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Luigi Rossi, Foteini Vakiarou, Federica Zoratto, Loredana Bianchi, Anselmo Papa, Enrico Basso, Monica Verrico, Giuseppe Lo Russo, Salvatore Evangelista, Guilia Rinaldi, Francesca Perrone-Congedi, Gian Paolo Spinelli, Valeria Stati, Davide Caruso, Alessandra Prete, Silverio TomaoDepartment of Medico-Surgical Sciences and Biotechnologies, "Sapienza" University of Rome, Rome, Italy; Oncology Unit, ICOT, Latina, ItalyAbstract: Management of metastatic colorectal cancer requires a multimodal approach and must be performed by an experienced, multidisciplinary expert team. The optimal choice of the individual treatment modality, according to disease localization and extent, tumor biology, and patient clinical characteristics, will be one that can maintain quality of life and long-term survival, and even cure selected patients. This review is an overview of the different therapeutic approaches available in metastatic colorectal cancer, for the purpose of defining personalized therapeutic algorithms according to tumor biology and patient clinical features.Keywords: metastatic colorectal cancer, patient clinical features, tumor biology, multidisciplinary approach

Abstract Introduction Dukes A stages of colorectal cancer are rarely reported to metastasize. Subcutaneous or skin metastases from colon cancer are rare events and usually indicate widespread disease. Case presentation We present the case of a 72-year-old Caucasian woman with Dukes A colorectal cancer at diagnosis and, three years later, a single secondary subcutaneous involvement with no other metastatic sites. The description of this case is supported by critical analysis of its clinical, radiological and pathological features. Our report illustrates that diagnosis can be difficult and controversial when relapse occurs in early stage patients and at uncommon sites. Conclusion The unusual and aggressive course of the reported disease stresses the importance of intensive follow-up in colorectal cancer patients with good prognostic factors.

Abstract Background Metastases to the pituitary gland are rare events, and usually indicate widespread malignant disease. The lung and the breast are the most common sites of primary tumors that metastasize to the pituitary gland. Metastases are more frequent in older patients and the most common symptoms at presentation are diabetes insipidus and visual alterations. Case presentation 72-year-old white woman was treated for a breast carcinoma with right superoexternal quadrantectomy, radiotherapy, and hormone therapy. Twelve years later, the patient presented with bone pain, bilateral progressive visual decline, and onset of hypopituitarism. A diagnosis of secondary bone involvement and pituitary metastasis was made. Conclusion This was an unusual disease course, and stresses the importance of intensive follow-up in patients with breast cancer even many years after the initial diagnosis This case emphasizes that diagnosis can be difficultand controversial when relapse occurs at uncommon sites.

Introduction: Thyroidectomy followed by radioactive iodine therapy (RAI) is the treatment of choice for differentiated thyroid carcinoma (DTC). Serum thyroglobulin (Tg) measurement has proved to be useful for predicting persistent and/or recurrent disease during follow-up of DTC patients. In our study, we evaluated the risk of disease recurrence in patients with papillary thyroid carcinoma (PTC), who were treated with thyroidectomy and RAI, by measuring serum Tg at different time-points: at least 40 days after surgery, in euthyroidism with TSH < 1.5 and usually 30 days before RAI (Tg -30 ), on the day of RAI (Tg 0 ), and seven days after RAI (Tg +7 )., Methods: One hundred and twenty-nine patients with PTC were enrolled in this retrospective study. All patients were treated with 131 I for thyroid remnant ablation. Disease relapse (nodal disease or distant disease) during at least 36 months follow-up was evaluated by serum measurements of Tg, TSH, AbTg at different time points and by imaging techniques (neck ultrasonography, 131 I-whole body scan (WBS) after Thyrogen ® stimulation). Typically, patients were assessed at 3, 6, 12, 18, 24, and 36 months after RAI. We classified patients in five groups: (i) those who developed nodal disease (ND), (ii) those who developed distant disease (DD), (iii) those with biochemical indeterminate response and minimal residual thyroid tissue (R), (iv) those with no evidence of structural or biochemical disease + intermediate ATA risk (NED-I), and (v) those with no evidence of structural or biochemical disease + low ATA risk (NED-L). ROC curves for Tg were generated to find potential discriminating cutoffs of Tg values in all patients' groups., Results: A total of 15 out of 129 patients (11.63%) developed nodal disease and 5 (3.88%) distant metastases, during the follow-up. We found that Tg -30 (with suppressed TSH) has the same sensitivity and specificity than Tg 0 (with stimulated TSH), and it is slightly better than Tg +7 , which can be influenced by the size of the residual thyroid tissue., Conclusion: Serum Tg -30 value, measured in euthyroidism 30 days before RAI, is a reliable prognostic factor to predict future nodal or distant disease, thus allowing to plan the most appropriate therapy and follow-up.

