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Background Immune checkpoint inhibitors (ICIs) have particular, immune-related adverse events (irAEs), as a consequence of interfering with self-tolerance mechanisms. The incidence of irAEs varies depending on ICI class, administered dose and treatment schedule. The aim of this study was to define a baseline (T0) immune profile (IP) predictive of irAE development. Methods A prospective, multicenter study evaluating the immune profile (IP) of 79 patients with advanced cancer and treated with anti-programmed cell death protein 1 (anti-PD-1) drugs as a first- or second-line setting was performed. The results were then correlated with irAEs onset. The IP was studied by means of multiplex assay, evaluating circulating concentration of 12 cytokines, 5 chemokines, 13 soluble immune checkpoints and 3 adhesion molecules. Indoleamine 2, 3-dioxygenase (IDO) activity was measured through a modified liquid chromatography–tandem mass spectrometry using the high-performance liquid chromatography-mass spectrometry (HPLC–MS/MS) method. A connectivity heatmap was obtained by calculating Spearman correlation coefficients. Two different networks of connectivity were constructed, based on the toxicity profile. Results Toxicity was predominantly of low/moderate grade. High-grade irAEs were relatively rare, while cumulative toxicity was high (35%). Positive and statistically significant correlations between the cumulative toxicity and IP10 and IL8, sLAG3, sPD-L2, sHVEM, sCD137, sCD27 and sICAM-1 serum concentration were found. Moreover, patients who experienced irAEs had a markedly different connectivity pattern, characterized by disruption of most of the paired connections between cytokines, chemokines and connections of sCD137, sCD27 and sCD28, while sPDL-2 pair-wise connectivity values seemed to be intensified. Network connectivity analysis identified a total of 187 statistically significant interactions in patients without toxicity and a total of 126 statistically significant interactions in patients with toxicity. Ninety-eight interactions were common to both networks, while 29 were specifically observed in patients who experienced toxicity. Conclusions A particular, common pattern of immune dysregulation was defined in patients developing irAEs. This immune serological profile, if confirmed in a larger patient population, could lead to the design of a personalized therapeutic strategy in order to prevent, monitor and treat irAEs at an early stage.

Our understanding of the gut microbiota has significantly evolved over the last two decades. Advances in the analysis of the gut microbiome continues to reveal complex microbial communities and discoveries about their role in health and diseases, including cancer development, are continuously growing. In addition, research has demonstrated that the use of antibiotics can modulate the gut microbiota composition negatively and influence cancer treatment outcomes, suggesting that antibiotics should be avoided if possible. In this article, we review the role of the gut microbiota in the formation of GI cancers. We show that specific bacterial populations can positively or negatively affect cancer formation with specific attention given to gastric and colorectal cancer. We also review the role of microbial-targeted therapies on cancer treatment outcomes.

Background: Immunotherapy has revolutionized the approach to metastatic triple-negative breast cancers (mTNBC). Atezolizumab was approved for patients with mTNBC whose tumours express PD-L1, determined by SP 142 assay. To assess the availability and practice of SP142 test we administered a survey to all the 15 Pathology Departments of the Lazio Region during a 6-months period.Methods: The survey comprised 12 questions regarding the availability of SP142 in the Pathology Departments, the percentage of positive tests, the difficulties of pathologists in case close to cut-off value and the tested samples.Results: The SP142 assay was available only in 8 Centers. In case of positive result, most Centers (5/8, 62.5%) reported values of PD-L1 expression ranging from > 1 to Conclusion: Our results raise some important issues concerning the evaluation of PD-L1 in the “real-life” setting, providing strategies for its implementation.

