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Several studies have shown that different tumour types sharing a driver gene mutation do not respond uniformly to the same targeted agent. Our aim was to use an unbiased network-based approach to investigate this fundamental issue using BRAFWe applied SWIM, a software able to identify putative regulatory (switch) genes involved in drastic changes to the cell phenotype, to gene expression profiles of different BRAFWe identified lung adenocarcinoma as the tumour with the highest number of switch genes (298) compared to its normal counterpart. By looking for switch genes encoding for kinases with homology sequences similar to known vemurafenib targets, we found that thyroid cancer and lung adenocarcinoma have a similar number of putative targetable switch gene kinases (5 and 6, respectively) whereas colorectal cancer has just one.We are persuaded that our network analysis may aid in the comprehension of molecular mechanisms underlying the different responses to vemurafenib in BRAF

Purpose Nodules located in the upper pole of the thyroid may carry a greater risk for malignancy than those in the lower pole. We conducted a study to analyze the risk of malignancy of nodules depending on location. Methods The records of patients undergoing thyroid-nodule fine-needle aspiration cytology (FNAC) at an academic thyroid cancer unit were prospectively collected. The nodules were considered benign in cases of a benign histology or cytology report, and malignant in cases of malignant histology. Pathological findings were analyzed based on the anatomical location of the nodules, which were also scored according to five ultrasonographic classification systems. Results Between November 1, 2015 and May 30, 2018, 832 nodules underwent FNAC, of which 557 had a definitive diagnosis. The prevalence of malignancy was not significantly different in the isthmus, right, or left lobe. Among the 227 nodules that had a precise longitudinal location noted (from 219 patients [155 females], aged 56.2±14.0 years), malignancy was more frequent in the middle lobe (13.2%; odds ratio [OR], 9.74; 95% confidence interval [CI], 1.95 to 48.59). This figure was confirmed in multivariate analyses that took into account nodule composition and the Thyroid Imaging, Reporting, and Data System (TIRADS) classification. Using the American College of Radiologists TIRADS, the upper pole location also demonstrated a slightly significant association with malignancy (OR, 6.92; 95% CI, 1.02 to 46.90; P=0.047). Conclusion The risk of thyroid malignancy was found to be significantly higher for mid-lobar nodules. This observation was confirmed when suspicious ultrasonographic features were included in a multivariate model, suggesting that the longitudinal location in the lobe may be a risk factor independently of ultrasonographic appearance.

Guidelines recommend thyroid-stimulating hormone (TSH) suppression before the first response to treatment assessment in papillary thyroid cancer (PTC) patients. The aim of this study was to assess the rate of structural disease (SD) in low- and intermediate-risk PTC patients according to TSH levels measured 1 year after primary treatment.A consecutive, prospective series of low- and intermediate-risk PTC patients with 3-years follow-up was collected. TSH, thyroglobulin (Tg), antithyroglobulin antibodies (TgAb), and neck ultrasonography (US) 1 and 3 years after primary treatment were analyzed. Recurrence risk and disease status at 1 year were defined according to the American Thyroid Association (ATA) guidelines and as the presence or absence of SD after 3 years. Patients were grouped according to TSH level at 1 year: group 1, TSH0.1 μUI/mL; group 2, TSH 0.1 to 0.5 μUI/mL; group 3, 0.5 to 2 μUI/mL; and group 42 μUI/mL.This study included 263 patients (70.9% female, median age 47.2 years) of whom the risk of recurrence was low in 170 (65%), intermediate-low in 63 (24%), and intermediate-high in 30 (11%). The response to initial treatment at 1 year was excellent in 149 (57%), biochemical incomplete in 18 (7%), indeterminate in 84 (32%), and structural incomplete in 12 (4%). Group 1 consisted of 53 (20%) patients, group 2 of 85 (32%), group 3 of 61 (23%), and group 4 of 64 (24%). The rate of SD at 1 and 3 years from primary treatment was not significantly different between TSH groups.TSH suppression before the first response to treatment assessment does not appear to influence the rate of SD evaluated 1 and 3 years after primary treatment.ATA = American Thyroid Association; DTC = differentiated thyroid cancer; FTC = follicular thyroid cancer; LT4 = levothyroxine; PTC = papillary thyroid cancer; SD = structural disease; Tg = thyroglobulin; TgAb = antithyroglobulin antibodies; TSH = thyroid-stimulating hormone; US = ultrasonography.

