia was observed in 234 thyroidectomized patients (75%) and thus did not need any treatment for it. CONCLUSION: The results obtained confirm that transient hypocalcemia can be observed after any operation; and particularly responsible is the decrease of the calcium concerning the proteins. We found that post-operative hypoparathyroidism is due to injury to the parathyroid glands (parathyroid ischaemia or surgical ablation of one or more glands). Here we see the delayed serum calcium level < or = 7.5 mg/dl or the delayed serum phosphorous level > 7.4 mg/dl. The results of our study, with 2 patients presenting transient post-operative hypoparathyroidism, contribute in confirming that the extracapsular total thyroidectomy aimed to reduce any injury to the parathyroid and to the recurrent nerves, represent the better operation also for the extended benignant thyroidopathies.

Amino acid sequence and some ligand binding properties of fatty acid-binding protein from bovine brain.

A fatty acid-binding protein (FABP) from the cytosol of bovine brain was purified by Sephadex G-75 filtration and electrofocusing. The purified protein migrated as a single protein band in 15% polyacrylamide gel electrophoresis with an apparent molecular mass of 14.7 kDa. To ascertain that the purified protein was a FABP, it was submitted to fatty acid-binding tests. Oleic and palmitic acids bound to brain FABP but this was not the case for palmitoyl CoA. By Scatchard analysis the ligand binding values were: Kd = 0.28 microM, Bmax (mol/mol) = 0.6 for oleic acid and Kd = 0.8 microM, Bmax (mol/mol) = 2.1 for palmitic acid. The complete amino acid sequence of the brain FABP was determined and a microheterogeneity was observed. Sequence comparison with other FABPs of known sequence and the observed microheterogeneity demonstrated the presence in brain of several homologous FABPs closely related to heart FABP.

Fatty-acid-binding protein from bovine brain. Amino acid sequence and some properties.

A fatty-acid-binding protein (FABP) from the cytosol of bovine brain was purified by Sephadex G-75 filtration and electrofocusing. The purified FABP behaved as an anionic protein with an apparent molecular mass of 14.7 kDa; its complete amino acid sequence was determined and microheterogeneity was observed. Sequence comparison with other FABPs of known sequence and the observed microheterogeneity demonstrated the presence in brain of several homologous FABPs closely related to heart FABP and bovine mammary-derived growth inhibitor (MDGI).