2553 Background: Immune checkpoint inhibitors (ICIs) have peculiar, immune-related adverse events (irAEs), as a consequence of interfering with self-tolerance mechanisms. The incidence of irAEs varies by ICI class, administered dose and treatment schedule. The aim of the study was to define a baseline (T0) immune profile (IP) predictive of irAE development. Methods: A prospective, multicenter study evaluating the IP of 79 patients with advanced cancer, treated with anti-PD-1drugs as a first- or second-line setting was performed. The results were then correlated with irAEs onset. The IP was studied by means of multiplex assay, evaluating circulating concentration of 12 cytokines, 5 chemokines, 13 soluble immune checkpoints and 3 adhesion molecules. IDO levels were evaluated through a modified liquid chromatography–tandem mass spectrometry. Data were first pre-processed by performing logarithmic transformation and Shapiro-Wilk-test. A connectivity heatmap was obtained by calculating Spearman correlation coefficients. Two different networks of connectivity were constructed, based on the toxicity profile. Results: Toxicity was predominantly of low/moderate grade. High-grade irAEs were relatively rare, while cumulative toxicity was high (23%). A positive and statistically significant correlation between the cumulative toxicity and IP10 and IL8, sLAG3, sPDL-2 sHEVM, sCD137, sCD27 and sICAM1 was found. Moreover, patients who experienced irAEs had a markedly different connectivity pattern characterized by disruption of most of the paired connections between cytokines (all the connections of the cytokine IL8, most of the connections between the pro-inflammatory chemokines, or all the connections of CD137, CD27, and CD28), while sPDL-2 pair-wise connectivity values seemed to be intensified. Network connectivity analysis identified a total of 187 statistically significant interactions in patients without toxicity and a total of 126 interactions in patients with toxicity. Ninety-eight interactions were common to both networks, while 29 were specifically observed in patients with toxicity. Conclusions: A peculiar pattern of immune dysregulation in patients who develop irAEs was defined. This immune serological profile could lead to the design of a personalized therapeutic strategy in order to prevent, monitor and treat irAEs at an early stage.

Unresectable recurrent and/or metastatic head and neck squamous cell carcinoma (R/M HNSCC) has a very poor prognosis. Soluble immune checkpoints (sICs) are circulating proteins that result from the alternative splicing of membrane proteins and can modulate the immune response to cancer cells. The aim of our pilot study was to determine the possible role of a comprehensive evaluation of sICs in the classification of prognosis and response to treatment in patients with advanced disease. We evaluated several sICs (CD137, CTLA-4, PD-1, PD-L1, PD-L2, TIM3, LAG3, GITR, HVEM, BTLA, IDO, CD80, CD27, and CD28) from peripheral blood at baseline and investigated the association with clinical characteristics and outcomes. A high baseline soluble LAG3 (sLAG3 &gt, 377 pg/mL) resulted in an association with poor PFS and OS (p = 0.047 and p = 0.003, respectively). Moreover, sLAG3 emerged as an independent prognostic factor using an MVA (p = 0.005). The evaluation of sICs, in particular sLAG3, may be relevant for identifying patients with worse prognoses, or resistance to treatments, and may lead to the development of novel targeted strategies.

Objective First-line therapy for metastatic squamous cell carcinoma of the head and neck (R/M HNSCC) has been revolutionized by the introduction of anti-checkpoint monoclonal antibodies, which have shown a significant improvement in overall survival (OS) gaining approval in a first line setting. Efficacy and safety of first-line weekly chemotherapy, compared to 3-weeks treatment, was retrospectively evaluated in a frail patient population with R/M HNSCC with the aim to evaluate its role as part of a personalized first-line approach. Methods A total of 124 patients with locally incurable R/M HNSCC receiving weekly (21) or three-weekly (103) chemotherapy plus cetuximab in a first line setting from December 2010 to September 2020 were retrospectively reviewed. Treatment outcomes in terms of objective response rate (ORR), progression-free survival (PFS), overall survival (OS) and toxicities were analysed. Results Patients in the three-week subgroup were ECOG PS 0 (39) and 1 (64) while patients in weekly group (21) were all PS 2. No significant differences were reported in terms of age, sex, smoking and previous alcohol abuse considering the two distinct subgroups. Moreover, no statistically significant difference was found in PFS and OS between the two treatment subgroups. The response rate was 35% (36 patients) and 34% (7 patients) in three-week and weekly treatment group, respectively. Seventy patients (68%) in the three-week group experienced chemotherapy-related toxicities, predominantly G3. In the weekly group a predominantly low-grade toxicity was found in a lower number of patients (52%). Conclusion The weekly schedule appears to be an active and safe strategy in frail patients with R/M HNSCC. Based on these data, a weekly schedule could be considered as a first line treatment in all frail patients excluded from pembrolizumab treatment and a study on the combination of weekly chemotherapy and immunotherapy should be performed.