Background: Pembrolizumab is approved in monotherapy for the first-line (1L) of advanced or metastatic NSCLC patients with high PD-L1 (≥50%). Despite a proportion of patients achieve long-term survival, about one-third of patients experience detrimental survival outcomes, including early death, hyperprogression, and fast progression. The impact of clinical factors on early progression (EP) development has not been widely explored., Methods: We designed a retrospective, multicenter study involving five Italian centers, in patients with metastatic NSCLC with PD-L1 ≥ 50%, treated with Pembrolizumab in a 1L setting. EP was defined as a progressive disease within three months from pembrolizumab initiation. Baseline clinical factors of patients with and without EP were collected and analyzed. Logistic regression was performed to identify clinical factors associated with EP and an EP prognostic score was developed based on the logistic model., Results: Overall, 321 out of 336 NSCLC patients treated with 1L pembrolizumab provided all the data for the analysis. EP occurred in 137 (42.7%) patients; the median PFS was 3.8 months (95% CI: 2.9-4.7), and median OS was not reached in the entire study population. Sex, Eastern Cooperative Oncology Group (ECOG) performance status (PS), steroids, metastatic sites ≥2, and the presence of liver/pleural metastasis were confirmed as independent factors for EP by multivariate analysis. By combining these factors, we developed an EP prognostic score ranging from 0-13, with three-risk group stratification: 0-2 (good prognosis), 3-6 (intermediate prognosis), and 7-13 (poor prognosis). The area under the curve (AUC) of the model was 0.76 (95% CI: 0.70-0.81)., Conclusions: We identified six clinical factors independently associated with EP. We developed a prognostic score model for EP-risk to potentially improve clinical practice and patient selection for 1L pembrolizumab in NSCLC with high PD-L1, in the real-world clinical setting.

In this coronavirus 2019 (COVID-19) era, when pneumonitis occurs in patients with lung cancer receiving immune checkpoint inhibitors (ICIs), a major challenge is to make a rapid and correct differential diagnosis among drug-induced pulmonary toxicity, tumour progression, and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-induced pneumonitis. While waiting for polymerase chain reaction (PCR) testing results, an accurate evaluation of the symptoms and serologic features can help us make a first diagnostic hypothesis and quickly start correct treatment. Physicians need a collaborative effort to develop and share a common database reporting clinical (anosmia, dysgeusia), serologic, and radiologic data in ICI-treated patients with lung cancer developing interstitial disease to create an evidence-based clinical diagnostic algorithm. This tool will continue to be helpful when we emerge from the pandemic crisis into a world in which COVID-19 may not have been eradicated to better select the target population requiring the most resource-consuming PCR tests.

The adoption of Immune checkpoint inhibitors (ICIs) allowed the achievement of impressive long-term survival results in non-small cell lung cancer (NSCLC), but most patients develop resistance to ICI treatment over time. Resistance to ICIs is mediated by several complex mechanisms affecting, but not limited to, tumour cell-intrinsic alterations and the tumour microenvironment. The possibility of modulating the immune response by interfering with specific alternative immune receptors, pathways and mediators might provide additional strategies to delay or prevent the development of resistance. Therefore, a greater in-depth investigation and understanding of these mechanisms aims to identify novel classes of immune targets and subsequently to evaluate potential new strategies for overcoming resistance, which will be assessed in this review., (Copyright © 2021 Elsevier B.V. All rights reserved.)

