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RAS mutation is considered one of the most relevant oncogenic drivers in human cancers. Unfortunately, for more than three decades, RAS has been considered an undruggable target. Recently, the discovery of selective and potent KRAS G12C inhibitors represented a light at the end of the tunnel. Indeed, sotorasib and adagrasib proved clinical activity in patients with refractory metastatic colorectal cancer harboring KRAS G12C mutation; however, responses are lower than expected, suggesting the presence of intrinsic resistance. Consequently, novel combinatory strategies to disrupt the RAS signaling pathways are under clinical investigation. This review aims to discuss the current knowledge and novel routes of KRAS G12C inhibition in metastatic colorectal cancer., Competing Interests: Disclosure DC: travel support from Sanofi, Bristol Myers Squibb (BMS) and Merk-Serono. BAM: travel support from Sanofi, BMS, Novartis. EM: has served as advisor and speaker for Amgen, Bayer, Eisai, Incyte, Merck-Serono, Roche, Servier, Pierre Fabre and ESMO, travel grant AstraZeneca, Pierre Fabre., (Published by Elsevier Ltd.)

Background: The study of cancer therapy is a key issue in the field of oncology research and the development of target therapies is one of the main problems currently under investigation. This is particularly relevant in different types of tumor where traditional chemotherapy approaches often fail, such as lung cancer. Results: We started from the general definition of robustness introduced by Kitano and applied it to the analysis of dynamical biochemical networks, proposing a new algorithm based on moment independent analysis of input/output uncertainty. The framework utilizes novel computational methods which enable evaluating the model fragility with respect to quantitative performance measures and parameters such as reaction rate constants and initial conditions. The algorithm generates a small subset of parameters that can be used to act on complex networks and to obtain the desired behaviors. We have applied the proposed framework to the EGFR-IGF1R signal transduction network, a crucial pathway in lung cancer, as an example of Cancer Systems Biology application in drug discovery. Furthermore, we have tested our framework on a pulse generator network as an example of Synthetic Biology application, thus proving the suitability of our methodology to the characterization of the input/output synthetic circuits. Conclusions: The achieved results are of immediate practical application in computational biology, and while we demonstrate their use in two specific examples, they can in fact be used to study a wider class of biological systems. [ABSTRACT FROM AUTHOR]

Objective: To evaluate usage patterns for nimotuzumab, safety and effectiveness in terms of survival in patients with high-grade gliomas treated in medical practice. Methods: A cohort prospective, longitudinal, multicenter study was designed in adult patients with histological confirmation of high grade malignant glioma newly diagnosis to receive nimotuzumab according to prescription recommendations. Patients were followed for 3 years. We collected data on patterns of use, dosage and time of exposure to nimotuzumab. Reported adverse events were classified acc ording to type, intensity and seriousness and also it was evaluated the survival time in months. Results: Between December 2005 and August 2012, seventy patients received nimotuzumab grouped according to histology in 44 glioblastoma, 24 astrocytoma, anaplastic and 2 anaplastic oligoastrocytoma. All patients received nimotuzumab in combination with radiation, mostly concurrent (78.6%); the remainder received it sequentially (21.4%). Completed the induction phase planned 94.3% of patients and continued in maintenance beyond 1 year 21.4%. The events related to nimotuzumab were 24.1%. The most common were fever, chills, and cutaneous erythema of light and moderate intensity. It was founded no association between toxicity and therapeutic modality, neither with the number of doses received. Patients with anaplastic astrocytoma had a survival at diagnosis over 45 months and with glioblastoma of 14.8 months; with a survival rate at 3 years the 50.8% and 20.2% respectively. Conclusions: The results of this observational study accompaniment those described in controlled studies. Nimotuzumab can be a therapeutic alternative safe, advantageous and feasible as part of conventional treatment in health care conditions. [ABSTRACT FROM AUTHOR]