Background The response to immunotherapy can be impaired by several factors including external intervention such as drug interactions with immune system. We aimed to examine the immunomodulatory action of opioids, since immune cells express opioid receptors able to negatively influence their activities. Methods This observational, multicenter, retrospective study, recruited patients with different metastatic solid tumors, who have received immunotherapy between September 2014 and September 2019. Immunotherapy was administered according to the standard schedule approved for each primary tumor and line of treatment. The concomitant intake of antibiotics, antifungals, corticosteroids and opioids were evaluated in all included patients. The relationship between tumor response to immunotherapy and the oncological outcomes were evaluated. A multivariate Cox-proportional hazard model was used to identify independent prognostic factors for survival. Results One hundred ninety-three patients were recruited. Overall, progression-free survival (PFS) and overall survival (OS) were significantly shorter in those patients taking opioids than in those who didn’t (median PFS, 3 months vs. 19 months, HR 1.70, 95% CI 1.37–2.09, p p Discussion Our study suggests that the concomitant administration of drugs as well as some clinical features could negatively predict the outcomes of cancer patients receiving immunotherapy. In particular, opioids use during immunotherapy is associated with early progression, potentially representing a predictive factor for PFS and negatively influencing OS as well. Conclusions A possible negative drug interaction able to impair the immune response to anti-PD-1/PD-L1 agents has been highlighted. Our findings suggest the need to further explore the impact of opioids on immune system modulation and their role in restoring the response to immunotherapy treatment, thereby improving patients' outcomes.

Primary squamous cell carcinoma of salivary gland (SCG) is an extremely rare type of malignant salivary gland tumor, which in turn results in scarcity of data available regarding both its treatment and associated genetic alterations. A retrospective analysis of 12 patients with primary SCG was conducted, along with analysis of the association between treatment, clinical/pathological characteristics, and outcomes. Most patients (8) were staged IVa, with the majority of them (10) having G3 fast growing cancer. Local and systemic recurrence were reported in only three out of nine parotid cases (0 out of 2 submandibular SCGs). In two out of eight patients local relapse occurred after integrated treatment, while recurrence occurred in two out of three patients undergoing exclusive surgery. Five patients eventually died. Treatment of resectable disease must be aggressive and multimodal, with achievement of loco-regional control in order to reduce rate of recurrence and improve outcomes. Metastatic disease would require a therapeutic strategy tailored to the molecular profile in order to improve the currently disappointing results.

The role of induction chemotherapy in the multidisciplinary treatment of locally advanced, nonlaryngeal high-risk human papilloma virus (HPV)-negative head and neck squamous cells carcinoma (HNSCC) is uncertain in terms of overall survival (OS). The primary objective of this study was to identify possible predictive factors of survival and outcome in patients with HNSCC who were treated with induction chemotherapy. Fifty-nine patients with stage IVa/b HPV-negative non-laryngeal HNSCC (mostly originating from the oral cavity) who underwent induction chemotherapy at Policlinico Umberto I were reviewed. Treatment outcomes in term of objective response rate (ORR), progression-free survival (PFS), OS and toxicities were analyzed. A significant association between nodal status, ORR, ongoing smoking use, toxicities and OS was demonstrated. ORR (obtained in 61% of patients) was associated with a reduction in mortality of 80% (P< 0.0001). Early discontinuation after just one cycle of induction chemotherapy was associated to a significantly shorter OS. In oral cavity radical surgery with negative margins was obtained in 15/16 patients. In 42% of patients G3-G4 toxicity occurred. Toxicity requiring hospitalization occurred in 42% and 21% of patients with oropharyngeal and oral cavity carcinoma, respectively. Five patients died of treatment-related causes. No treatment-related mortality occurred in oral cavity patients. G5 toxicities were different according to the sub-sites of disease (P = 0.05). Induction chemotherapy in non-laryngeal high-risk HNSCC is an active strategy, most importantly in oral cavity cancer, even though burdened with a high (G ≥ 3) toxicity and early discontinuation rate. These data will however need to be confirmed in further and larger studies.

With the introduction of immune checkpoint inhibitors (ICIs) and next-generation vascular endothelial growth factor receptor&ndash, tyrosine kinase inhibitors (VEGFR&ndash, TKIs), the survival of patients with advanced renal cell carcinoma (RCC) has improved remarkably. However, not all patients have benefited from treatments, and to date, there are still no validated biomarkers that can be included in the therapeutic algorithm. Thus, the identification of predictive biomarkers is necessary to increase the number of responsive patients and to understand the underlying immunity. The clinical outcome of RCC patients is, in fact, associated with immune response. In this exploratory pilot study, we assessed the immune effect of TKI therapy in order to evaluate the immune status of metastatic renal cell carcinoma (mRCC) patients so that we could define a combination of immunological biomarkers relevant to improving patient outcomes. We profiled the circulating levels in 20 mRCC patients of exhausted/activated/regulatory T cell subsets through flow cytometry and of 14 immune checkpoint-related proteins and 20 inflammation cytokines/chemokines using multiplex Luminex assay, both at baseline and during TKI therapy. We identified the CD3+CD8+CD137+ and CD3+CD137+PD1+ T cell populations, as well as seven soluble immune molecules (i.e., IFN&gamma, sPDL2, sHVEM, sPD1, sGITR, sPDL1, and sCTLA4) associated with the clinical responses of mRCC patients, either modulated by TKI therapy or not. These results suggest an immunological profile of mRCC patients, which will help to improve clinical decision-making for RCC patients in terms of the best combination of strategies, as well as the optimal timing and therapeutic sequence.