In February 2020, Italy became one of the first countries to be plagued by the SARS-CoV-2 pandemic, COVID-19. In March 2020, the Italian government decreed a lockdown for the whole country, which overturned communication systems, hospital organization, and access to patients and their relatives and carers. This issue had a particular regard for cancer patients. Our Thoracic Oncology Division therefore reorganized patient access in order to reduce the risk of contagion and, at the same time, encourage the continuation of treatment. Our staff contacted all patients to inform them of any changes in treatment planning, check that they were taking safety measures, and ascertain their feelings and whether they had any COVID-19 symptoms. To better understand patients' fears and expectations of during the pandemic period, we created a nine-question interview, administered from April to May 2020 to 156 patients with lung cancer. Patients were classified by age, sex, comorbidity, disease stage, prior treatment, and treatment type. The survey showed that during the pandemic period some patients experienced fear of COVID-19, in particular: women (55% vs. 33%), patients with comorbidities (24% vs. 9%), and patients who had already received prior insult (radiotherapy or surgery) on the lung (30% vs. 11%). In addition, the patients who received oral treatment at home or for whom intravenous treatment was delayed, experienced a sense of relief (90% and 72% respectively). However, only 21% of the patients were more afraid of COVID-19 than of their cancer, in particular patients with long-term (> 12 months) vs. short-term cancer diagnosis (28% vs. 12.5%, respectively). Furthermore, the quarantine period or even just the lockdown period alone, worsened the quality of life of some patients (40%), especially those in oral treatment (47%). Our data demonstrate how lung cancer patients are more afraid of their disease than of a world pandemic. Also this interview indirectly highlights the clinician's major guiding principle in correctly and appropriately managing not just the patient's expectations of their illness and its treatment, but also and especially of the patient's fears., (Copyright © 2020 Catania, Spitaleri, Del Signore, Attili, Radice, Stati, Gianoncelli, Morganti and de Marinis.)

Immune checkpoint inhibitors (ICIs) represent one of the main steps forward for the treatment of advanced or metastatic non-small-cell lung cancer (NSCLC), without oncogenic driver alterations. Despite this recent progress, only a minority of patients achieve a broad and durable benefit and another proportion report poor survival and sometimes fast disease progression, confirming the need to optimise the patient's selection. To date, several issues are unsolved about how to personalise the immunotherapy treatment for individual patients. In this review, analysing data from pivotal randomised clinical trials (RCTs), we discuss patient baseline clinical and demographic features, including sex, age, ECOG performance status, smoking habit and specific site of metastases (liver, bone and brain) that may influence the efficacy outcomes in patients treated with ICIs. The high performance of the ICIs blurred the vision on different efficacy-limiting factors, which require extensive evaluation to improve the understanding ofthe tumour-specificimmune response, in which clinical drivers could be useful for better patient stratification., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background: The 2015 American Thyroid Association (ATA) guidelines proposed a three-category system for estimating the risk of recurrence of differentiated thyroid carcinoma (DTC). This system includes several perioperative features, but not age at diagnosis. However, age has traditionally been recognized as a critical factor in the survival of DTC patients, and the eighth edition of TNM stated that patients older than 55 years were at higher risk of death. In this study, we raised the question of whether age at DTC diagnosis impacts on its risk of recurrence. Specifically, the present study aimed to (i) evaluate the association between age at diagnosis and structural recurrence and (ii) investigate whether age at diagnosis could improve the performance of the ATA system. Methods: During the study period, four institutions selected DTC patients treated with both thyroidectomy and radioiodine and who had follow-up for at least one year. Patients with proven structural evidence of disease during follow-up were identified, and disease-free survival (DFS) was calculated accordingly. Results: The study involved 1603 DTC patients with a median age of 49 years and DFS of 44 months. Disease recurred in 8%. The shortest DFS was found in the oldest patients. The Kaplan-Meier curves were calculated for each decade of age, and there was a significant association with DFS ( p  = 0.0014). Patients older than 55 years had significantly higher risk (hazard ratio [HR] 1.78, 95% confidence interval [CI 1.23-2.56]). The Kaplan-Meier curves of DFS in high-, intermediate- and low-risk groups showed a significant association only in the high-risk group ( p  = 0.0058). Patients older than 55 years had significantly higher risk of relapse over time only in the high-risk group (HR 2.15 [CI 2.01-4.53]). Cox's proportional analysis showed that the age cutoff of 55 years and the ATA system were significant predictors of relapse. Adding age at diagnosis above 55 years to the ATA system identified a subgroup of patients at highest risk for relapse. Conclusions: The age threshold adopted in the eighth edition of TNM staging system for DTC patients' prognosis also identifies cases at higher risk of relapse. Applying age at diagnosis, with a cutoff of 55 years, to the ATA risk stratification system identifies cases at highest risk of relapse.