Standard treatment of cervical cancer (CC) consists of surgery in the early stages and of chemoradiation in locally advanced disease. Metastatic CC has a poor prognosis and is usually treated with palliative platinum-based chemotherapy. Current chemotherapeutic regimens are associated with significant adverse effects and only limited activity, making identification of active and tolerable novel targeted agents a high priority. Angiogenesis is a complex process that plays a crucial role in the development of many types of cancer. The dominant role of angiogenesis in CC seems to be directly related to human papillomavirus-related inhibition of p53 and stabilization of hypoxia-inducible factor-1α. Both of these mechanisms are able to increase expression of vascular endothelial growth factor (VEGF). Activation of VEGF promotes endothelial cell proliferation and migration, favoring formation of new blood vessels and increasing permeability of existing blood vessels. Since bevacizumab, a recombinant humanized monoclonal antibody binding to all isoforms of VEGF, has been demonstrated to significantly improve survival in gynecologic cancer, some recent clinical research has explored the possibility of using novel therapies directed toward inhibition of angiogenesis in CC too. Here we review the main results from studies concerning the use of antiangiogenic drugs that are being investigated for the treatment of CC. [ABSTRACT FROM AUTHOR]

Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cause of cancer death worldwide. Its treatment is complex and evolving. In general, early-stage disease may be managed with single-modality treatment while an advanced stage (about 60% of clinical presentation) needs a multidisciplinary approach. In this setting concurrent chemoradiation has been associated with improvement in locoregional control and organ preservation, but at the cost of significant acute and chronic toxicity. Molecular target therapies specially directed to epidermal growth factor receptor (EGFR) might improve the outcomes and reduce toxicities. In recurrent-metastatic (R/M) HNSCC, cetuximab, a monoclonal antibody against EGFR, plus platinum-based chemotherapy (CT) allow an overall survival (OS) of about 10 months. However, the prognosis for R/M-HNSCC remains dismal and additional efforts are needed. At the 2013 American Society of Clinical Oncology (ASCO) Meeting, data on induction CT, anti-EGFR inhibitors, innovative molecular targets and predictor factors were reported. Further results on target therapies were presented at the European Cancer Congress (ECC) 2013, where a large study also showed that hyperfractionated radiotherapy (RT) improve OS rates compared with standard RT. The aim of this review is to discuss current standards and emerging therapies by considering recent new updates. © 2014 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Abstract: 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. [Copyright &y& Elsevier]

Primary immunodeficiencies (PID) are rare, complex diseases that can be characterised by a spectrum of phenotypes, from increased susceptibility to infections to autoimmunity, allergy, auto-inflammatory diseases and predisposition to malignancy. With the introduction of genetic testing in these patients and wider use of next-Generation sequencing techniques, a higher number of pathogenic genetic variants and conditions have been identified, allowing the development of new, targeted treatments in PID. The concept of precision medicine, that aims to tailor the medical interventions to each patient, allows to perform more precise diagnosis and more importantly the use of treatments directed to a specific defect, with the objective to cure or achieve long-term remission, minimising the number and type of side effects. This approach takes particular importance in PID, considering the nature of causative defects, disease severity, short- and long-term complications of disease but also of the available treatments, with impact in life-expectancy and quality of life. In this review we revisit how this approach can or is already being implemented in PID and provide a summary of the most relevant treatments applied to specific diseases., Competing Interests: The authors declare that the review was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Pinto and Neves.)

Bullous pemphigoid is a subepidermal blistering disease associated with autoantibodies (auto-ab) to BP180 and BP230 which affects elderly patients, predominately. Although it is a rare disease, bullous pemphigoid is the most common among the autoimmune bullous skin diseases. Systemic corticosteroids and immunosuppressants represent milestones in the treatment of patients suffering from bullous pemphigoid; however, therapeutic management of patients still represents a clinical challenge, owing to the chronic nature of the disease and to potential adverse effects related to the long-term use of systemic treatments. Recent discoveries on the pathogenesis of bullous pemphigoid have allowed investigation of new target therapies against selective pro-inflammatory mediators. These therapies appear to yield satisfactory results with fewer side effects in cases of refractory disease. The review discusses current evidence on these new therapeutic targets and specific drugs under investigation.