Mutations in TERT promoter have been detected in the more aggressive papillary thyroid cancers (PTCs). To elucidate the role of TERT as an eligible molecular target in these tumors, the expression of hTERT was analyzed in a series of PTCs and the effects of both pharmacological and RNA-interference-induced hTERT silencing were investigated in two human PTC cell lines (K1 and BCPAP). The expression levels of hTERT mRNA and protein were evaluated by real-time PCR and western blot assays, respectively. Effects of hTERT silencing on PTC cell lines were analyzed by MTT, migration and western blot assays. Pharmacological inhibition of hTERT was performed using two bromodomain and extra-terminal (BET) inhibitors, JQ1 and I-BET762. hTERT expression results increased in 20 out of 48 PTCs, including tumors either positive or negative for the presence of hTERT promoter and/or BRAF mutations. In K1 and BCPAP cells, hTERT silencing determined a reduction in cell viability (~50% for K1 and ~70%, for BCPAP, vs control) and migration properties that were associated with a decrease of AKT phosphorylation and β-Catenin expression. Moreover, hTERT mRNA levels were down-regulated by two BET inhibitors, JQ1 and I-BET762, which at the same dosage (0.5 and 5 µM) reduced the growth of these thyroid cancer cells. These findings demonstrate that hTERT may represent an excellent therapeutic target in subgroups of aggressive PTCs.

Context The prevalence of thyroid nodules in the general population is increasingly high, and at least half of those biopsied prove to be benign. Sonographic risk-stratification systems are being proposed as “rule-out” tests that can identify nodules that do not require fine-needle aspiration (FNA) cytology. Objective To comparatively assess the performances of five internationally endorsed sonographic classification systems [those of the American Thyroid Association, the American Association of Clinical Endocrinologists, the American College of Radiology (ACR), the European Thyroid Association, and the Korean Society of Thyroid Radiology] in identifying nodules whose FNAs can be safely deferred and to estimate their negative predictive values (NPVs). Design Prospective study of thyroid nodules referred for FNA. Setting Single academic referral center. Patients Four hundred seventy-seven patients (358 females, 75.2%); mean (SD) age, 55.9 (13.9) years. Main Outcome Measures Number of biopsies classified as unnecessary, false-negative rate (FNR), sensitivity, specificity, predictive values, and diagnostic ORs for each system. Results Application of the systems’ FNA criteria would have reduced the number of biopsies performed by 17.1% to 53.4%. The ACR Thyroid Imaging Reporting and Data System (TIRADS) allowed the largest reduction (268 of 502) with the lowest FNR (NPV, 97.8%; 95% CI, 95.2% to 99.2%). Except for the Korean Society of Thyroid Radiology TIRADS, all other systems exhibited significant discriminatory performance but produced significantly smaller reductions in the number of procedures. Conclusions Internationally endorsed sonographic risk stratification systems vary widely in their ability to reduce the number of unnecessary thyroid nodule FNAs. The ACR TIRADS outperformed the others, classifying more than half the biopsies as unnecessary with a FNR of 2.2%.

This study aimed to identify clinicopathological factors associated with the outcome of elderly patients with gastric cancer (GC), and to construct a nomogram for individual risk prediction. Tumor characteristics of 143 patients aged ≥ 80 years underwent surgery for GC were collected and analyzed by uni- and multivariate analyses. A prognostic nomogram was constructed using the factors which resulted to be significantly associated with overall survival. Discrimination of nomogram was tested by Kaplan–Meier (KM) curves and boxplots. With a median follow up of 18.37 months, overall 1-year survival rate was 51% and it was 60 and 40% for older and younger than 83 years, respectively (P = 0.003). Univariate analysis indicated that age (P = 0.008), pre-operatory performance status (P

Tonsillar metastases are absolutely rare. Small cell lung cancer (SCLC) is known to be the most frequent histological type of tonsillar metastases, however the way of tumor cells spreading to tonsil remains controversial. We described a case report of 76-year-old man with SCLC and tonsillar metastases, to highlight the importance of oral cavity evaluation as a part of a clinical exam and to show the rare tumor cells spreading.

