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Purpose of research Revision of the literature on targeted therapy-induced diarrhea (TT-ID). Principal results TT-ID is frequent; the mechanisms are mainly secretive, followed by ischemic or autoimmune ones. The duration of TT-ID is protracted over time. Its intensity is of grade G1–G3 but may be fatal in patients with diffuse colitis or on ipilimumab. However, no specific guidelines are available on management of different grades of TT-ID. Preventive measures with antibiotics, probiotics or activated charcoal should be further investigated. Loperamide is the first choice drug followed by octreotide. The role of corticosteroids is controversial. Conclusion Early assessment and management of TT-ID is essential to prevent the worsening of this side-effect, patients’ hospitalization and dose reduction or oncological treatment discontinuation. Future research is needed to better understand the pathophysiological mechanisms of TT-ID and it should also be investigated whether a specific pharmacological and/or non pharmachological approach is indicated.

The treatment of advanced disease (stage IIIb and IV) of non-small cell lung cancer (NSCLC) is based on systemic treatment with platinum-based chemotherapy or biological compounds depending on the disease molecular profile. In the last few years, intensive investigational efforts in anticancer therapy have led to the registration of new active chemotherapeutic agents, combination regimens, and biological drugs, expanding choices for customizing individual treatment. However, the introduction of new drugs in the clinical setting has led to several new toxicities, creating some difficulties in daily management. Among these, ocular toxicity is generally overlooked as more common toxicities such as myelosuppression, stomatitis, diarrhea, vomiting, “hand–foot syndrome”, and neurological alterations attract greater attention. Ophthalmic complications from cytotoxic chemotherapeutics are rare, transient, and of mild/moderate intensity but irreversible acute disorders are possible. The best way to prevent potential irreversible visual complications is an awareness of the potential for ocular toxicity because dose reductions or early drug cessation can prevent serious ocular complications in the majority of cases. However, given the novelty of many therapeutic agents and the complexity of ocular pathology, oncologists may be unfamiliar with these adverse effects of anticancer therapy. Although toxicities from chemotherapy are generally intense but short lasting, toxicities related to targeted drugs are often milder but longer lasting and can persist throughout treatment. Here we review the principal clinical presentations of ocular toxicity arising from chemotherapy [1–3], target therapies [4], and newly developed drugs and provide some recommendations for monitoring and management of ocular toxicity.

An estimated 25% to 30% of all neuroendocrine tumors (NETs) have their origin in the bronchial tree and into the lungs. Although lung NETs account for less than 1% of all pulmonary malignancies, the incidence of these neoplasms has risen precipitously since the mid 1970s. Currently, according to the 2004 World Health Organization categorization, these tumors are separated into 4 subtypes characterized by increasing biologic aggressiveness: low-grade typical carcinoid (TC), intermediate-grade atypical carcinoid (AC), high-grade large-cell neuroendocrine carcinoma (LCNEC) and small-cell carcinoma (SCLC). Surgery is the treatment of choice for typical and atypical carcinoid lung NETs with loco-regional disease. At diagnosis up to 64% of patients with atypical carcinoid lung NETs present with lymph node metastases, and 5-year survival ranges from 61% to 88%. In contrast, lymph node metastases are present in fewer than 15% of typical carcinoid lung NETs, and 5-year survival exceeds 90%. To date, there is no recognized standard of treatment for advanced carcinoid lung NETs. In recent years only two trials reported intriguing results regarding lung NETs: a phase 2 retrospective study of dacarbazine derivative temozolomide and the phase 3, RADIANT-2 trial in advanced NETs. Successful management requires a multidisciplinary team management. This review is restricted to typical/atypical NETs.