Background: ROS1 fusions are driver molecular alterations in 1-2% of non-small cell lung cancers (NSCLCs). Several tyrosine kinase inhibitors (TKIs) have shown high efficacy in patients whose tumors harbour a ROS1 fusion. However, the limited availability of preclinical models of ROS1-positive NSCLC hinders the discovery of new drugs and the understanding of the mechanisms underlying drug resistance and strategies to overcome it., Methods: The ADK-VR2 cell line was derived from the pleural effusion of a treatment-naïve NSCLC patient bearing SDC4-ROS1 gene fusion. The sensitivity of ADK-VR2 and its crizotinib-resistant clone ADK-VR2 AG143 (selected in 3D culture in the presence of crizotinib) to different TKIs was tested in vitro , in both 2D and 3D conditions. Tumorigenic and metastatic ability was assessed in highly immunodeficient mice. In addition, crizotinib efficacy on ADK-VR2 was evaluated in vivo ., Results: 2D-growth of ADK-VR2 cells was partially inhibited by crizotinib. On the contrary, the treatment with other TKIs, such as lorlatinib, entrectinib and DS-6051b, did not result in cell growth inhibition. TKIs showed dramatically different efficacy on ADK-VR2 cells, depending on the cell culture conditions. In 3D culture, ADK-VR2 growth was indeed almost totally inhibited by lorlatinib and DS-6051b. The clone ADK-VR2 AG143 showed higher resistance to crizotinib treatment in vitro , compared to its parental cell line, in both 2D and 3D cultures. Similarly to ADK-VR2, ADK-VR2 AG143 growth was strongly inhibited by lorlatinib in 3D conditions. Nevertheless, ADK-VR2 AG143 sphere formation was less affected by TKIs treatment, compared to the parental cell line. In vivo experiments highlighted the high tumorigenic and metastatic ability of ADK-VR2 cell line, which, once injected in immunodeficient mice, gave rise to both spontaneous and experimental lung metastases while the crizotinib-resistant clone ADK-VR2 AG143 showed a slower growth in vivo . In addition, ADK-VR2 tumor growth was significantly reduced but not eradicated by crizotinib treatment., Conclusions: The ADK-VR2 cell line is a promising NSCLC preclinical model for the study of novel targeted therapies against ROS1 fusions and the mechanisms of resistance to TKI therapies., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-22-163/coif). Andrea Ardizzoni received grants and personal fees from Bristol-Myers Squibb, Merck Sharp & Dohme, Eli Lilly, Boehringer Ingelheim and Pfizer, grants from Celgene and grants and personal fees from Roche, outside of the submitted work. FG received grants from Astrazeneca and honoraria for advisory board participation from Eli-Lilly. The other authors declare no conflicts of interest., (2022 Translational Lung Cancer Research. All rights reserved.)

Introduction: Acute myeloid leukemia (AML) is a genetically heterogeneous disease for which the treatment armamentarium has been historically restricted to chemotherapy. However, genomic and epigenomic alterations that contribute to AML initiation, maintenance, and relapse have disclosed new insights to the 5th update in WHO Classification of Haematolymphoid Tumours., Areas Covered: After four decades of intensive chemotherapy as a 'one-size-fits-all' concept, several targeted agents have been approved for the treatment of AML. Several compounds, directed against regulators of apoptotic, epigenetic, or micro-environmental pathways, and immune-system modulators, are currently in development and investigation in clinical trials. We review advances in target-based therapy for AML focusing on their mechanism of action, examining the intracellular events and pathways, and the results from published clinical trials., Expert Opinion: To improve patient clinical outcomes, find new biomarkers for therapeutic response, and pinpoint patients who might benefit from novel targeted medicines, next-generation sequencing is being used to evaluate AML-associated mutations. In fact, the new 5th edition of WHO classification has reaffirmed the importance of genetically defined entities that have a prognostic impact, but not all have a specific treatment available. New class of target drugs are in clinical development and could be beneficial to improve the therapeutic armamentarium available.

Summary: Thymic malignancies are extremely rare although usually affect young adults and continue to remain an important health problem. Like other rare diseases, progress in thymic malignancies has been slow and the treatment cornerstone still remains surgical resection. Next generation sequencing and other advances in molecular biology are shedding light onto the multiple genetic aberrations involved and have opened a new field for research with molecularly targeted therapies such as CKIT inhibitors or anti-EGFR therapies. In this review we will summarize the current knowledge in the pathophysiology, diagnosis, prognosis and latest advances in the management of thymomas and thymic carcinomas. [Copyright &y& Elsevier]