Background In recent years, proton pump inhibitors (PPIs) have been investigated at high-dose to modulate tumour microenvironment acidification thus restoring chemotherapeutic sensitivity. Moreover, several clinical data supports the role of cytotoxic drugs at low-dose continuously delivered as anticancer therapy. Methods Clinical records of three patients affected with gastrointestinal cancer refractory to standard treatments, who had received a combination of high-dose rabeprazole and metronomic chemotherapy were reviewed. Results The first case, a 78-year-old man was treated for lung metastasis from colon adenocarcinoma. The second case, a 73-year-old man was treated for metastatic rectal cancer to the liver. The third one, a 68-year-old man, underwent the combination regimen for colon cancer with lung, liver and peritoneal metastases. Conclusions Despite the failure of previous standard chemotherapy for metastatic disease, good clinical outcome was shown in these patients treated with an unconventional association of high-dose PPIs and metronomic chemotherapy.

Hyperprogressive disease (HPD) has been recently proposed as a new pattern of progression in patients treated with immune checkpoint inhibitors (ICIs). Until now, no biological marker has been found to predict this accelerated tumour growth. We describe the case of a 62-year-old women who experienced a marked increase in absolute eosinophil count (AEC) concurrently with a huge radiological progression after the first nivolumab dose in absence of other immune-related adverse events (irAEs). Further investigations are needed to establish the role of early hypereosinophilia as a marker of progression and to identify patients who might not benefit from ICI treatment.

Incidental sonographic discovery of thyroid nodules is an increasingly common event. The vast majority is benign, and those that are malignant, are generally associated with an indolent course and low mortality. Sonographic scoring systems have been developed to help clinicians identify nodules that warrant prompt fine-needle aspiration cytology (FNAC), but they are based largely on experience with papillary thyroid cancers. We analyzed the performance of four scoring systems widely used for this purpose (American Thyroid Association Guidelines, American Association of Clinical Endocrinologists/American College of Endocrinology/Associazione Medici Endocrinologi Guidelines, European Thyroid Imaging Reporting and Data System, and Korean Thyroid Imaging Reporting and Data System) in patients whose nodules proved to be metastases from other solid cancers. Such nodules reportedly account for 0.2% to 3% of all thyroid malignancies. Each scoring system was used to assess retrospectively the malignancy risk and indications for FNAC of five patients’ thyroid nodules that were ultimately diagnosed as metastases (from renal cell carcinoma, breast cancer, and lung cancer in two cases and esophageal cancer). The primaries identified in these cases are those most commonly reported to metastasize to the thyroid. In two cases, the thyroid metastases were the first sign of undetected neoplastic disease. Although sonography alone cannot distinguish thyroid metastases from primary thyroid malignancies, all four scoring systems classified the metastatic nodules as suspicious enough to require FNAC. The five cases accounted for 0.2% of those cytologically examined in our center. In most cases, cytology provided useful guidance for the subsequent management of these lesions, which differs from that of primary thyroid cancers and requires multidisciplinary input., Sonographic systems for assessing the risk of primary thyroid cancer in thyroid nodules can also guide management decisions for the rare nodules that prove to be metastases from other solid tumors.

