Locally advanced rectal cancer:The importance of a multidisciplinary approach

Rectal cancer accounts for a relevant part of colorectal cancer cases,with a mortality of 4-10/100000 per year.The development of locoregional recurrences and the occurrence of distant metastases both influences the prognosis of these patients.In the last two decades,new multimodality strategies have improved the prognosis of locally advanced rectal cancer with a significant reduction of local relapse and an increase in terms of overall survival.Radical surgery still remains the principal curative treatment and the introduction of total mesorectal excision has significantly achieved a reduction in terms of local recurrence rates.The employment of neoadjuvant treatment,delivered before surgery,also achieved an improved local control and an increasedsphincter preservation rate in low-lying tumors,with an acceptable acute and late toxicity.This review describes the multidisciplinary management of rectal cancer,focusing on the effectiveness of neoadjuvant chemoradiotherapy and of post-operative adjuvant chemotherapy both in the standard combined modality treatment programs and in the ongoing research to improve these regimens.

Medical treatment for gastro-entero-pancreatic neuroendocrine tumours

Gastro-entero-pancreatic neuroendocrine neoplasms(GEPNENs) represents a various family of rare tumours. Surgery is the first choice in GEP-NENs patients with localized disease whilst in the metastatic setting many other treatment options are available. Somatostatin analogues are indicated for symptoms control in functioning tumours. Furthermore they may be effective to inhibit tumour progression. GEP-NENs pathogenesis has been extensively studied in the last years therefore several driver mutations pathway genes have been identified as crucial factors in their tumourigenesis. GEP-NENs can over-express vascular endothelial growth factor(VEGF), basic-fibroblastic growth factor, transforming growth factor(TGF-α and-β), platelet derived growth factor(PDGF), insulin-like growth factor-1(IGF-1) and their receptors PDGF receptor, IGF-1 receptor, epidermal growth factor receptor, VEGF receptor, and c-kit(stem cell factor receptor) that can be considered as potential targets. The availability of new targeted agents, such as everolimus and sunitinib that are effective in advanced and metastatic pancreatic neuroendocrine tumours, has provided new treatment opportunities. Many trials combing new drugs are ongoing.

Gastro-entero-pancreatic neuroendocrine tumors:Is now time for a new approach?

Gastro-entero-pancreatic tumors(GEP-NETs) are rare neoplasms often characterized by an overexpression of somatostatin receptors.Thus,radiolabeled somatostatin analogues have showed an increasing relevance both in diagnosis and treatment,especially in low-and intermediate-differentiated GEP-NETs.These evidences have led to a growing development of new functional imaging techniques as 68 Ga-DOTATATE positron emission tomography/computed tomography(PET/CT) proved useful in the management of these neoplasms.However these tumors have a heterogeneous behavior also modifying their aggressiveness through time.Therefore sometimes 18 F-fluorodeoxyglucose PET/CT appears to be more appropriate to obtain a better assessment of the disease.According to these considerations,the combination of different functional imaging techniques should be considered in the management of GEP-NETs patients allowing clinicians to choose the tailored therapeutic approach among available options.

Are liver nested stromal epithelial tumors always low aggressive?

Nested stromal-epithelial tumor(NSET) is a nonhepatocytic and non-biliary tumor of the liver consisting of nests of epithelial and spindled cells with associated myofibroblastic stroma and variable intra-lesional calcification and ossification, which represents a very rare and challenging disease. Most of the reported cases have been treated with surgery, obtaining a long survival outcome. Here, we report the case of a 31-year-old Caucasian man who underwent surgery at our institution for a large, lobulated, multinodular mass of the right hemi-liver. The histological exam confirmed the diagnosis of NSET. After 6 mo from surgery, a liver recurrence was described and a chemoembolization was performed. After a further disease progression, based on the correlation between the histological features of the disease and those of the hepatoblastoma, a similar chemotherapy regimen(with cisplatin and ifosfamide/mesna chemotherapy, omitting doxorubicin due to liver impairment) was administered. However, infection of the biliary catheter required a dose modification of the treatment. No benefit was noted and a progression of disease was radiologically assessed after only four cycles. The worsening of the clinical status prevented further treatments, and the patient died a few months later. This case report documents how the NSET might have an aggressive and non-preventable behavior. No chemotherapy schedules with a proved efficacy are available, and new data are needed to shed light on this rare neoplasm.

New findings on thymic epithelial tumors:Something is changing

Thymic epithelial tumors(TETs) are uncommon neoplasms with a wide range of anatomical, clinical, histological and molecular malignant entities. To date the management of TETs within clinical practice is based on a multimodal therapeutic strategy including surgery, chemotherapy and radiotherapy with a multidisciplinary approach and prognostic evaluation is mainly based on Masaoka staging and World Health Organization classification. Therefore novel strategies are needed, especially for refractory and/or recurrent TETs and for thymic carcinomas that present a poor prognosis. Personalized approaches are currely being developed and molecular targets are emerging from recent integrated genomic analyses. Targeted therapy will represent an important treatment option for TETs with an aggressive histology. To date, data indicate that vascular endothelial growth factor molecules, insulinlike growth factor 1 receptor, cyclin-dependent kinases and mammalian target of rapamycin may be potentially useful as targeted biological therapies.