Three EGFR tyrosine kinase inhibitors have been compared to standard chemotherapy as up-front treatment in patients with advanced EGFR-positive NSCLC. We performed a systematic review and meta-analysis using indirect comparisons to estimate the risk/benefit associated with each drug. EGFR-TKIs fared better than chemotherapy in terms of PFS. The relative probability of overall response was gefitinib versus erlotinib 0.96 (95% CI 0.69-1.34), gefitinib versus afatinib 0.91 (95% CI 0.67-1.23), erlotinib versus afatinib 0.94 (95% CI 0.65-1.35). Indirect comparisons for safety showed the RR for diarrhea gefitinib versus erlotinib 0.80 (95% CI 0.63-1.01), gefitinib versus afatinib 0.29 (95% CI 0.20-0.41), erlotinib versus afatinib 0.36 (95% CI 0.25-0.54); for rash gefitinib versus erlotinib 1.00 (95% CI 0.82-1.22), gefitinib versus afatinib 0.41(95% CI 0.25-0.65), erlotinib versus afatinib 0.41 (95% CI 0.25-0.66); for hypertransaminasemia gefitinib versus erlotinib 2.29 (95% CI 1.63-3.23). Our analysis showed that all treatments had similar efficacy but they differ for toxicities.

Thymic epithelial tumors (TETs) are rare primary mediastinal tumors arising from thymic epithelium. Their rarity and complexity hinder investigations of their causes and therapy development. Here, we summarize the existing knowledge regarding medical treatment of these tumors, and thoroughly review the known genetic aberrations associated with TETs and the present status of potential biological treatments. Epidermal growth factor receptor (EGFR), stem-cell factor receptor, insulin-like growth factor-1 receptor (IGF1R), and vascular endothelial growth factors (VEGF-A, VEGF-B, and VEGF-2) are overexpressed in TETs. EGFR overexpression in TETs is associated with higher stage, and IGF1R overexpression has poor prognostic value. Data indicate that anti-IGF1R monoclonal antibodies, and inhibitors of angiogenesis, somatostatin receptors, histone deacetylase, mammalian target of rapamycin, and cyclin-dependent kinases may be active against TETs. Continued investigations in this field could lead to advancement of targeted and biological therapies for TETs.

Recently, a better understanding of the specific mechanisms of oncogene addiction has led to the development of antitumor strategies aimed at blocking these abnormalities in different malignancies, including lung cancer. These abnormalities trigger constitutive activation of tyrosine kinase receptors (RTKs) involved in fundamental cell mechanisms such as proliferation, survival, differentiation and migration, and consequently the aberrant signaling of RTKs leads to cancer growth and survival. The inhibition of aberrant RTKs and downstream signaling pathways has opened the door to the targeted therapy era. In non-small-cell lung cancer (NSCLC), molecular research has allowed the discrimination of different aberrant RTKs in lung cancer tumorigenesis and progression, and thus the identification of several targetable oncogenic drivers. Following the development of small molecules (gefitinib/erlotinib and crizotinib) able to reversibly inhibit the epidermal growth factor receptor (EGFR) and signaling pathways mediated by anaplastic lymphoma kinase (ALK), respectively, the MET signaling pathway has also been recognized as a potential target. Moreover, according to current knowledge, MET could be considered both as a secondary oncogenic mechanism and as a prognostic factor. Several therapeutic strategies for inhibiting activated hepatocyte growth factor receptor (HGFR) and the subsequent downstream signaling transduction have been improved in order to block tumor growth. This review will focus on the MET pathway and its role in resistance to EGFR TK (tyrosine kinase) inhibitors, the different strategies of its inhibition, and the potential approaches to overcoming acquired resistance.