ROS1+ patients represent a unique molecular subset of non-small cell lung cancer (NSCLC). Early phase clinical trials have shown a high response rate to crizotinib in these patients. We describe a case of an 18 years old woman, never smoker, with NSCLC ROS1+ and miliary brain metastases treated with crizotinib and radiotherapy. From October 2014 to June 2015 the Patient was treated with crizotinib. The first intracranial time to progression (IT-TTP) occurred after 7 months; the patient underwent stereotactic radiosurgery (SRS) and continued TKI treatment. The second IT-TTP appeared after 16 months. A continued response in the chest was observed for all the 23 months of crizotinib treatment. At the progression, we assessed programmed death ligand 1 (PD-L1) expression by immunohistochemistry, that resulted highly expressed. Our report indicates that the integration of crizotinib with local treatments should be considered in ROS1 NSCLC patients experiencing oligometastatic progression. Moreover, this case is an example of PD-L1 strong in oncogene addicted patients.

Pancreatic tumours, the majority of which arise from the exocrine pancreas, have recently shown an increasing incidence in western countries. Over the past few years more and more new selective molecules directed against specific cellular targets have become available for cancer therapy, leading to significant improvements. However, despite such advances in therapy, prognosis of pancreatic cancer remains disappointing. Metronomic chemotherapy (MCT), which consists in the administration of continuous, low-dose anticancer drugs, has demonstrated the ability to suppress tumour growth. Thus, it may provide an additional therapeutic opportunity for counteracting the progression of the tumour. Here we discuss evidence arising from preclinical and clinical studies regarding the use of MCT in pancreatic cancer. Good results have generally been achieved in preclinical studies, particularly when MCT was combined with standard dose chemotherapy or antinflammatory, antiangiogenic and immunostimolatory agents. The few available clinical experiences, which mainly refer to retrospective data, have reported good tolerability though mild activity of metronomic schedules. Further studies are therefore awaited to confirm both preclinical findings and the preliminary clinical data.

In recent years, many anticancer drugs have been tested at metronomic dosages for a variety of tumours. Mechanisms of action attributed to metronomic chemotherapy (MCT) include antiangiogenesis, immunomodulation, direct inhibition of tumour growth, effect on tumour initiating cells and the modulation of clonal evolution. An active clinical research, aimed at testing MCT in several cancers, has been conducted over the past 15 years. However, because the majority of available results come from earlier phase II studies, mainly performed in the area of breast cancer (BC), it is clear that there are areas still to be investigated. We considered current studies dealing with MCT according to the clinical setting of patients. Despite a certain degree of overlap, we were able to identify four main clinical indications for MCT: refractory disease and frailty of patients, advanced stage disease (requiring first and second-line therapy), early stage disease and maintenance therapy after induction chemotherapy. In addition, a section of this review has been addressed to the combination of MCT with immunotherapy following the growing interest in the reinstatement of immune-surveillance. Crucial questions, such as the definition of optimal schedules of continuously delivered, low-dose chemotherapy and the recognition and validation of predictive biomarkers, need to be further addressed. Moreover, comparisons with the best supportive care are especially lacking and thus urgently awaited to establish the key role of MCT in the care of pretreated and frail patients. Maintenance therapy promises to be one of the most worthwhile developments for MCT. Currently, several combination strategies with standard chemotherapy, target agents or immunotherapy are under investigation but further efforts are needed to fill the gaps of knowledge in this field.

On account of the lack of predictive biomarkers of toxicity, we investigated whether polymorphisms of genes involved in fluoropyrimidine metabolism and 5-fluorouracil (5-FU) degradation rate were associated with outcomes of adjuvant capecitabine in patients with early stage gastrointestinal cancers. Genotyping of DPYD GIVS14A, MTHFR C677T and A1298C SNPs were performed by pyro-sequencing technology. PCR analysis was used for genotyping TYMS-TSER. We also evaluated the 5-FU degradation rate, which determines the amount of drug consumed by PBMC in a time unit. Association of these variables with clinical outcome was evaluated using multivariate logistic regression analysis. One hundred forty-two patients with early stage colon (39%), rectal (28%), stomach (20%) and pancreatic (13%) cancer, treated with adjuvant capecitabine, were included in this retrospective analysis. Seventy and 20% of the patients suffered from at least one G1–4 and G3–4 adverse events, respectively. According to the 5-FU degradation rate, three and 13 patients were assigned as poor ( 2.1 ng/mL/106 cells/min) metabolizers, respectively. At a multivariate logistic regression analysis, an altered 5-FU degradation rate (values 2.10 ng/mL/106 cells/min) was associated with grade 3–4 adverse events (OR = 2.09, 95% CI: 1.14–3.82, P = 0.01). No correlation was reported between toxicity and gene polymorphisms except for hand–foot syndrome that was more frequent in the MTHFR 1298CC homozygous variant genotype (OR = 2.03, 95% CI 1.04–3.96, P = 0.03). 5-FU degradation rate may be regarded as possible predictive biomarker of capecitabine toxicity in early stage gastrointestinal cancer.