Background: Previous locoregional treatment could affect the response to nivolumab in platinum-refractory recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC). The aim of this study is to evaluate the impact of the clinicopathological characteristics and previous treatment in predicting early progression to nivolumab in a real-world population. Methods: This is an observational, multicenter retrospective/prospective study including patients (pts) with platinum refractory R/M HNSCC who received nivolumab 240 mg every 2 weeks from October 2018 to October 2019. We analyzed the association between previous treatment, clinicopathological characteristics, and early progression (within 3 months). Results: Data from 61 pts were reviewed. Median age was 67 years (30&ndash, 82). Forty-two pts (69%) received previous locoregional treatment. Early progression to nivolumab occurred in 36 pts (59%), while clinical benefit (stable disease and partial response) was achieved in 25 pts (41%). Early progression to nivolumab was significantly associated to previous locoregional treatment both at univariate and multivariate analysis (p = 0.005 and p = 0.048, respectively). Conclusion: nivolumab in R/M HNSCC is burdened with a high early progression rate. Previous wide neck dissection and high dose radiotherapy may compromise the efficacy of nivolumab, distorting the anatomy of the local lymphatic system and hindering the priming of immune response.

Background: Clinical trials showed that only a subset of patients benefits from immunotherapy, suggesting the need to identify new predictive biomarker of resistance. Indoleamine-2,3-dioxygenase (IDO) has been proposed as a mechanism of resistance to anti-PD-1 treatment, and serum kynurenine/tryptophan (kyn/trp) ratio represents a possible marker of IDO activity.Methods: Metastatic non-small cell lung cancer (NSCLC), renal cell carcinoma (RCC), and head and neck squamous cell carcinoma (HNSCC) treated with nivolumab as second-line treatment were included in this prospective study. Baseline serum kyn and trp levels were measured by high-performance liquid chromatography to define the kyn/trp ratio. The χ2-test and t-test were applied to compare frequencies and mean values of kyn/trp ratio between subgroups with distinct clinical/pathological features, respectively. Median baseline kyn/trp ratio was defined and used as cutoff in order to stratify the patients. The association between kyn/trp ratio, clinical/pathological characteristics, response, progression-free survival (PFS), and overall survival (OS) was analyzed.Results: Fifty-five patients were included. Mean baseline serum kyn/trp ratio was significantly lower in female than in male patients (0.048 vs. 0.059, respectively, p = 0.044) and in patients with lung metastasis than in others (0.053 vs. 0.080, respectively, p = 0.017). Mean baseline serum kyn/trp ratio was significantly higher in early progressor patients with both squamous and non-squamous NSCLC (p = 0.003) and with a squamous histology cancer (19 squamous NSCLC and 14 HNSCC, p = 0.029). The median value of kyn/trp ratio was 0.06 in the overall population. With the use of median value as cutoff, patients with kyn/trp ratio > 0.06 had a higher risk to develop an early progression (within 3 months) to nivolumab with a trend toward significance (p = 0.064 at multivariate analysis). Patients presenting a baseline kyn/trp ratio ≤0.06 showed a longer PFS [median 8 vs. 3 months; hazard ratio (HR): 0.49; 95% confidence interval (CI) 0.24–1.02; p = 0.058] and a significantly better OS than did those with a kyn/trp ratio > 0.06 (median 16 vs. 4 months; HR: 0.39; 95% CI 0.19–0.82; p = 0.013).Conclusion: Serum kyn/trp ratio could have both prognostic and predictive values in patients with solid tumor treated with immunotherapy, probably reflecting a primary immune-resistant mechanism regardless of the primary tumor histology. Its relative weight is significantly related to gender, site of metastasis, NSCLC, and squamous histology, although these suggestive data need to be confirmed in larger studies.