Tumors of the biliary tract (gallbladder tumors, cholangiocarcinomas and ampullary carcinomas) are low incidence tumors with poor prognosis. The five-year overall survival is 50% for stage I, 30% stage II, 10% stage III and 0% stage IV. Treatment is based on surgery for potentially resectable tumors. Chemotherapy and chemo-radiotherapy is the treatment of choice when surgery is not amenable, however it has not achieved encouraging results. These patients use to have very few symptoms, which is the reason for the delay in diagnosis and the poor prognosis. They frequently develop biliary obstruction: obstructive jaundice, right upper quadrant pain and weight loss. Ampullary carcinomas are frequently related to steatorrhea due to malabsorption. The most effective chemotherapy drugs used in monotherapy are 5FU (response rate 20%) and gemcitabine (response rate of 13%-60%), so they have been selected for further development in multiple phase II clinical trials to explore their efficacy and safety in combination with other agents. In a phase III clinical trial, combination of gemcitabine and cisplatin has been selected as the schedule of choice. Target therapies are also being developed in this malignancy. The present work reviews the most current knowledge of the pathogenesis, diagnosis and natural history of biliary tract tumors. Further, review of surgery, current adjuvant treatment and therapies for unresectable and advanced disease is provided. The most recent understanding for target therapies and molecular biology is also summarized. [ABSTRACT FROM AUTHOR]

Despite progress in the treatment of locally advanced head and neck squamous cell cancer (HNSCC), the prognosis remains dismal and 5-year survival does not exceed 40%. In metastatic and recurrent disease, in spite of the introduction of cetuximab in combination with platinum and fluorouracil, the median overall survival rate remains lower than 11 months. There are many possible reasons for these disappointing results including acquired drug resistance and tumor hypoxia. Angiogenesis plays an important role in HNSCC development and proliferation. Promising preclinical results with antiangiogenic therapies have engendered a number of clinical trials, but so far there have not been any conclusive results on the value of such treatments. This paper aims to review the role of angiogenesis in head and neck cancer and to suggest future perspectives. Copyright © 2012 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

The routine use of ancillary studies is reshaping the practice of cytopathology. Currently, most cytopathologists recognize the importance of immunocytochemistry and molecular techniques as adjuncts to morphology to achieve a precise diagnosis. Cytopathologists also are expected to include specific prognostic and predictive information in their reports. The objective of this review was to address the use of immunocytochemistry and molecular techniques to refine the preoperative diagnosis and classification of lung cancer, thyroid cancer, kidney cancer, gastrointestinal cancer, and soft tissue tumors. Fine-needle aspiration also offers a suitable alternative to biopsy in a variety of clinical settings, in particular, when it may be useful to obtain material to study prognostic and predictive markers. This is particularly relevant to obtain material from metastatic sites. The study of KRAS in colon cancer, CKIT in gastrointestinal stromal tumors, and epidermal growth factor receptor mutational status in lung cancer also are addressed particularly in this report. Cancer (Cancer Cytopathol) 2012;. © 2012 American Cancer Society. [ABSTRACT FROM AUTHOR]

K. Masui, T. F. Cloughesy and P. S. Mischel (2012) Neuropathology and Applied Neurobiology 38, 271-291 Molecular pathology in adult high-grade gliomas: from molecular diagnostics to target therapies The classification of malignant gliomas is moving from a morphology-based guide to a system built on molecular criteria. The development of a genomic landscape for gliomas and a better understanding of its functional consequences have led to the development of internally consistent molecular classifiers. However, development of a biologically insightful classification to guide therapy is still a work in progress. Response to targeted treatments is based not only on the presence of drugable targets, but rather on the molecular circuitry of the cells. Further, tumours are heterogeneous and change and adapt in response to drugs. Therefore, the challenge of developing molecular classifiers that provide meaningful ways to stratify patients for therapy remains a major challenge for the field. In this review, we examine the potential role of MGMT methylation, IDH1/2 mutations, 1p/19q deletions, aberrant epidermal growth factor receptor and PI3K pathways, abnormal p53/Rb pathways, cancer stem-cell markers and microRNAs as prognostic and predictive molecular markers in the setting of adult high-grade gliomas and we outline the clinically relevant subtypes of glioblastoma with genomic, transcriptomic and proteomic integrated analyses. Furthermore, we describe how these advances, especially in epidermal growth factor receptor/PI3K/mTOR signalling pathway, affect our approaches towards targeted therapy, raising new challenges and identifying new leads. [ABSTRACT FROM AUTHOR]

