Immune checkpoint inhibitors in oncogene-addicted non-small cell lung cancer: A systematic review and meta-analysis

BACKGROUND: Treatment of oncogene-addicted non-small cell lung cancer (NSCLC) has been changed by the advent of tyrosine kinase inhibitors (TKIs). Albeit great benefits are achieved with target therapies, resistance invariably occurs and recourse to alternative treatments is unavoidable. Immune checkpoint inhibitors (ICIs) role and the best setting of immunotherapy administration in oncogene-driven NSCLC are matter of debate. METHODS: We performed a systematic literature review through PubMed, in order to gather all the available information regarding ICI activity and efficacy in oncogene-addicted NSCLC, from both prospective trials and retrospective series. A meta-analysis of objective response rate in different molecular subgroups was provided. Combinatorial strategies including ICIs and related toxicities were also recorded. RESULTS: Eighty-seven studies were included in the qualitative analysis. EGFR mutation may be a biomarker of poor response to single-agent ICIs (7% of EGFR-mutant NSCLC patients achieved disease response in prospective trials), while encouraging results have been shown with combination strategies. KRAS-mutated disease (response rate, RR, 22%) has different clinical and pathological characteristics, and the co-existence of additional mutations (e.g., STK11 or TP53) influence tumor microenvironment and response to immunotherapy. Other molecular alterations have been marginally considered prospectively, and data from clinical practice are variegated, given poor effectiveness of ICIs in ALK-rearranged disease (RR 9.5%, pooling the data of retrospective studies) or some encouraging results in BRAF-(RR 25%, retrospective data) or MET-driven one (with estimations conditioned by the presence of both exon 14 skipping mutations and gene amplification in reported series). CONCLUSIONS: In oncogene-addicted NSCLC (with the exception of KRAS-mutated), ICIs are usually administered at the failure of other treatment options, but administering single-agent immunotherapy in later disease phases may limit its efficacy. With the progressive administration of TKIs and ICIs in early-stage disease, molecular characterization will become fundamental in this setting

Immune checkpoint inhibitors in oncogene-addicted non-small cell lung cancer: A systematic review and meta-analysis

Background: Treatment of oncogene-addicted non-small cell lung cancer (NSCLC) has been changed by the advent of tyrosine kinase inhibitors (TKIs). Albeit great benefits are achieved with target therapies, resistance invariably occurs and recourse to alternative treatments is unavoidable. Immune checkpoint inhibitors (ICIs) role and the best setting of immunotherapy administration in oncogene-driven NSCLC are matter of debate. Methods: We performed a systematic literature review through PubMed, in order to gather all the available information regarding ICI activity and efficacy in oncogene-addicted NSCLC, from both prospective trials and retrospective series. A meta-analysis of objective response rate in different molecular subgroups was provided. Combinatorial strategies including ICIs and related toxicities were also recorded. Results: Eighty-seven studies were included in the qualitative analysis. EGFR mutation may be a biomarker of poor response to single-agent ICIs (7% of EGFR-mutant NSCLC patients achieved disease response in prospective trials), while encouraging results have been shown with combination strategies. KRASmutated disease (response rate, RR, 22%) has different clinical and pathological characteristics, and the coexistence of additional mutations (e.g., STK11 or TP53) influence tumor microenvironment and response to immunotherapy. Other molecular alterations have been marginally considered prospectively, and data from clinical practice are variegated, given poor effectiveness of ICIs in ALK-rearranged disease (RR 9.5%, pooling the data of retrospective studies) or some encouraging results in BRAF-(RR 25%, retrospective data) or MET-driven one (with estimations conditioned by the presence of both exon 14 skipping mutations and gene amplification in reported series). Conclusions: In oncogene-addicted NSCLC (with the exception of KRAS-mutated), ICIs are usually administered at the failure of other treatment options, but administering single-agent immunotherapy in later disease phases may limit its efficacy. With the progressive administration of TKIs and ICIs in early-stage disease, molecular characterization will become fundamental in this setting

Impact of time to surgery after neoadjuvant chemotherapy in patients with operable breast cancer.