The immune checkpoint inhibitors, a class of drugs able to block immune suppressive pathways in order to prime an anticancer immunity, revolutionized standard of care in platinum-refractory recurrent and/or metastatic head and neck carcinoma (R/M HNSCC). The PD-1/ PD-L1 axis is involved in the genesis, maintenance and progression of HNSCC and represents the target of checkpoint inhibitors. HNSCC is an immunosuppressive disease with a high inflammatory component in tumor microenvironment. Recent clinical trials showed that only a small subset of patients really benefits from immunotherapy. This review aims to highlight the five W-points of immunotherapy: why immunotherapy is promising in HNSCC, what is currently available in daily clinical practice, when immunotherapy can be integrated into the therapeutic strategy, where it can be useful according to predictive response biomarker, who, among patients, could get the best benefit from immunotherapy and how improve the achieved results.

Two or more histological types characterize more than 60% of testicular germ cell tumors (GCTs). Burned-out testicular tumor refers to partial or complete histological regression of the primary testicular lesions. The most frequent GCT type involved in this kind of histological regression is choriocarcinoma, followed by embryonal carcinoma. To our knowledge, there are no cases of the burned-out phenomenon in teratoma. We report a case of a 19-year-old man presenting to our institute with a right testicular lesion, evidence of mediastinal and abdominal lymph node metastasis, and high levels of GCT serum biomarkers. After orchiectomy, the histopathological examination showed a mixed GCT: mature teratoma, immature teratoma, and histological features of testicular cancer regression (burned-out phenomenon). The patient underwent first-line chemotherapy (BEP regimen) which resulted in a complete instrumental and biochemical response after 4 cycles. Teratoma is considered a less aggressive type of GCT. In this particular case, metastatic disease seems to result from non-germ cell components which underwent early spontaneous regression.

Data from 423 human epidermal growth factor receptor 2-negative (HER2−), hormone receptor-positive (HR+) advanced breast cancer (aBC) patients treated with palbociclib and endocrine therapy (ET) were provided by 35 Italian cancer centers and analyzed for treatment outcomes. Overall, 158 patients were treated in first line and 265 in second/later lines. We observed 19 complete responses and 112 partial responses. The overall response rate (ORR) was 31% (95% confidence interval [CI], 26.6–35.4) and clinical benefit was 52.7% (95% CI, 48–57.5). ORR was negatively affected by prior exposure to everolimus/exemestane (p = 0.002) and favorably influenced by early line-treatment (p < 0.0001). At 6 months, median progression-free survival was 12 months (95% CI, 8–16) and median overall survival was 24 months (95% CI, 17–30). More favorable outcomes were associated with palbociclib in early lines, no visceral metastases and no prior everolimus/exemestane. The main toxicity reported was neutropenia. Our results provide further support to the use of palbociclib with ET in HER2−, HR+ aBC. Differences in outcomes across patients subsets remain largely unexplained.

Simple Summary Mesenchymal triple negative breast cancer subtype expresses genes involved in proliferation, epithelial to mesenchymal transition, stromal interaction and cell motility. Moreover, this subgroup is characterized by an immunosuppressive microenvironment. This review focuses on the intracellular pathways involved in tumorigenesis and cancer progression, as well as in the immune evasion mechanisms. Furthermore, we provide an overview of current clinical trials investigating the efficacy and safety of different therapeutic molecules for this aggressive subtype of triple negative breast cancer. The challenge is to restore immunocompetence by overcoming the chemo and immune-resistance profile of mesenchymal triple negative breast cancer to achieve a lasting response to therapy. Abstract The pathologic definition of triple negative breast cancer (TNBC) relies on the absence of expression of estrogen, progesterone and HER2 receptors. However, this BC subgroup is distinguished by a wide biological, molecular and clinical heterogeneity. Among the intrinsic TNBC subtypes, the mesenchymal type is defined by the expression of genes involved in the epithelial to mesenchymal transition, stromal interaction and cell motility. Moreover, it shows a high expression of genes involved in proliferation and an immune-suppressive microenvironment. Several molecular alterations along different pathways activated during carcinogenesis and tumor progression have been outlined and could be involved in immune evasion mechanisms. Furthermore, reverting epithelial to mesenchymal transition process could lead to the overcoming of immune-resistance. This paper reviews the current knowledge regarding the mesenchymal TNBC subtype and its response to conventional therapeutic strategies, as well as to some promising molecular target agents and immunotherapy. The final goal is a tailored combination of cytotoxic drugs, target agents and immunotherapy in order to restore immunocompetence in mesenchymal breast cancer patients.