BRCA mutations and gastrointestinal cancers:When to expect the unexpected?

BRCA1/2 pathogenic variants are widely known as major risk factors mainly for breast and ovarian cancer,while their role in gastrointestinal(GI)malignancies such as colorectal cancer(CRC),gastric cancer and oesophageal cancer(OeC)is still not well established.The main objective of this review is to summarise the available evidence on this matter.The studies included in the review were selected from PubMed/GoogleScholar/ScienceDirect databases to identify published articles where BRCA1/2 pathogenic variants were assessed either as a risk factor or a prognostic/predictive factor in these malignancies.Our review suggests that BRCA1/2 might have a role as a risk factor for colorectal,gastric and OeC,albeit with differences among these diseases:In particular BRCA1 seems to be much more frequently mutated in CRC whereas BRCA2 appears to be much more closely associated with gastric and OeC.Early-onset cancer seems to be also associated with BRCA1/2 mutations and a few studies suggest a positive prognostic role of these mutations.The assessment of a potentially predictive role of these mutations is hampered by the fact that most patients with these diseases have been treated with platinum compounds,where it is expected that a higher probability of response should be seen.A few clinical trials focused on poly(ADPribose)polymerase inhibitors use in GI cancers are currently ongoing.

Syndrome of inappropriate antidiuresis in prostate adenocarcinoma with neuroendocrine differentiation: a case report and literature review

Syndrome of inappropriate antidiuresis (SIAD) is a common paraneoplastic syndrome commonly associated with thoracic malignancies, gastrointestinal cancers and kidney tumors. It is defined as hyponatremia in euvolemic patients, often due to abnormal secretion of antidiuretic hormone by tumor cells. Tolvaptan, a vasopressin-2-receptor antagonist, is currently recommended for patients affected by SIAD with mild or moderate symptoms. Among patients with prostatic cancer, SIAD represents a rare condition but it is frequently associated with poorly differentiated adenocarcinoma or pure small-cell carcinoma histotype. We report a case of SIAD appeared at disease progression in a 60-year-old male patient with acinar adenocarcinoma with neuroendocrine differentiation together with a literature review.

Immunotherapy in colorectal cancer treatment: actual landscape and future perspectives

Colorectal cancer(CRC)represents the second most common cancer in Europe with marked differences in prognosis and response to treatments.In the past years research showed emerging interest in genomic and immunologic fields.The clinical heterogeneity,that occurs during the pathogenesis of CRC,is driven by chromosomal alterations and defective function of DNA mismatch repair genes.CRC is classified in four consensus molecular subtypes(CMS)with different immunogenic characteristics and prognosis.CMS1 microsatellite instable(MSI)-like and CMS4,both characterized by high levels of immune infiltration,are recognized as the most immunogenic subtypes,even though functional characteristic leading to different prognosis are reported.In particular,MSI tumors have been identified as the best candidates for immunotherapy treatment and a number of studies have evaluated the efficacy of anti-programmed cell death ligand-1(PDL-1)and anti-cytotoxic T-lymphocyte-associated protein 4(CTLA4)in this setting.However,literature data show that the majority of patients with CRC have microsatellite stable(MSS)tumors and this status seems related to lower response to PDL-1/programmed cell death-1 or CTLA4 blockade.The aim of this paper is to investigate the role of immunotherapy in MSI and MSS CRC.

Medical therapy for advanced gastro-entero-pancreatic and bronchopulmonary neuroendocrine tumors

Neuroendocrine tumors(NETs)represent a spectrum of rare neoplasms arising in different organism sites.Depending on the site of onset,they also can be distinguished using lab exams(secreting vs.nonsecreting),clinical symptoms(functioning vs.nonfunctioning),behavioral,morphological characteristics(tumor cells’architectural growth patterns,mitotic and Ki-67 index,presence of necrosis),and grade of cellular differentiation.The aim of this review is to focus on the main signaling pathways targeted by medical treatments of advanced sporadic gastro-entero-pancreatic(GEP)and bronchopulmonary(BP)neuroendocrine neoplasms.The scientific literature regarding treatment of advanced GEP and BP-NETs has been extensively reviewed using MEDLINE and PubMed databases,selecting principal and more recent research articles,clinical trials,and updated guidelines.Somatostatin analogues represent a valid approach to control symptoms in functioning tumors and to inhibit tumor progression in certain categories on the basis of the typical somatostatin receptor expression observed in NETs.The pathogenesis of NETs has been the subject of increased interest in recent years.Many driver mutations pathway genes have been identified as important factors in the carcinogenesis process and,therefore,as potential targets for new anticancer therapies.Activating mutations have been shown in epidermal growth factor receptor,stem cell factor receptor,platelet-derived growth factor receptor,vascular endothelial growth factor,basic-fibroblastic growth factor,transforming growth factor,insulin-like growth factor-1,and their receptors.Effective M-Tor inhibition pathway modulation has led to the approval of drugs in this field such as everolimus.New drugs and several combination regimens with targeted and newer biological agents are being developed and tested in recently conducted and ongoing trials.