Background: Some studies of adjuvant chemotherapy (CT) suggested that a shorter interval before the start of therapies may improve survival outcomes in many groups of patients. Time to surgery (TTS) after neoadjuvant CT and survival outcomes have not been established yet. The aim of this study is to evaluate the impact of TTS after neoadjuvant CT in terms of Overall Survival (OS) and Disease Free Survival (DFS). Patients and Methods: A retrospective analysis was conducted in 295 patients receiving neoadjuvant CT for stage I-IIIc breast cancer between 1991 and 2013. 56 pts underwent surgery within 21 days (group A) from last CT cycle, 148 pts within 22-35 days (group B) and 91 pts after 36 days (group C). The majority were infiltrating ductal carcinoma, stage IIA (37.6%) and IIB (33.9%), with nodal involvement in 51.6% of the cases. LumA 18.3%, LumB/HER2- 28.2%, LumB/Her2+ 20.7%, HER2+ 9.8%, TNBC 21%. All patients were treated with neoadjuvant CT: 70.5% with anthra-taxanes based regimen, 18% with anthra- alone, 10.9% with taxanes alone, 0.3% with CMF; plus Trastuzumab in 70% of HER2+ diseases. Results: After a median follow up of 4.6 years, it was observed that patients in group A showed a significant better OS than group B (HR 4.22; 95% CI, 1.27 \u2013 14.00, p=0.018) and group C (HR 3.61; 95% CI, 1.01 \u2013 12.86, p=0.048). Moreover group A showed a significant better DFS than group B (HR 3.41; 95% CI 1.34 to 8.65, p=0.010) and group C (HR 3.77; 95% CI 1.42 to 9.95, p=0.007). No correlations with OS were found in pts who achieved pCR (20.7%); pCR was predictive of better 5- and 10-years DFS independently from TTS (95.4% in the pCR-group vs 75.4% of non-pCR group, HR 0.16; 95% CI 0.04 to 0.66, p=0.011). TTS may influence DFS in non-pCR group: indeed 5-years DFS is 97.3% in group A, 72.7% in group B (HR 2.89; 95% CI 1.14 to 7.36, p=0.026), and 68.5% in group C (HR 3.44; 95% CI 1.3 to 9.1, p=0.013). No significant correlations with regard of stage at diagnosis or molecular subtypes were found. Conclusions: These results suggest that TTS after primary CT may influence patients' survival, regardless of stage at diagnosis and tumor subtype, so that a shorter interval between that last cycle of neoadjuvant chemotherapy and breast surgery should be addressed whenever possible

Should the host reaction to anisakiasis influence the treatment? Different clinical presentations in two cases

Gastrointestinal anisakiasis is a parasitic infection occurring in people that consume raw or inadequately cooked fish or squid. It is frequently characterized by severe epigastric pain, nausea and vom iting caused by the penetration of the larvae into the gastric wall. Acute gastric anisakiasis with severe chest discomfort is rarely report ed in Italy. On the other hand, gastro-allergic anisakiasis with rash, urticaria and isolated angioedema or anaphylaxis is a clinical entity that has been described only recently. Also, if patients usually develop symptoms within 12 hours after raw seafood ingestion, not always endoscopic exploration can promptly identify the Anisakis larvae. Moreover, some authors consider the prevailing allergic reaction as a natural and effective defense against the parasitic attack. We report two cases of peculiar manifestations of anisakiasis in both acute and chronic forms (severe chest discomfort and anaphylactoid reaction)

Deepening the knowledge of ros1 rearrangements in non-small cell lung cancer: Diagnosis, treatment, resistance and concomitant alterations

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

Dissecting Tumor Growth: The Role of Cancer Stem Cells in Drug Resistance and Recurrence

Emerging evidence suggests that a small subpopulation of cancer stem cells (CSCs) is responsible for initiation, progression, and metastasis cascade in tumors. CSCs share characteristics with normal stem cells, i.e., self-renewal and differentiation potential, suggesting that they can drive cancer progression. Consequently, targeting CSCs to prevent tumor growth or regrowth might offer a chance to lead the fight against cancer. CSCs create their niche, a specific area within tissue with a unique microenvironment that sustains their vital functions. Interactions between CSCs and their niches play a critical role in regulating CSCs’ self-renewal and tumorigenesis. Differences observed in the frequency of CSCs, due to the phenotypic plasticity of many cancer cells, remain a challenge in cancer therapeutics, since CSCs can modulate their transcriptional activities into a more stem-like state to protect themselves from destruction. This plasticity represents an essential step for future therapeutic approaches. Regarding self-renewal, CSCs are modulated by the same molecular pathways found in normal stem cells, such as Wnt/β-catenin signaling, Notch signaling, and Hedgehog signaling. Another key characteristic of CSCs is their resistance to standard chemotherapy and radiotherapy treatments, due to their capacity to rest in a quiescent state. This review will analyze the primary mechanisms involved in CSC tumorigenesis, with particular attention to the roles of CSCs in tumor progression in benign and malignant diseases; and will examine future perspectives on the identification of new markers to better control tumorigenesis, as well as dissecting the metastasis process

Primary and secondary prevention to effectively reduce the risk of bisphosphonate-related osteonecrosis of the jaw in patients with bone metastases .