INTRODUCTION: Since a few years ago no effective medical therapies were available to cure metastatic renal cell carcinoma (RCC). Nowadays, encouraging preliminary results support some new therapeutic agents, collectively named as targeted therapies (TT).. This paper reviews our experience with the use of TT in the setting of RCC with metastasis at the diagnosis. MATERIAL AND METHODS: Retrospective evaluation of the data of 24 patients (7 females, 17 males, median age: 59aa) affected by clear cell RCC with distant metastatis at diagnosis, treated with TT from 2005 to 2012.20 of the 24 patients (83,3%) underwent preliminary cytoreductive nephrectomy, whereas for the others a percutaneous biopsy of the renal tumor was obtained. 5 (20.8%) patients received an immunotherapy with IL-2 or IFN and then a TT due to a progression., Schedules were applied following heterogeneous regimens along the period of data collection (randomized clinical trial, expanded access, standard indication). Response has been evaluated by RECIST criteria. RESULTS: AS first-line therapy ofTT18 patients received Sunitinib, 4 Sorafenib, 2 Temsirolimus; 11 received a second-line (8 Sorafenib, 2 Sunitinib, 1 Everolimus); 6 received also a third-line (5 Everolimus, 1 Tensirolimus). At last available control, after a mean follow up time of 13,7 months (1-29) a progressive disease was present in 12 cases (50%), a stable disease in 6 (25%), a reduction of the disease in 4 (16.5%); 7 patients (29.5%) died; overall mean survival of the entire group was 14,7 months. Even if the study suffers from the limitations related to the small number of cases and the retrospective design, seems that no factors played a role in determining the response to theraphy. CONCLUSIONS: The results of TT in clinical practice resemble the ones from randomised clinical trials. It's extremely hard to predict the response to treatment. [ABSTRACT FROM AUTHOR]

Recent studies have indicated that targeting glutathione-S-transferase (GST) isoenzymes may be a promising novel strategy to improve the efficacy of conventional chemotherapy in the three most common musculoskeletal tumours: osteosarcoma, Ewing's sarcoma, and rhabdomyosarcoma. By using a panel of 15 drug-sensitive and drug-resistant human osteosarcoma, Ewing's sarcoma, and rhabdomyosarcoma cell lines, the efficay of the GST-targeting agent 6-(7-nitro-2,1,3-benzoxadiazol-4-ylthio)hexanol (NBDHEX) has been assessed and related to GST isoenzymes expression (namely GSTP1, GSTA1, GSTM1, and MGST). NBDHEX showed a relevant in vitro activity on all cell lines, including the drug-resistant ones and those with higher GSTs levels. The in vitro activity of NBDHEX was mostly related to cytostatic effects, with a less evident apoptotic induction. NBDHEX positively interacted with doxorubicin, vincristine, cisplatin but showed antagonistic effects with methotrexate. In vivo studies confirmed the cytostatic efficay of NBDHEX and its positive interaction with vincristine in Ewing's sarcoma cells, and also indicated a positive effect against the metastatisation of osteosarcoma cells. The whole body of evidence found in this study indicated that targeting GSTs in osteosarcoma, Ewing's sarcoma and rhabdomyosarcoma may be an interesting new therapeutic option, which can be considered for patients who are scarcely responsive to conventional regimens. [ABSTRACT FROM AUTHOR]

“Translational research” (TR) has the main aim of transferring the results of preclinical research into clinical practice and includes the study of the biology of the disease to provide solid rationales for the development or improvement of new drugs, the evaluation of the biological effects of the drugs in animals to define how to best use those drugs in humans and the study of the biological effects of those drugs in humans. To facilitate the development of new cancer targeted therapies, TR focuses its efforts on the discovery and validation of biomarkers, defined as “a characteristic that is objectively measured and evaluated as an indicator of normal biological processes, pathogenic processes or pharmacologic responses to a therapeutic intervention”. Biomarkers could allow a rational development of targeted agents, based on the mechanistic assessment of their effects. This knowledge can then be used during the subsequent steps of drug discovery, screening, preclinical and clinical testing. This review will focus on the contributions provided by biomarkers to facilitate the development of new targeted therapies. [ABSTRACT FROM AUTHOR]