e18508 Background: Immunotherapy is the standard of care in the treatment of platinum-refractory recurrent/metastatic head and neck squamous cell carcinoma (R/M-HNSCC). Previous loco-regional treatment could have an impact on the immune system and response to Nivolumab. The aim of this study is to evaluate the efficacy and safety of Nivolumab in a real world population, identifying the impact of the clinic-pathological characteristics and previous treatment in prediction of early progression. Methods: This is a observational, multicenter retrospective/prospective study including patients (pts) with platinum refractory R/M HNSCC who received Nivolumab 240 mg every 2 weeks until disease progression or unacceptable toxicity, from October 2018 to October 2019. We analyzed treatment outcomes in term of early progression (within 3 months), clinical benefit, progression free survival (PFS) and overall survival (OS). To determine the influence on outcomes, the following variables were investigated: primary tumor sub-site, age, gender, ECOG, previous loco-regional treatment, previous systemic therapy, metastatic site. Results: Data from 61 pts were reviewed: 15 oral cavity, 14 oropharynx, 7 hyphofarynx, 19 larynx, 6 paranasal sinus. Median age was 66 years (29-82), 48 pts were men. Forty-nine pts (80%) had performance status (ECOG) ≥ 1 at baseline evaluation. Eleven pts (18%) had only loco-regional recurrence, while 50 pts (82%) had one or more metastatic site. 32 (52%) and 17 pts (28%) had smoking and alcohol abuse history, respectively. 44 pts (72%) received surgery followed by adjuvant radiant treatment at standard dose (28, 46%) or concomitant definitive radiotherapy (16, 26%) as upfront treatment with curative intent. With a median follow up of 4 months (range 1-11), early progression occurred in 39 pts during Nivolumab treatment (64%), while clinical benefit (stable disease and partial response) was achieved in 22 pts (36%). No G3-G4 toxicities occurred. Early progression to Nivolumab was significantly associated to previous loco-regional treatment both at univariate and multivariate analysis (p=0.003 and p= 0.04, respectively). Conclusions: Nivolumab in R/M HNSCC is effective and safe even though burdened with a high early progression rate. Loco-regional treatment, including wide neck dissection and high dose radiotherapy, may compromise the efficacy of Nivolumab, distorting the anatomy of the local lymphatic system and hindering the priming of immune response.

e18506 Background: In head and neck squamous cell carcinoma (HNSCC) only a small subset of patients (pts) really benefits from immunotherapy, suggesting the need of validated molecular and immunological predictive biomarkers. The aim of the study was to evaluate both the genomic and immune profile of HNSCC correlating it to early progression to immunotherapy. Methods: This is a pilot study evaluating immune and molecular profile in platinum-refractory HNSCC pts treated with Nivolumab. Blood samples were collected at baseline (T0) and at second cycle of therapy (T1). The immune profile was studied by multiplex assay, evaluating circulating: CD137, CTLA4, PD1, PDL1, PDL2, CD27, TIM3, LAG3, GITR, HVEM, BTLA, CD80, CD28 and IDO. The comprehensive genomic profile was evaluated at baseline on formalin-fixed paraffin-embedded samples of the tumor through Foundation One Cdx test. The results obtained were correlated with early progression (within 3 months from the start of therapy). Results: Ten pts were enrolled in the study. Early progression occurred in 6 pts (60%). Median progression free survival and overall survival were 3 months (1-11) and 6.5 months (1-12), respectively. In all patients ≥ 5 genetic mutations were detected; median number of mutation was 6 (5-14); 8/10 pts had a tumor mutational burden less than 10 Muts/mb. The more frequent genetic alterations involved the cycline-dependent-kynase pathway (9/10), the transcription factor associated gene TP53 (8/10) and the PI3K-Akt-PTEN signaling pathways (5/10). Less frequent alterations involved FGFR family (4/10), NOTCH signaling pathway (3/10) and TERT (4/10). Early progression was slightly associated with the number of mutations detected (p = 0.06). The rising or falling trend of circulating levels of biomarkers were detected in 9/10 pts and included modification in IDO (1/10), LAG3 (3/10), GITR (3/10), BTLA (3/10), CD137 (4/10), CTLA4 (4/10), PD1 (2/10), Tim3 (3/10), CD28 (3/10), HVEM (3/10), CD80 (2/10). No modifications were recorded in PDL1, PDL2 and CD27. Conclusions: Our results, although in a small cohort, highlighted the complexity and heterogeneity of landscape in HNSCC pts. A novel evaluation that combines molecular and immune profile is needed. In the context of a poor prognosis disease the combination of personalized molecular and immune approaches could represent a promising strategy to improve survival.