Background Bone is one of the most frequent sites of metastasis in patients with advanced cancer. Nearly all patients with myeloma, 65–75% of patients with prostate or breast cancer, and 30–40% of patients with lung cancer or other solid tumors, eventually develop bone metastases. Bisphosphonates (BP), particularly zoledronic acid and denosumab, were demonstrated to effectively reduce skeletal complications in patients with bone metastases. However, bisphosphonate-related osteonecrosis of the jaw (BRONJ) can occur spontaneously, favored by dental extraction, dental implant surgery, or denture wearing. The purpose of this study was to underline the role of dental prevention as an effective tool to reduce the risk of BRONJ. Material and methods BRONJ was identified with the standardized query “osteonecrosis” among all data from patients treated at Modena Cancer Center from 2005 to 2016. For each case, demographic and medical information were analyzed, as well as data about notification (year of occurrence, outcome), type and duration of BP exposure, and associated risk factors (dento-alveolar surgery, chemotherapy, antiangiogenics). Data were differently analyzed taking into account the implementation of a Dental Prevention Service in patients who are candidates for BP therapy.Results Among 1663 patients treated with BP, 63 cases of BRONJ were identified (3.8%). 44 female and 19 men with a median age of 69 years (range 47-90 years), have been treated with BP for bone metastases from breast cancer (54%), hematologic malignancy (21%), prostate cancer (13%), renal cancer (5%), lung cancer (2%) and other tumors (5%). 15 maxillae and 48 mandibles were involved. The trigger event was a dental extraction in 29% of the cases, being spontaneously the other 71%. The median time to BRONJ was 28 months (range 1-89.1 months) from the first dose of BP, and 25 was the mean number of BP doses administered before BRONJ. Overall, a preliminary odontoiatric evaluation was performed in only 14 cases (22%). All but one of these dentistry opinions were obtained after 2010 when the Dental Prevention Service was created, which is a drop out of the risk of BRONJ from 4.1 to 1.9%. Conclusions. Prevention of the BRONJ is critical in in bone metastatic patients. The incidence of BRONJ over time can drop to 1.9% when primary and secondary prevention measures are implemented in routine clinical practice

Dissecting Immunotherapy Strategies for Small Cell Lung Cancer: Antibodies, Ionizing Radiation and CAR-T

Small cell lung cancer (SCLC) is a highly aggressive malignancy that accounts for about 14% of all lung cancers. Platinum-based chemotherapy has been the only available treatment for a long time, until the introduction of immune checkpoint inhibitors (ICIs) recently changed first-line standard of care and shed light on the pivotal role of the immune system. Despite improved survival in a subset of patients, a lot of them still do not benefit from first-line chemo-immunotherapy, and several studies are investigating whether different combination strategies (with both systemic and local treatments, such as radiotherapy) may improve patient outcomes. Moreover, research of biomarkers that may be used to predict patients’ outcomes is ongoing. In addition to ICIs, immunotherapy offers other different strategies, including naked monoclonal antibodies targeting tumor associated antigens, conjugated antibody, bispecific antibodies and cellular therapies. In this review, we summarize the main evidence available about the use of immunotherapy in SCLC, the rationale behind combination strategies and the studies that are currently ongoing in this setting, in order to give the reader a clear and complete view of this rapidly expanding topic

Doubly Constrained C-terminal of Roc (COR) Domain-Derived Peptides Inhibit Leucine-Rich Repeat Kinase 2 (LRRK2) Dimerization

Missense mutations along the leucine-rich repeat kinase 2 (LRRK2) protein are a major contributor to Parkinson's Disease (PD), the second most commonly occurring neurodegenerative disorder worldwide. We recently reported the development of allosteric constrained peptide inhibitors that target and downregulate LRRK2 activity through disruption of LRRK2 dimerization. In this study, we designed doubly constrained peptides with the objective of inhibiting C-terminal of Roc (COR)-COR mediated dimerization at the LRRK2 dimer interface. We show that the doubly constrained peptides are cell-permeant, bind wild-type and pathogenic LRRK2, inhibit LRRK2 dimerization and kinase activity, and inhibit LRRK2-mediated neuronal apoptosis, and in contrast to ATP-competitive LRRK2 kinase inhibitors, they do not induce the mislocalization of LRRK2 to skein-like structures in cells. This work highlights the significance of COR-mediated dimerization in LRRK2 activity while also highlighting the use of doubly constrained peptides to stabilize discrete secondary structural folds within a peptide sequence.</p