Medullary thyroid carcinoma (MTC) is a rare calcitonin-producing neuroendocrine tumour that originates from the parafollicular C-cells of the thyroid gland. The RET proto-oncogene encodes the RET receptor tyrosine kinase, which has essential roles in cell survival, differentiation and proliferation. Activating mutations of RET are associated with the pathogenesis of MTC and have been demonstrated in nearly all hereditary and in 30–50% of sporadic MTC cases, making this receptor an excellent target for small-molecule inhibitors for this tumour. Clinical trials of small organic inhibitors of tyrosine kinase receptors (TKIs) targeting the RET receptor have shown efficacy for treatment of metastatic MTC with 30–50% of patients responding to these agents. Despite the importance of the RET receptor in MTC, it is clear that other signal transduction pathways, tyrosine kinase receptors, and tumour suppressor genes are involved in MTC tumourigenesis and progression. A better understanding of molecular cross-talk between these signal pathways and the RET receptor may lead to combinatorial therapy that will improve outcomes beyond what is currently possible with RET-directed TKIs. Finally, there is evidence that immunological-based therapy using dendritic cell vaccination strategies have been effective for reducing tumour mass in a small number of patients. The identification of additional MTC-specific tumour antigens and a better understanding of specific epitopes in these tumour antigens may lead to improvement of response rates. [ABSTRACT FROM AUTHOR]

Abstract: In the past decade the incidence of lung cancer among women has risen, whereas among men it has slightly declined. Important differences in lung cancer have been demonstrated between men and women, although many areas still remain controversial. Some biologic differences may justify the increase in response of women to therapy for lung cancer and can partially explain the improved survival of women compared with men. We extensively reviewed the published scientific literature on this topic in order to investigate the clinical and genetic profiling underlying lung cancer in women and to use this information as a tool for medical therapy. [Copyright &y& Elsevier]

Simple Summary: Kaposi sarcoma (KS) incidence has declined substantially since the advent of effective ART but it remains a frequent cancer among people living with HIV, including those on ART with a sustained undetectable HIV viral load and in late presenters. ART is responsible for KS improvement and resolution, but new onset (unmasking KS-IRIS) or sudden progression of preexisting KS (paradoxical KS-IRIS) can occur, even in patients with a low degree of immunocompromise. Both paradoxical and unmasking KS-IRIS have been associated with significant morbidity and mortality. We carried out a literature review regarding the incidence, pathogenic mechanisms, risk factors, clinical presentation, and management strategies of KS-IRIS in the ART era. People living with HIV (PLWH) with advanced immunosuppression who initiate antiretroviral therapy (ART) are susceptible to the occurrence of an immune reconstitution inflammatory syndrome (IRIS). Although ART is responsible for AIDS- associated Kaposi sarcoma (KS) improvement and resolution, new onset (unmasking KS-IRIS) or sudden progression of preexisting KS (paradoxical KS-IRIS) can occur after a time delay of between a few days and 6 months after the initiation or resumption of ART, even in patients with a low degree of immunocompromise. KS-IRIS incidence varies from 2.4% to 39%, depending on study design, populations, and geographic regions. Risk factors for developing KS-IRIS include advanced KS tumor stage (T1), pre-treatment HIV viral load >5 log10 copies/mL, detectable pre-treatment plasma-KSHV, and initiation of ART alone without concurrent chemotherapy. Both paradoxical and unmasking KS-IRIS have been associated with significant morbidity and mortality, and thrombocytopenia (<100,000 platelets/mm3 at 12 weeks) has been associated with death. KS-IRIS is not to be considered as ART failure, and an ART regimen must be pursued. Systemic chemotherapy for KS in conjunction with ART is recommended and, in contrast with management of IRIS for other opportunistic infections, glucocorticoids are contra-indicated. Despite our preliminary results, the place of targeted therapies in the prevention or treatment of KS-IRIS needs further assessment. [ABSTRACT FROM AUTHOR]

Renal cell carcinoma (RCC) is an increasingly common malignancy that can progress to metastatic renal cell carcinoma (mRCC) in approximately one-third of RCC patients. The 5-year survival rate for mRCC is abysmally low, and, at the present time, there are sparingly few if any effective treatments. Current surgical and pharmacological treatments can have a long-lasting impact on renal function, as well. Thus, there is a compelling unmet need to discover novel biomarkers and surveillance methods to improve patient outcomes with more targeted therapies earlier in the course of the disease. Circulating biomarkers, such as circulating tumor DNA, noncoding RNA, proteins, extracellular vesicles, or cancer cells themselves potentially represent a minimally invasive tool to fill this gap and accelerate both diagnosis and treatment. Here, we discuss the clinical relevance of different circulating biomarkers in metastatic renal cell carcinoma by clarifying their potential role as novel biomarkers of response or resistance to treatments but also by guiding clinicians in novel therapeutic approaches. [ABSTRACT FROM AUTHOR]

