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Lenvatinib is an emerging multi-kinase inhibitor with a preferential anti-angiogenic activity, which has shown efficacy in the treatment of renal cell carcinoma, differentiated thyroid cancer and hepatocellular carcinoma. It inhibits vascular endothelial growth factor receptor family (VEGFR1-3), fibroblast growth factor receptor family (FGFR1-4), platelet-derived growth factor receptor-alpha (PDGFRα), tyrosine-kinase receptor (KIT) and rearranged during transfection receptor (RET). In this review we have evaluated the development from bench to bedside of lenvatinib. PubMed, MEDLINE and clinicaltrials.gov are the sources of data. Furthermore, the preclinical in vitro and in vivo data, as well as efficacy and toxicity results of lenvatinib in the clinic, are presented and discussed. Treatment with lenvatinib causes side effects (hypertension, proteinuria, fatigue and diarrhea), which are predominantly related to the inhibition of angiogenesis. For these reasons, the identification of biomarkers of efficacy and resistance to lenvatinib is a key challenge in order to select responsive patients. This review provides an overview on lenvatinib's clinical use, perspectives and indications for future development.

Background Combination of chemotherapies (fluoropirimidines, oxaliplatin and irinotecan) with biologic drugs (bevacizumab, panitumumab, cetuximab) have improved clinical responses and survival of metastatic colorectal cancer (mCRC). However, patients’ selection thorough the identification of predictive factors still represent a challange. Cetuximab (Erbitux®), a chimeric monoclonal antibody binding to the Epidermal Growth Factor Receptor (EGFR), belongs to the Immunoglobulins (Ig) grade 1 subclass able to elicite both in vitro and in vivo the Antibody-Dependent Cell-mediated Cytotoxicity (ADCC). ADCC is the cytotoxic killing of antibody-coated target cells by immunologic effectors. The effector cells express a receptor for the Fc portion of these antibodies (FcγR); genetic polymorphisms of FcγR modify the binding affinity with the Fc of IgG1. Interestingly, the high-affinity FcγRIIIa V/V is associated with increased ADCC in vitro and in vivo . Thus, ADCC could partially account for cetuximab activity. Methods/design CIFRA is a single arm, open-label, phase II study assessing the activity of cetuximab in combination with irinotecan and fluorouracile in FcγRIIIa V/V patients with KRAS, NRAS, BRAF wild type mCRC. The study is designed with a two-stage Simon model based on a hypothetical higher response rate (+ 10%) of FcγRIIIa V/V patients as compared to previous trials (about 60%) assuming ADCC as one of the possible mechanisms of cetuximab action. The test power is 95%, the alpha value of the I-type error is 5%. With these assumptions the sample for passing the first stage is 14 patients with > 6 responses and the final sample is 34 patients with > 18 responses to draw positive conclusions. Secondary objectives include toxicity, responses’ duration, progression-free and overall survival. Furthermore, an associated translational study will assess the patients’ cetuximab-mediated ADCC and characterize the tumor microenvironment. Discussion The CIFRA study will determine whether ADCC contributes to cetuximab activity in mCRC patients selected on an innovative immunological screening. Data from the translational study will support results’ interpretation as well as provide new insights in host-tumor interactions and cetuximab activity. Trial registration The CIFRA trial (version 0.0, June 21, 2018) has been registered into the NIH-US National Library of Medicine, ClinicalTrials.gov database with the identifier number ( NCT03874062 ).

Background: The diagnosis and monitoring of primitive lung neuroendocrine tumors (lung pNETs) are usually performed by the measurement of serum chromogranin A (CgA) and urinary 5-hydroxyindolacetic acid (5-HIAA) levels. However, imaging techniques are necessary due to the poor diagnostic efficiency of the laboratory tests. Methods: A total-body computed tomography and bone scintigraphy scans showed multiple hepatic and bone metastases of a 55-year-old man affected by well-differentiated lung pNETs without severe initial symptoms. After diagnosis, he started therapy and was monitored with serum, urinary markers, and imaging techniques. Results: During follow-up, the urinary 5-HIAA levels did not significantly increase, while serum CgA and urinary para-hydroxyphenylacetic acid (pHPAA) levels (urinary organic acid physiologically present in the urines of healthy subjects) showed significant increases related to worsening clinical condition. Conclusions: The early increase in urinary pHPAA levels—usually not dosed in pNET patient monitoring—could be a promising prognostic marker.