A novel coronavirus causing severe acute respiratory syndrome (SARS), named SARS-CoV-2, was identified at the end of 2019. The spread of coronavirus disease 2019 (COVID-19) has progressively expanded from China, involving several countries throughout the world, leading to the classification of the disease as a pandemic by the World Health Organization (WHO). According to published reports, COVID-19 severity and mortality are higher in elderly patients and those with active comorbidities. In particular, lung cancer patients were reported to be at high risk of pulmonary complications related to SARS-CoV2 infection. Therefore, the management of cancer care during the COVID-19 pandemic is a crucial issue, to which national and international oncology organizations have replied with recommendations concerning patients receiving anticancer treatments, delaying follow-up visits and limiting caregiver admission to the hospitals. In this historical moment, medical oncologists are required to consider the possibility to delay active treatment administration based on a case-by-case risk/benefit evaluation. Potential risks associated with COVID-19 infection should be considered, considering tumor histology and natural course, disease setting, clinical conditions, and disease burden, together with the expected benefit, toxicities (e.g., myelosuppression or interstitial lung disease), and response obtained from the planned or ongoing treatment. In this study, we report the results of proactive measures including social media, telemedicine, and telephone triage for screening patients with lung cancer during the COVID-19 outbreak in the European Institute of Oncology (Milan, Italy). Proactive management and containment measures, applied in a structured and daily way, has significantly aided the identification of advance patients with suspected symptoms related to COVID-19, limiting their admission to our cancer center; we have thus been more able to protect other patients from possible contamination and at the same time guarantee to the suspected patients the immediate treatment and evaluation in referral hospitals for COVID-19., (Copyright © 2020 de Marinis, Attili, Morganti, Stati, Spitaleri, Gianoncelli, Del Signore, Catania, Rampinelli, Omodeo Salè, Spaggiari, Mastrilli and Passaro.)