Neuroendocrine tumors:a multidisciplinary approach for a complex disease

Neuroendocrine neoplasms include a heterogeneous group of neoplasms,representing a spectrum of rare neoplasms arising in different organism sites with different malignant potential and behavior.They typically occur in gastrointestinal and bronchopulmonary tracts.

Squamous cell carcinoma of the lung: clinical criteria for treatment strategy

Aim:Primary lung cancer is the leading cause of human cancer deaths worldwide,and squamous cell carcinoma(SCC)is one of the most frequent histologic subtypes.The aim of our study was to analyze clinical factors potentially affecting the overall outcome of advanced lung SCC patients.Methods:A series of 72 consecutive patients with advanced SCC undergoing chemotherapy at our institution between January 2007 and July 2013 were eligible for our analysis.Results:By univariate analysis,a better overall survival(OS)was related to response to first-line chemotherapy:median OS were 19.7 vs.7.17 months,respectively,for responders and nonresponders patients(P<0.0001).Eastern Cooperative Oncology Group performance status,gender,and surgery were other prognostic factors.No signifi cant relationship between OS and smoking status,age,body mass index,or type of treatment was found.In the third-line setting,a better OS was associated with objective response to second-line treatment(P=0.015).Conclusion:Our results suggest that differences in OS seem strictly associated with clinical response to previous treatments.These data should be considered in the therapeutic strategy and management of patients with SCC of the lung.

Electrolyte disorders in cancer patients: a systematic review

Electrolyte disorders are very common complications in cancer patients. They might be associated to a worsening outcome, influencing quality of life, possibility to receive anticancer drugs, and conditioning survival. In fact, they might provoke important morbidity, with dysfunction of multiple organs and rarely causing life-threatening conditions. Moreover, recent studies showed that they might worsen cancer patients' outcome, while a prompt correction seems to have a positive impact. Furthermore, there is evidence of a correlation between electrolyte alterations and poorer performance status, delays in therapy commencement and continuation, and negative treatment outcomes. These alterations usually involve sodium, potassium, calcium, and magnesium serum levels. Several causes might contribute to electrolyte disorders in cancer patients: cancer effects, such as paraneoplastic syndrome of inappropriate antidiuresis and tumor lysis syndrome;anti-cancer therapies;and other concomitant clinical conditions or treatments. However, the origin of the electrolyte disorder is often multifactorial, thus identifying and correcting the causes is not always feasible. Furthermore, they are often not recognized or not considered in clinical practice, worsening these alterations and patient condition. An improvement of knowledge about the physiological mechanisms underlying electrolyte disorders is necessary to strengthen their identification and set up a prompt, adequate, and effective treatment. The aim of this systematic review is to provide an analysis of the pathophysiological mechanisms of electrolyte abnormalities in cancer patients to facilitate their identification, management, and therapy to improve patient outcome.

Tailored therapy in patients treated with fluoropyrimidines: focus on the role of dihydropyrimidine dehydrogenase

Fluoropyrimidines are widely used in the treatment of solid tumors, mainly gastrointestinal, head and neck and breast cancer. Dihydropyrimidine dehydrogenase (DPD) is the rate-limiting enzyme for catabolism of 5-FU and it is encoded by DPYD gene. To date, many known polymorphisms cause DPD deficiency and subsequent increase of 5-FU toxicity. In addition, reduced inactivation of 5-FU could lead to increased 5-FU intracellular concentration and augmented efficacy of this drugs. Therefore DPD expression, particularly intratumoral, has been investigated as predictive and prognostic marker in 5-FU treated patients. There also seems to be a tendency to support the correlation between DPD expression and response/survival in patients treated with fluoropyrimidine even if definitive conclusions cannot be drawn considering that some studies are conflicting. Therefore, the debate on intratumoral DPD expression as a potential predictor and prognostic marker in patients treated with fluoropyrimidines is still open. Four DPD-polymorphisms are the most relevant for their frequency in population and clinical relevance. Many studies demonstrate that treating a carrier of one of these polymorphisms with a full dose of fluoropyrimidine can expose patient to a severe, even life-threatening, toxicity. Severe toxicity is reduced if this kind of patients received a dose-adjustment after being genotyped. CPIC (Clinical Pharmacogenetics Implementation Consortium) is an International Consortium creating guidelines for facilitating use of pharmacogenetic tests for patient care and helps clinicians ensuring a safer drug delivery to the patient. Using predictive DPD deficiency tests in patients receiving 5FU-based chemotherapy, in particular for colorectal cancer, has proven to be a cost-effective strategy.