Background Many studies have disclosed the prognostic effect of microsatellite instability (MSI) and/or loss of mismatch repair proteins in colorectal cancer. Nevertheless, little evidence supports their role in the decision-making of adjuvant therapy for patients with stage II disease. Materials and Methods The aim of this systematic review was to evaluate the prognostic and/or predictive role of MSI status in patients with stage II colorectal cancer on disease-free survival and overall survival. MEDLINE, EMBASE, and Cochrane libraries were searched to identify eligible studies. Results Only 2 of 389 articles identified fulfilled the eligibility criteria. In both treated and untreated patients, high-level MSI improved disease-free survival compared with low-level MSI, suggesting a prognostic role but not supporting the hypothesis of a predictive effect of MSI. Conclusions Further studies are needed to explore the predictive role of MSI/mismatch repair proteins, because available data do not allow definitive conclusions.

In recent years, metronomic chemotherapy, consisting of continuous administration of low doses of cytotoxic agents, has being used as rescue therapy for different tumours. The aim of this study was to retrospectively assess the efficacy and safety of low-dose metronomic, oral capecitabine in pretreated or frail patients with recurrent upper gastrointestinal tract cancer. Patients with pretreated upper gastrointestinal tract cancer or who were not candidates for standard chemotherapy because of toxicity concerns received capecitabine at 1500 mg per day continuously until disease progression or occurrence of toxicity. Forty-seven patients (25 oesophagogastric cancer, 22 pancreatobiliary cancer; 25 men, 22 women; median age 69 years, range 42-90) were included in the study. Forty-five percent of the patients had received at least two previous lines of treatment and the median number of previous treatments was 1 (range 0-5). Twelve (31.6%) patients achieved clinical benefit (one partial response, 11 stable disease), whereas nine (23.7%) patients were progression free for at least 6 months. In an exploratory analysis, there was a significant relationship between performance status and clinical benefit (hazard ratio=8.25; P=0.01). The median overall survival was 5 months. A good performance status was associated with a longer survival (hazard ratio=0.26; P

The aim of the study was to retrospectively assess the efficacy and safety of low-dose metronomic oral capecitabine in pretreated or frail patients with recurrent colorectal cancer. Patients with recurrent colorectal cancer and prior treatment with fluoropyrimidines, oxaliplatin, and irinotecan or unable to receive standard chemotherapy because of toxicity concerns were included. Treatment consisted of oral capecitabine 1,500 mg daily until disease progression or unacceptable toxicity. Response rates were determined according to RECIST criteria. The end points were disease control rate [(DCR) consisting of complete response, partial response (PR), and stable disease (SD)], overall survival (OS), and safety. Sixty-eight patients, median age 72.5 years, were treated. The median number of previous treatments was 2 (range 0–5). Sixty-two percent of patients had received ≥2 previous lines of treatment. The overall DCR was 26 %, PR in 2 (3 %) and SD in 14 (23 %). Nineteen percent of patients were progression free for at least 6 months. In an exploratory analysis, there was a significant relation of performance status with DCR (HR = 3.3; P = 0.05). The median OS was 8 months. DCR was associated with a longer survival (HR = 0.4; P < 0.01). Grade 3 toxicities included anemia (1), diarrhea (1), and hand-foot syndrome (1). There were no cases of grade 4 toxicity or treatment-related deaths. Metronomic capecitabine was moderately active and well-tolerated in pretreated or frail patients with recurrent colorectal cancer.