Objectives: The incidence of any and of severe-grade immune-related adverse events (irAEs) with second-line nivolumab monotherapy is 31-65 % and 2-5 % respectively. While potentially serious and even fatal, in the absence of an appropriate therapy, such events might be indicators of the activation of the immune system and, potentially, of efficacy., Materials and Methods: We collected the records of 1959 non-small-cell lung cancer (NSCLC) patients treated with nivolumab in the Italian expanded access program, and we registered the appearance of any and of severe grade irAEs. We retrospectively searched for correlations between toxicity and efficacy parameters by using Cox's regression analysis., Results: Overall, 342 (17.8%) patients developed an irAE of any grade. We observed that patients developing irAE of any grade achieved a significantly higher response rate (RR 27.2% vs 15.2%; p < 0.0001), disease control rate (DCR 60.5% vs 40.2%; p < 0.0001), median progression-free survival (mPFS 6.0 months [95% CI 4.9-7.1] vs 3.0 [95% CI: 2.8-3.2], p < 0.0001) and median overall survival (mOS 16.7 months [95% CI: 13.5-19.9] vs 9.4 [95% CI: 8.4-10.4], p < 0.00001) compared to patients who did not. At multivariate analysis the development of an irAE remained an independent indicator of nivolumab efficacy (HR 1.44 [95% CI: 1.22-1.71] p < 0.0001)., Conclusions: This report, performed in Caucasian NSCLC patients, showed that the appearance of irAEs correlated with outcome., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Checkpoint kinases 1 and 2 (CHK1 and CHK2) are important multifunctional proteins of the kinase family. Their main function is to regulate DNA replication and DNA damage response. If a cell is exposed to exogenous damage to its DNA, CHK1/CHK2 stops the cell cycle to give time to the cellular mechanisms to repair DNA breakage and apoptosis too, if the damage is not repairable to activate programmed cell death. CHK1/CHK2 plays a crucial role in the repair of recombination-mediated double-stranded DNA breaks. The other important functions performed by these proteins are the beginning of DNA replication, the stabilization of replication forks, the resolution of replication stress and the coordination of mitosis, even in the absence of exogenous DNA damage. Prexasertib (LY2606368) is a small ATP-competitive selective inhibitor of CHK1 and CHK2. In preclinical studies, prexasertib in monotherapy has shown to induce DNA damage and tumor cells apoptosis. The preclinical data and early clinical studies advocate the use of prexasertib in solid tumors both in monotherapy and in combination with other drugs (antimetabolites, PARP inhibitors and platinum-based chemotherapy). The safety and the efficacy of combination therapies with prexasertib need to be better evaluated in ongoing clinical trials.

Background/aim: The role of anti-PD1/PD-L1 therapy (IO) in NSCLC harboring driver mutations is questionable. This study aimed to examine the efficacy of IO in patients with non-small cell lung cancer (NSCLC) with a KRAS mutation (KRAS + )., Patients and Methods: We retrospectively identified NSCLC patients harboring KRAS mutation treated with IO in our Institution. We analyzed the results in comparison to non-KRAS patients., Results: Among 328 consecutive KRAS + NSCLC patients, 43 (13.1%) received IO in our Institution. In parallel 117 non-KRAS NSCLC patients treated with IO were selected for comparison. The baseline characteristics were similar between the two groups. No significant difference was observed between KRAS + and non-KRAS patients in terms of mPFS (4.6 vs. 3.3 months, p=0.58) or OS (8.1 vs. 13.0 months, p=0.38)., Conclusion: KRAS mutations seem to be irrelevant for selecting patients for IO that could be therefore considered an effective therapy for NSCLC patients, independently of KRAS status., (Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

A clear cell tumor is a histological entity that rarely originates outside of the kidney. We describe a rare case of a clear cell tumor of the lung, also known as "sugar cancer," that occurred in a 74 year-old male patient, and perform a brief literature review. This report highlights the importance of an adequate disease management team, including surgeons, oncologists, and pathologists, to identify the best therapeutic approach to improve survival rates and the quality of life of patients affected by this rare disease., (© 2019 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd.)