Whether non–small cell lung carcinoma (NSCLC) unveiled by immunohistochemistry (IHC) has the same clinical outcome as those typed by morphology is still matter of debate. A total of 145 stage III-IV, consecutive inoperable NSCLC patients treated by chemotherapy (133 cases) or EGFR tyrosine kinase inhibitor (12 cases) and including 100 biopsies, 11 surgical specimens, and 34 cytological samples had originally accounted for 120 adenocarcinomas (ADs), 19 squamous cell carcinomas (SQCs), and 6 adenosquamous carcinomas (ADSQCs) by integrating morphology and thyroid transcription factor-1 (TTF1)/p40 IHC. Thirty-two NSCLC–not otherwise specified (NSCLC-NOS) cases were identified by morphology revision of the original diagnoses, which showed solid growth pattern ( P < .001), 22 ADs, 5 SQCs, and 5 ADSQCs by IHC profiling ( P < .001), and 10 gene-altered tumors (3 EGFR, 5 KRAS, and 2 ALK). While no significant relationships were observed between response to therapy and original, morphology or IHC diagnoses, driver mutations and tumor differentiation by TTF1 expression, AD run better progression-free survival (PFS) or overall survival (OS) than other tumor types by morphology ( P = .010 and P = .047) and IHC ( P = .033 and P = .046), respectively. Furthermore, patients with NSCLC-NOS confirmed as AD by IHC tended to have poorer OS ( P = .179) and PFS ( P = .193) similar to that of ADSQC and SQC ( P = .702 and P = .540, respectively). A category of less differentiated AD with poorer prognosis on therapy could be identified by IHC, while there were no differences for SQC or ADSQC. The terminology of “NSCLC-NOS, favor by IHC” is appropriate to alert clinicians toward more aggressive tumors.

Dear Editor, Hepatic portal venous gas (HPVG) is a rare clinical entity [1]. The prognosis is mostly correlated with the underlying disease, and for this reason, treatment selection can vary according to its etiology. Although oncological situations represent a minority of cases of HPVG, an increasing use of multislice CT in emergency situation has also led to an increased detection of this condition in the oncological setting. However, further evidence is required to better elucidate the diagnosis of HPVG in oncological patients, its management, and the risk associated with this condition. Here, we report the case of a patient with advanced colorectal cancer and distal intestinal occlusion who received an endoluminal implant and subsequent chemotherapy.

Aim: CD133 positive cells have been identified as tumor initiating cells in non-small cell lung cancer (NSCLC) and have been shown to be resistant to conventional cytotoxic chemotherapy in experimental studies, suggesting a possible role in chemoresistance and disease relapse. However their prognostic relevance in the context of clinical treatment of NSCLC has not been fully investigated. Methods: We analyzed tumor samples from 60 consecutive NSCLC patients with stage IIIA-B undergoing neo-adjuvant chemotherapy with platinum-based regimens followed by radically surgery. Tumor specimen collection included pre-treatment mediastinal lymph-node biopsies (n = 23) and post-treatment surgical specimens (25 from lymph-nodes and 52 from primary tumors). CD133 status was determined by immunohistochemistry and correlations with clinico-pathological variables were evaluated using univariable and multivariable Cox models. Results: CD133 positive cells (mean 5% of total tumor cells, range 1-40%) were detected in 35% of pre-treatment samples and after chemotherapy in 38% and 32% of resected primary tumors and metastatic lymph-nodes, respectively. When both lymph nodes and primary tumor were available (24 patients) no correlation was found between CD133 status, possibly indicating different dynamics in primary tumor maintenance and dissemination. CD133 positive cells were detected more frequently in tumors with best response to chemotherapy (by ≥30% size reduction: 14/28, 50% vs. 6/24, 25%) suggesting enrichment of chemoresistant cells after treatment. CD133 positivity after induction chemotherapy was correlated with higher risk of local and distant recurrence (73% vs 53%), especially in patients with pre-treatment CD133+ lymph nodes (87% vs. 53%). Finally, positivity for CD133 after treatment seems to be correlated with worse overall survival (HR 2.42, 95% CI: 0.93-6.32, p = 0.184). Conclusions: Investigation of tumors after chemotherapy provides indirect evidence of chemoresistance of CD133+ cells. CD133 positive cells are correlated with worse prognosis in neo-adjuvant treatment of locally advanced NSCLC and could provide clinical relevant information for personalized therapies. Disclosure: All authors have declared no conflicts of interest.