Rationale: Small bowel adenocarcinoma (SBA) is an uncommon gastrointestinal cancer, thus limited data about treatment for advanced disease are available. The lack of specific guidelines has justified the use of therapeutic protocols usually applied in advanced colorectal cancer. Few and preliminary data have suggested possible clinical benefit from the use of target therapy such as bevacizumab and cetuximab. Patient concerns: We present the case of a young woman who was admitted to the emergency department for acute abdominal pain, nausea, and vomiting related to a jejunal stenosis. Diagnoses: An enteroscopy with jejunal biopsy showed poorly differentiated cancerous cells suggestive for primary intestinal cancer. There were no signs of metastatic disease at radiological evaluation. A jejunal resection was subsequently carried out and the diagnosis of mucinous adenocarcinoma of the jejunum was confirmed. Interventions: The computed tomography scan performed 1 month after surgery showed metastatic disease. Therefore, the patient received combined protocols of chemotherapy and either bevacizumab or the anti-epidermal growth factor receptor (EGFR) panitumumab. Outcomes: A partial response (PR) was achieved with Folfox plus panitumumab and a maintenance therapy with panitumumab is being conducted with a mild toxicity and a progression free survival of 19 months since the beginning of panitumumab. Lessons: This is, to the best of our knowledge, the first report in the literature of a patient with SBA who has benefitted from panitumumab with an overall survival of 83 months.

Here, we evaluate clinical trials on chemotherapy for patients with pancreatic or biliary tract cancer after first-line treatment failure. Clinical trials on conventional and innovative medical treatments for progressive pancreatic and biliary cancer were analyzed. Metronomic chemotherapy, which consists of the administration of continuative low-dose of anticancer drugs, was also considered. A significant extension of overall survival was achieved with second-line, regimens in patients with gemcitabine-refractory pancreatic cancer. Moreover, many Phase II studies, including chemotherapy and target molecules and immunotherapy, have reported promising results, in both pancreatic and biliary cancer. However, data in these patients' setting are very heterogeneous, and only few randomized studies are available.

Rationale:Regorafenib is the new standard third-line therapy in metastatic colorectal cancer (mCRC). However, the reported 1-year overall survival rate does not exceed 25%.Patient concerns:A 55-year-old man affected by mCRC, treated with regorafenib combined with stereotactic body radiothera

Lung cancer is the leading cause of cancer-related death around the world; the addition of chemotherapy to treatment of this disease has been shown to significantly increase progression-free survival and overall survival. Despite newer chemotherapies, it is important to personalize the care (treatment and dose) upon each single patient's susceptibility for controlling and reducing adverse side-effects, at best. The present review describes the current status of pharmacogenomics studies regarding germline DNA variants that may alter response and tolerability to chemotherapeutic agents used to treat lung cancer, including perspective studies.

Simple Summary Considering the high incidence and mortality of breast cancer, a lot of trials evaluating new drugs for the treatment of this disease are currently ongoing. However, few drugs show a statistically and clinically significant improvement in the outcomes leading to the Competent Authority approval. In this review we analyzed the European Medicines Agency breast cancer drug indications issued between January 2015 and June 2021 and we evaluated the clinical trials results leading to the approval and their update. Abstract Breast cancer represents the first cause of cancer worldwide and the leading cause of cancer mortality for women. Therefore, new therapies are needed to improve the prognosis of women diagnosed with this disease. In this review, we summarize the new drug indications for the treatment of breast cancer approved by European Medicines Agency between January 2015 and June 2021. In particular, we analyzed the clinical trials results leading to approvals and their update (when available), according to setting (localized and locally advanced or metastatic) and clinical features (hormone receptor positive, HER2 positive, triple negative, BRCA 1/2 mutation). The aim of this paper is to describe the clinical benefit obtained with the new indications.