The therapeutic management of recurrent malignant gliomas (MGs) is not determined. Therefore, the efficacy of a multimodal approach and a combination systemic therapy was investigated. A retrospective analysis of 26 MGs patients at first relapse treated with multimodal therapy (chemotherapy plus surgery and/or reirradiation) or chemotherapy alone was performed. Second-line chemotherapy consisted of fotemustine (FTM) in combination with bevacizumab (BEV) (cFTM/BEV) or followed by third-line BEV (sFTM/BEV). Subgroup analyses were performed. Multimodal therapy provided a higher overall response rate (ORR) (73 vs. 47%), disease control rate (DCR) (82 vs. 67%), median progression-free survival (mPFS) (11 vs. 7 months; P=0.08) and median overall survival (mOS) (13 vs. 8 months; P=0.04) compared with chemotherapy. Concomitant FTM/BEV resulted in higher ORR (84 vs. 36%), DCR (92 vs. 57%), mPFS (10 vs. 5 months; P=0.22) and mOS (11 vs. 5.2 months; P=0.15) compared with sFTM/BEV. Methylated patients did not experience additional survival benefits with multimodality treatment but had higher mPFS (10 vs 7.1 months; P=0.33) and mOS (11 vs. 8 months; P=0.33) with cFTM/BEV. Unmethylated patients experienced the greatest survival benefit with the multimodal approach (mPFS: 10 vs. 5 months; mOS 11 vs 6 months; both P=0.02) and cFTM/BEV (mPFS: 5 vs. 2 months; mOS 6 vs. 3.2 months; both P=0.01). In conclusion, in recurrent MGs, multimodal therapy and cFTM/BEV provide survival and response benefits. Methylated patients benefit from a cFTM/BEV but not from a multimodal approach. Notably, unmethylated patients had the highest survival benefit with the two strategies.

The relationship between fertility, reproductive hormones, and risk of malignant melanoma has acquired much interest in recent years. Melanocytes are hormonally responsive cells, and some in vitro studies demonstrated that estrogen hormones stimulate the growth of melanocytes. Moreover, estrogen receptors have been identified in melanoma cells, as well as in melanocytic nevi and in normal skin. Some evidences suggest a possible link between fertility treatments and the increased risk of malignant melanoma. This article addresses this association through a scrupulous search of the literature published thus far. The aim of this review is to determine the incidence of malignant melanoma in women treated with fertility drugs and to examine if the exposure to fertility treatments really increases the risk of malignant melanoma. In particular, our analysis focused on the different types of drugs and different treatment schedules used. Finally, this study provides additional insights regarding the long-term relationships between fertility drugs and the risk of malignant melanoma.

Several adverse effects have been related to infertility treatments, such as cancer development. In particular, the relationship between infertility, reproductive strategies, and risk of gynecological cancers has aroused much interest in recent years. The evaluation of cancer risk among women treated for infertility is very complex, mainly because of many factors that can contribute to occurrence of cancer in these patients (including parity status). This article addresses the possible association between the use of fertility treatments and the risk of ovarian cancer, through a scrupulous search of the literature published thus far in this field. Our principal objective was to give more conclusive answers on the question whether the use of fertility drug significantly increases ovarian cancer risk. Our analysis focused on the different types of drugs and different treatment schedules used. This study provides additional insights regarding the long-term relationships between fertility drugs and risk of ovarian cancer.

Introduction: Lymphoepithelioma is a very rare form of malignant tumor originating from epithelial line cells. Its occurrence has potential clinical, therapeutic and prognostic implications. In the present report we describe an unusual case of bladder cancer with two different histological varieties: transition cell carcinoma and lymphoepithelioma-like carcinoma. Lymphoepithelioma-like carcinoma of the bladder has only been rarely reported in the literature to date., Case Presentation: We present the case of a 68-year-old Caucasian man who, after occurrence of hematuria, underwent transurethral resection of a bladder tumor. The results of a histological examination confirmed a high-grade non-muscle-invasive pT1 lymphoepithelioma-like carcinoma of the urinary bladder, associated with a concurrent high-grade transition cell carcinoma. After analyzing the histological features, our patient was subjected to treatment with intra-vesical instillations of bacillus Calmette-Guérin. Our work stresses that diagnosis and therapeutic approaches can be difficult and controversial, especially in the early stages of this rare carcinoma., Conclusions: This report emphasizes the importance of extending our knowledge and experiences regarding this uncommon carcinoma. Further studies are needed to better understand this rare disease and define more accurate diagnostic and therapeutic strategies.