We performed a meta-analysis in order to analyze and quantify the effect on survival of starting therapy in RAS wild-type (wt) metastatic colorectal cancer (mCRC) patients with anti-EGFR agents or bevacizumab. Randomized, phase II or III, clinical trials reporting overall survival (OS) in RAS wt mCRC patients treated with first-line chemotherapy (CT) associated with bevacizumab or anti-EGFR agents were selected. The primary end-point of this meta-analysis was OS; findings were depicted in classical Forest plots. Seven studies met the criteria for meta-analysis including 3,805 patients. The pooled second-line cross-over rate to bevacizumab was 36.6%, to anti-EGFR 33.2%. Only one study was selected reporting comparison between CT vs. CT plus bevacizumab in RAS wt patients with a HR of 1.13 in favor of CT (CI: 0.89-1.43, = 0.317). The pooled HRs were 0.89 (95% CI: 0.79-1.00) for CT plus anti-EGFR vs. CT and 0.81 (95% CI: 0.71-0.92) in favor of CT plus anti-EGFR vs. CT plus bevacizumab. Subgroup analysis showed a positive prognostic impact of starting CT plus anti-EGFR in left colon cancer (pooled HR: 0.70; CI: 0.54-0.85) while a positive trend of starting CT plus bevacizumab was observed in right colon cancer (pooled HR: 1.29; CI: 0.81-1.77). This meta-analysis shows that starting therapy in RAS wt mCRC patients with an anti-EGFR agent improves OS when the primary tumor location is in the left colon but a strong limitation of previous studies is the very low rate of biologic drug therapy cross-over.

Breast cancer is a heterogeneous disease consisting of different biological subtypes, with differences in terms of incidence, response to diverse treatments, risk of disease progression, and sites of metastases. In the last years, several molecular targets have emerged and new drugs, targeting PI3K/Akt/mTOR and cyclinD/CDK/pRb pathways and tumor microenvironment have been integrated into clinical practice. However, it is clear now that breast cancer is able to develop resistance to these drugs and the identification of the underlying molecular mechanisms is paramount to drive further drug development. Autophagy is a highly conserved homeostatic process that can be activated in response to antineoplastic agents as a cytoprotective mechanism. Inhibition of autophagy could enhance tumor cell death by diverse anti-cancer therapies, representing an attractive approach to control mechanisms of drug resistance. In this manuscript, we present a review of autophagy focusing on its interplay with targeted drugs used for breast cancer treatment.

Genetics and immunologic dynamics pushing the evolution of colorectal cancer (CRC) from the primary tumor to the metastases are largely unknown; cancer heterogeneity makes challenging both therapy and mechanistic studies. We selected patients developing CRC with lung-limited metastatic disease as only illness during their life in order to find any relevant genotype–phenotype relationship. Analysis of 523 cancer-relevant genes and of immune cells infiltration in primary and metastatic tissues revealed atypical genomic trajectories (TMB decrease, KRAS and SMAD4 regressive mutations), specific genetic events ( ERBB2 point mutations) and scarce T-cell infiltration. These insights provide novel information in oligometastatic CRC biology and new perspectives for cancer monitoring and anti-cancer therapeutic strategies.

Neuroendocrine neoplasms (NENs) comprise a heterogeneous group of rare malignancies, mainly originating from hormone-secreting cells, which are widespread in human tissues. The identification of mutations in ATRX/DAXX genes in sporadic NENs, as well as the high burden of mutations scattered throughout the multiple endocrine neoplasia type 1 (MEN-1) gene in both sporadic and inherited syndromes, provided new insights into the molecular biology of tumour development. Other molecular mechanisms, such as the NOTCH signalling pathway, have shown to play an important role in the pathogenesis of NENs. NOTCH receptors are expressed on neuroendocrine cells and generally act as tumour suppressor proteins, but in some contexts can function as oncogenes. The biological heterogeneity of NENs suggests that to fully understand the role and the potential therapeutic implications of gene mutations and NOTCH signalling in NENs, a comprehensive analysis of genetic alterations, NOTCH expression patterns and their potential role across all NEN subtypes is required.