Salivary gland malignant tumor (SGMT) is a malignant disease requiring multidisciplinary approach. The rare incidence and the consequent lack of robust evidence-based medicine has called for a comprehensive update to draw recommendations for clinical practice. This paper is a summary of the XXX Head and Neck Unit guidelines regarding the management of SGMT. Recommendations include the indications for exclusive and adjuvant therapy, as well as metastatic management, for both major and minor SGMT.

Background: The aim of this study was to assess the surgical and oncological outcome for the management of endometrial cancer (EC) by laparoendoscopic single-site surgery (LESS). Patients and Methods: We performed a retrospective chart review of patients who underwent a LESS for EC. All the patients were treated by the same surgical team between July 2009 and June 2013 at the Gynaecologic Oncologic Unit, Regina Elena National Cancer Institute, Rome, Italy. Results: A total of 50 women were included, with a median age of 45 years (range, 39-84 years) and a median body mass index (BMI) of 21.8 kg/m2 (range, 19-48 kg/m2). Median operative time was 100 min (range, 50-240 min), median blood loss was 90 mL (range, 10-300 mL) and median hospital stay was 3 days (range, 2-9 days). The median number of pelvic lymph nodes retrieved was 14 (range, 5-20). No intraoperative complications occurred, but there were 4 postoperative complications. Two patients required a laparoscopic conversion. The median follow-up was 36 months (range, 16-62 months) and no recurrence occurred. Conclusion: Our report showed that the LESS approach in the treatment of early EC can be a safe and reliable technique in terms of surgical and oncological outcomes.

Objective The primary aim is to evaluate the surgical and oncological outcome of robotic radical hysterectomy (RRH) plus pelvic lymphadenectomy in locally advanced cervical cancer (LACC) after neoadjuvant chemotherapy (NACT). The secondary aim is to compare the surgical and oncological results of RRH after NACT with a historical cohort of patients undergoing laparoscopic radical hysterectomy or abdominal radical hysterectomy plus pelvic lymphadenectomy for LACC after NACT. Methods We enrolled a total of 41 patients in this study with LACC undergoing RRH, who achieved a clinical partial or complete response to NACT. The surgical and oncological outcomes of 2 historical groups were compared: the laparoscopic group (41 patients) with the laparotomic group (43 patients). Results The median estimated blood loss, operative time, and length of hospital stay were statistically significant and in favor of the robotic group. No conversion to laparotomy in the robotic group was necessary. There were no significant differences between the 3-year overall survival and disease-free survival rates in the minimally invasive groups; nevertheless, the robotic group showed the same recurrence rate of laparoscopic in a short-interval follow-up. Conclusions The robotic approach could be considered a feasible and safe alternative to other surgical options. Multicenter randomized clinical trials with longer follow-ups are necessary to evaluate the overall oncologic outcomes of this procedure.

Objective To compare surgical outcomes and cost of robotic single-site hysterectomy (RSSH) versus robotic multiport hysterectomy (RMPH) in early stage endometrial cancer. Methods This is a retrospective case-control study, comparing perioperative outcomes and costs of RSSH and RMPH in early stage endometrial cancer patients. RSSH were matched 1:2 according to age, body mass index, comorbidity, the International Federation of Gynecology and Obstetric (FIGO) stage, type of radical surgery, histologic type, and grading. Mean hospital cost per discharge was calculated summarizing the cost of daily hospital room charges, operating room, cost of supplies and length of hospital stay. Results A total of 23 women who underwent RSSH were matched with 46 historic controls treated by RMPH in the same institute, with the same surgical team. No significant differences were found in terms of age, histologic type, stage, and grading. Operative time was similar: 102.5 minutes in RMPH and 110 in RSSH (p=0.889). Blood loss was lower in RSSH than in RMPH (respectively, 50 mL vs. 100 mL, p=0.001). Hospital stay was 3 days in RMPH and 2 days in RSSH (p=0.001). No intraoperative complications occurred in both groups. Early postoperative complications were 2.2% in RMPH and 4.3% in RSSH. Overall cost was higher in RMPH than in RSSH (respectively, $7,772.15 vs. $5,181.06). Conclusion Our retrospective study suggests the safety and feasibility of RSSH for staging early endometrial cancer without major differences from the RMPH in terms of surgical outcomes, but with lower hospital costs. Certainly, further studies are eagerly warranted to confirm our findings.