Breast cancer stem cells are defined as cancer cells with self-renewal capacity. These cells represent a small subpopulation endowed with the ability to form new tumours when injected in nude mice. Markers of differentiation have been used to identify these cancer cells. In the case of breast cancer, CD44+/CD24− select a population with stem cell properties. The fact that these cells have self-renewal ability has suggested that this population could be responsible for new tumour formation and cancer relapse. These cells have been shown to be more resistant to chemotherapy and radiotherapy than normal cancer cells. The identification of the molecular druggable alterations responsible for the initiation and maintenance of cancer stem cells is an important goal. In this article we will review all these points with special emphasis on the possible role of new drugs designed to interact with molecular pathways of cancer stem cells. [ABSTRACT FROM AUTHOR]

Summary: Biliary tract cancer is a quite rare disease; despite recent significant advances in imaging modalities, most of the patients have advanced disease at presentation thus making radical surgery not feasible. Many different chemotherapeutic regimens have been investigated in small uncontrolled studies, with generally disappointing results. We extensively reviewed the literature on this topic trying to give an explanation to chemoresistance in this setting of patients and considering the molecular profiling as a tool for treatment decision. This review is divided in two parts, in the first one we illustrated chemotherapy results and possible mechanisms of resistance. In the second part we analysed the new molecular targets developing an hypothesis about the future therapeutics perspectives. [Copyright &y& Elsevier]

In this article we shall discuss the subject of target therapies concerning squamous cell carcinoma of the head and neck. Indeed, taking into account the molecular modifications generated by the carcinogenesis of squamous cell carcinoma of the head and neck, new treatment strategies have been developed and have joined the arsenal of conventional chemotherapy and radiotherapy. These new molecules target the molecular alterations and block the metabolic tracts by acting on the tumoral progression. The leader is the receptor for EGF (the EGFR). [ABSTRACT FROM AUTHOR]

Acute myeloid leukemia (AML) accounts for approximately 15-20% of all childhood leukemia cases. The overall survival of children with acute myeloid leukemia does not exceed 82%, and the 5-year event-free survival rates range from 46% to 69%. Such suboptimal outcomes are the result of numerous mutations and epigenetic changes occurring in this disease that adversely affect the susceptibility to treatment and relapse rate. We describe various molecular-targeted therapies that have been developed in recent years to meet these challenges and were or are currently being studied in clinical trials. First introduced in adult AML, novel forms of treatment are slowly beginning to change the therapeutic approach to pediatric AML. Despite promising results of clinical trials investigating new drugs, further clinical studies involving greater numbers of pediatric patients are still needed to improve the outcomes in childhood AML.

Introduction: Non-muscle invasive bladder cancer (NMIBC) accounts for 70-75% of all bladder cancers and is a heterogeneous disease characterized by a wide spectrum of recurrences and progression. Adjuvant treatment for intermediate- and high-risk NMIBC is mainly represented by Bacillus Calmette Guerin (BCG). However, 20%-40% of patients develop disease recurrences or persistence following BCG treatment and are classified as "BCG unresponsive' (BCGu), thus representing a therapeutic challenge due to their worse prognosis and unavailability of effective intravesical treatments., Areas Covered: We provide an overview of completed and ongoing clinical trials assessing the role of innovative immunological and target agents in patients with BCGu and BCG naive (BCGn) NMIBCs. New treatment options are emerging, demonstrating promising clinical activity, namely, pembrolizumab, atezolizumab, oportuzumab monatox, nadofaragene firadenovec, and N-803., Expert Opinion: The increasing number of newer therapeutic agents for patients with NMIBC poses challenges regarding the choice of the most suited treatment option for each patient and the best treatment sequence, given their diverse mechanisms of action and varying degrees of activity. Tailored treatment approaches are advocated, based on a deeper comprehension of disease features, available therapies, patient's characteristics, and consequently, on the identification and validation of prognostic and predictive biomarkers.