Background. Platinum-based chemotherapy is the mainstay of front-line treatment of patients affected by pluri-metastatic intermediate/high grade NeuroEndocrine Neoplasms (NENs). However, there are no standard second-line treatments at disease progression. Previous clinical experiences have evidenced that temozolomide (TMZ), an oral analog of dacarbazine, is active against NENs at standard doses of 150 to 200 mg/mq per day on days 1 to 5 of a 28-day cycle, even if a significant treatment-related toxicity is reported. Methods. Metastatic NENs patients were treated at the ENETS (European NeuroEndocrine Tumor Society) center of excellence of Naples (Italy), from 2014 to 2017 with a second-line alternative metronomic schedule of TMZ, 75 mg/m2 per os “one week on/one week off”. Toxicity was graded with NCI-CTC criteria v4.0; objective responses with RECIST v1.1 and performance status (PS) according to ECOG. Results. Twenty-six consecutive patients were treated. Median age was 65.5 years. The predominant primary organs were pancreas and lung. Grading was G2 in 11 patients, G3 in 15. More than half of patients had a PS 2 (15 vs. 11 with PS 1). The median time-on-temozolomide therapy was 12.2 months (95% CI: 11.4–19.6). No G3/G4 toxicities were registered. Complete response was obtained in 1 patient, partial response in 4, stable disease in 19 (disease control rate: 92.3%), and progressive disease in 2. The median overall survival from TMZ start was 28.3 months. PS improved in 73% of patients. Conclusions. Metronomic TMZ is a suitable treatment for G2 and G3 NENs particularly in PS 2 patients. Prospective and larger trials are needed to confirm these results.

Background and Objectives: Ectopic pregnancy (EP) is a potentially life-threatening condition and the leading cause of maternal mortality in the first trimester. Although both surgical and medical approaches are effective, selection criteria for Methotrexate (MTX) treatment remain inconsistent across international guidelines. Additionally, limited data on long-term reproductive outcomes are available. Materials and Methods: We conducted a single-center retrospective cohort study of 107 patients diagnosed with tubal EP and treated at the Obstetrics and Gynecology Unit of the University Hospital of Parma between 2019 and 2023. MTX (50 mg/m2) was offered to patients with β-hCG < 5000 mIU/mL, sac diameter < 40 mm, and no embryonic cardiac activity or hemoperitoneum; others underwent salpingectomy. Treatment outcomes, predictors of MTX success, and fertility outcomes were analyzed. Results: Medical treatment was offered to 36 patients (33.6%), with an overall success rate of 72%: in total, 20 resolved after a single dose and 6 after a second dose. Surgical conversion was necessary in 10 patients. The remaining 71 patients (66.4%) underwent primary salpingectomy. Initial β-hCG levels and gestational age did not significantly predict MTX failure (p 0.14 and 0.73, respectively), whereas gestational sac diameter was identified as a reliable predictor of treatment success (p = 0.01). In particular, a gestational sac maximum diameter of <2 cm emerged as a positive factor for MTX success (OR 1.13, 95% CI: 1.1–1.3, p = 0.04). Among the 50 patients with follow-up data, 68% achieved a term live birth, with no significant difference between the MTX (52.9%) and surgical (75.8%) groups (p 0.12). Most of the pregnancies (90%) occurred spontaneously, while only 10% required assisted reproductive technologies. Conclusions: MTX is a safe and effective treatment for tubal EP when patients are appropriately selected. Gestational sac diameter appears to be a reliable predictor of success. Both medical and surgical treatments yielded comparable reproductive outcomes, supporting individualized care models that prioritize fertility preservation.

Antibiotic resistance in Gram-positive pathogens is a relevant concern, particularly in the hospital setting. Several antibiotics are now available to treat these drug-resistant pathogens, such as daptomycin, dalbavancin, linezolid, tedizolid, ceftaroline, ceftobiprole, and fosfomycin. However, antibiotic resistance can also affect these newer molecules. Overall, this is not a frequent phenomenon, but it is a growing concern in some settings and can compromise the effectiveness of these molecules, leaving few therapeutic options. We reviewed the available evidence about the epidemiology of antibiotic resistance to these antibiotics and the main molecular mechanisms of resistance, particularly methicillin-resistant Sthaphylococcus aureus, methicillin-resistant coagulase-negative staphylococci, vancomycin-resistant Enterococcus faecium, and penicillin-resistant Streptococcus pneumoniae. We discussed the interpretation of susceptibility tests when minimum inhibitory concentrations are not available. We focused on the risk of the emergence of resistance during treatment, particularly for daptomycin and fosfomycin, and we discussed the strategies that can be implemented to reduce this phenomenon, which can lead to clinical failure despite appropriate antibiotic treatment. The judicious use of antibiotics, epidemiological surveillance, and infection control measures is essential to preserving the efficacy of these drugs.