Objective To compare different techniques of minimally invasive surgery (laparoscopy and robotics) to abdominal surgery in order to identify the optimal surgical technique in the treatment of endometrial cancer. Methods and materials A single-institutional, matched, retrospective, cohort study was performed. All patients with clinical stage I or occult stage II endometrial cancer who underwent robotic hysterectomy, bilateral salpingo-oophorectomy ± lymphadenectomy from August 2010 and December 2013 were identified. Surgical and oncological outcomes were compared with patients matched by age, body mass index, tumor histology, and grade, who underwent abdominal or laparoscopic surgery between January 2001 and December 2013. Results Three groups were identified: 177 laparotomies (group A), 277 laparoscopies (group B) and 72 robotics (group C). There were no statistically significant differences between the three groups in terms of age, BMI and FIGO stage. The operative time was shortest in group B (p = 0.0001). Blood loss and transfusions were equivalent in group B and C, while they were greater in group A (p = 0.0001). The intra-operative, early and late postoperative complications, rate of conversion, the re-intervention and median hospital stay were lower in group C. The rate of recurrence and death from disease was similar in all three groups. Conclusions Minimally invasive surgery was superior to abdominal surgery in terms of surgical outcomes. Robotic surgery was superior to laparoscopy in terms of intra- and post-operative complications, conversion rates, length of hospital stay and re-interventions. In terms of oncological outcomes the three groups were equivalent.

Objective To compare the surgical outcome of robotic radical hysterectomy (RRH) versus laparoscopic radical hysterectomy (LRH) for the treatment of locally advanced cervical cancer (LACC) after neoadjuvant chemotherapy (NACT). Materials and methods From August 1st 2010 to July 1st 2012 a prospective data collection of women undergoing RRH for cervical cancer stage FIGO IB2 to IIB, after neoadjuvant chemotherapy, was conducted at National Cancer Institute “Regina Elena” of Rome. All patients deemed operable underwent class C1 RRH with pelvic lymphadenectomy within 4 weeks from the last chemotherapy cycle. Results A total of 25 RRH were analyzed, and compared with 25 historic LRH cases. The groups did not differ significantly in body mass index, stage, histology, number of pelvic lymph nodes removed. The median operative time was the same in the two groups with 190 min respectively. The median estimated blood loss (EBL) was statistically significant in favor of RRH group. Median length of stay was shorter, for the RRH group (4 versus 6 days, P = 0.28). There was no significant difference in terms of intraoperative and postoperative complications between groups but in the RRH group we observed a greater number of total complications compared to the control group. Conclusion This study shows that RRH is safe and feasible in LACC after NACT compare to LRH. However, a comparison of oncologic outcomes and cost–benefit analysis is still needed and it has to be carefully evaluated in the future.

Background Papillary thyroid carcinoma is rarely associated with metastatic disease. The most common sites of metastasis are the lungs and bones, while only few cases of ovarian metastasis are described in literature. Case We report the case of a 51 years old woman, treated 9 years before for papillary thyroid carcinoma, presenting to our Institute with a pelvic ovarian mass revealed by ultrasound imaging. After bilateral salpingo-oophorectomy, the histologic examination detected a left ovarian metastasis from papillary thyroid carcinoma. Conclusion Even if the diagnosis of ovarian metastasis from thyroid carcinoma is often controversial, it should be considered when a woman with an ovarian lesion of unknown origin, has a personal history of malignant thyroid disease. Virtual Slides The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/13000_2014_193

In the last decades, minimally invasive surgery has taken a leading role in the treatment of benign and malignant gynecological pathology. The introduction at first of laparoscopy and then of da Vinci robotic system has made possible the improvement of morbidity and surgical outcomes in the gynecological surgery. The last goal in minimally invasive surgery has been to get better cosmesis results and to decrease the postoperative pain reducing the size and number of ports needed to complete the surgical procedures. Laparoendoscopic single-site surgery (LESS) contemplates the use of a single skin incision within the umbilicus instead of the multiple ports created in the traditional laparoscopy. The development of technology and the introduction of new laparoscopic instruments have allowed to improve the application of LESS surgery in many surgical specialties. The published literature has showed that it was possible to overcome some technical challenges, making LESS safe and feasible in the achievement of complex surgery. However, new trials and data are needed to define the long-term surgical outcomes.