ROS proto-oncogene 1 (ROS1) rearrangements are reported in about 1–2% of non-squamous non-small-cell lung cancer (NSCLC). After efficacy of crizotinib was demonstrated, identification of ROS1 translocations in advanced disease became fundamental to give patients the chance of specific and effective treatment. Different methods are available for detection of rearrangements, and probably the real prevalence of ROS1 rearrangements is higher than that reported in literature, as our capacity to detect gene rearrangements is improving. In particular, with next generation sequencing (NGS) techniques, we are currently able to assess multiple genes simultaneously with increasing sensitivity. This is leading to overcome the "single oncogenic driver" paradigm, and in the very near future, the co-existence of multiple drivers will probably emerge more frequently and represent a therapeutic issue. Since recently, crizotinib has been the only available therapy, but today, many other tyrosine kinase inhibitors (TKI) are emerging and seem promising both in first and subsequent lines of treatment. Indeed, novel inhibitors are also able to overcome resistance mutations to crizotinib, hypothesizing a possible sequential strategy also in ROS1-rearranged disease. In this review, we will focus on ROS1 rearrangements, dealing with diagnostic aspects, new therapeutic options, resistance issues and the coexistence of ROS1 translocations with other molecular alterations. [ABSTRACT FROM AUTHOR]

Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in childhood. Recently, we demonstrated the overexpression of both DNA methyltransferase 3A (DNMT3A) and 3B (DNMT3B) in RMS tumour biopsies and cell lines compared to normal skeletal muscle. Radiotherapy may often fail due to the abnormal expression of some molecules able to drive resistance mechanisms. The aim of this study was to analyse the involvement of DNMT3A and DNMT3B in radioresistance in RMS. RNA interference experiments against DNMT3A/3B were performed in embryonal RMS cells, upon ionizing radiation (IR) exposure and the effects of the combined treatment on RMS cells were analysed. DNMT3A and DNMT3B knocking down increased the sensitivity of RMS cells to IR, as indicated by the drastic decrease of colony formation ability. Interestingly, DNMT3A/3B act in two different ways: DNMT3A silencing triggers the cellular senescence program by up-regulating p16 and p21, whilst DNMT3B depletion induces significant DNA damage and impairs the DNA repair machinery (ATM, DNA-PKcs and Rad51 reduction). Our findings demonstrate for the first time that DNMT3A and DNMT3B overexpression may contribute to radiotherapy failure, and their inhibition might be a promising radiosensitizing strategy, mainly in the treatment of patients with metastatic or recurrent RMS tumours. [ABSTRACT FROM AUTHOR]

Bone sarcomas are a group of heterogeneous malignant mesenchymal tumors. Complete surgical resection is still the cornerstone of treatment, but, in the advanced/unresectable setting, their management remains challenging and not significantly improved by target- and immuno-therapies. We focused on the tyrosine kinase Eph type-A receptor-2 (EphA2), a key oncoprotein implicated in self-renewal, angiogenesis, and metastasis, in several solid tumors and thus representing a novel potential therapeutic target. Aiming at better characterizing its expression throughout the main bone sarcoma histotypes, we investigated EPHA2 expression in the Cancer Cell Lines Encyclopedia and in public datasets with clinical annotations. looking for correlations with molecular, histopathological and patients' features and clinical outcomes in a total of 232 osteosarcomas, 197 Ewing's sarcomas, and 102 chondrosarcomas. We observed EPHA2 expression in bone sarcoma cell lines. We demonstrated higher EPHA2 expression in tumor tissues when compared to normal counterparts. A significant correlation was found between EPHA2 expression and Huvos grade (osteosarcoma) and with worse overall survival (dedifferentiated chondrosarcoma). Next, we characterized EPHA2 expression and activation in bone sarcoma primary tissues and in patient-derived xenografts generated in our laboratory to verify their reliability as in vivo models of osteosarcoma, Ewing's sarcoma and chondrosarcoma. Furthermore, for the first time, we demonstrated EPHA2 expression in chondrosarcoma, suggesting its potential key role in this histotype. Indeed, we observed a significant dose-dependent antitumor effect of the EphA2-inhibitor ALW-II-41-27 in patient-derived in vitro models. In conclusion, EphA2 targeting represents a promising novel therapeutic strategy against bone sarcomas. [ABSTRACT FROM AUTHOR]