An insight into lung cancer: a comprehensive review exploring ALK TKI and mechanisms of resistance

Implementation of precision medicine in lung cancer has benefited from intense research in the past years, developing subsequently an improved quality of life and increased overall survival of the patients. Targeted therapy has become one of the most important therapeutic innovations for the non-small cell lung cancer (NSCLC) category with anaplastic lymphoma kinase (ALK) gene rearrangement. The aim of this review is to provide a through overview of the main molecules of ALK tyrosine kinase inhibitors (TKI) with their general and particular mechanisms of resistance, the main methods of ALK gene detection, each with advantages and limits and the future perspectives currently under research which try to overcome the mechanisms of resistance. We have used two of the most reliable medical databases EMBASE and PubMed to properly select the latest and the most relevant articles for this topic. Encouraged by the promising results, the clinical practice was enriched by the approval of tyrosine kinase inhibitor molecules, three generations being developed, each one with more powerful agents than the previous ones. Unfortunately, the resistance to TKI eventually occurs and it may be induced by several mechanisms, either known or unknown. Crizotinib was the most intensely studied TKI , becoming the first molecule approved into clinical practice and although four other drugs have been broadly used (alectinib, ceritinib, brigatinib and lorlatinib) it seems that even the most recently developed one remains imperfect due to the resistance mutations that developed. There are two types of resistance generally described for the entire class and for the particular drugs, but half of them remain unknown &nbsp

Dynamic microglial activation is associated with LPS-induced depressive-like behavior in mice: An [18F] DPA-714 PET imaging study

Major depressive disorder (MDD) is a highly pervasive, severe psychological condition for which the precise underlying pathophysiology is incompletely understood, although microglial activation is known to play a role in this context. In this study we analyzed the association between neuroinflammation and depressive-like behaviors in a lipopolysaccharide (LPS)-induced mouse model system using 10-12-week-old male C57BL/6 mice. Microglial activation and associated neuroinflammatory activity were monitored via positron emission tomography (PET) imaging. Animals were assessed at three time points, including 24 h prior to LPS injection, 24 h post-LPS injection, and 72 h post-LPS injection. Analyses of microglial activation and hippocampal neuroinflammation were conducted through [18]F DPA-714 PET imaging and immunohistochemical staining for ionized calcium-binding adapter molecule 1 (Iba-1) and translocator protein (TSPO). Moreover, NOD-like receptor protein 3 (NLRP3) inflammasome activity and interleukin-1β (IL-1β) levels were assessed at 24 h post-LPS injection. We found that LPS treatment was associated with a marked increase in depressive-like behavior at 24 h post-injection time point, and that it was less pronounced at the 72 h post-injection time point. These changes coincided with enhanced [18F] DPA-714 PET uptake in the whole brain, hippocampus, cortex and amygdala together with increased hippocampal microglial activation as evidenced by immunofluorescent staining. By 72 h post-injection, however, these PET and immunofluorescence phenotypes had returned to baseline levels. Furthermore, increased NLRP3 inflammasome activation and IL-1β expression were evident at 24 h post-LPS injection. These data demonstrate that dynamic microglial activation is associated with LPS-induced depressive-like behaviors and hippocampal neuroinflammation in a mouse model system

Poorly differentiated clusters and tumor budding are important prognostic factors in colorectal carcinomas

The aim of our study was to assess the prognostic value of the two new grading systems based on the quantification of tumor budding - TB (GBd) and poorly differentiated clusters - PDCs (PDCs-G) in colorectal carcinomas (CRC). We performed a retrospective study on 71 CRC patients who underwent surgery at the Emergency County Hospital, Timișoara. CRC cases were classified based on haematoxylin-eosin slides, using the conventional grading system, GBd and PDCs-G, respectively. We used two-tier and three-tier grading schemes for each system. Subsequently,  we evaluated  associations with other prognostic factors in CRC. Based on the three-tier GBd (GBd-3t)  most cases (34/69, 49.27%) were classified as G3Bd-3t, while based on the conventional grading system, the majority of the cases (55/69, 79.71%) were considered G2. On the other hand, based on the three-tier PDCs-G system (PDCs-G-3t), most cases (31/69, 44.93%) were PDCs-G2-3t. We also noted a more significant association of GBd-3t with other prognostic parameters analyzed, as compared to the conventional grading system. Nodal status, tumor stage, and lymphovascular invasion were strongly correlated with GBd-3t (p=0.0001). Furthermore, we noted that PDCs-G-3t correlated more significantly than the conventional grading system with nodal status (p<0.0001), tumor stage (p=0.0003), lymphovascular invasion (p<0.0001), perineural invasion (p=0.005) and the tumor border configuration (p<0.0001). High GBd and PDCs-G grades correlate directly with other negative prognostic factors in CRC.Thus, these new parameters/classification methods could be used as additional tools for risk stratification in patients with CRC

Six RNA binding proteins (RBPs) related prognostic model predicts overall survival for clear cell renal cell carcinoma and is associated with immune infiltration

The aim of this article was to construct an accurate prognostic model by using RNA-binding proteins (RBPs) to predict overall survival (OS) for patients with clear cell renal cell carcinoma (ccRCC) as well as to reveal its associations with immune infiltration. Expression profiles based on RNA-binding proteins (RBPs) and  clinical follow-up parameters were obtained from the Cancer Genome Atlas (TCGA) and the ArrayExpress databases. Through univariate COX and LASSO regression analyses, the RBPs based signature was developed. A total of six RBPs (CLK2, IGF2BP2, RNASE2, EZH2, PABPC1L, RPL22L1) were eventually used to establish a prognostic signature. Based on this signature, ccRCC patients were classified into high-risk and low-risk subgroups and significant OS was obtained in both the internal and external datasets (p<0.05). AUCs of its ROC curve were all above 0.70 and this signature was an independent prognostic factor of OS for ccRCC (p<0.05). Nomograms were also constructed to visualize the relationships among individual predictors and 1-, 3- and 5-year OS for ccRCC. Furthermore, the established RBPs based signature was strongly related to critical clinicopathologic characteristics such as grade (p=8.921e−12), stage (p=1.421e−11), M (p=1.662e−05), and T stage (p=7.907e−10). Moreover, 12 kinds of tumor-infiltrating immune cells were significantly linked to high-risk and low-risk groups classified by our constructed model (all p<0.05). Our study successfully identified six RBPs as a robust prognostic signature in ccRCC by both external and internal verification. Besides, our established model displayed significant associations with immune infiltration. In addition to original clinical parameters, our findings may further help clinicians in predicting patients’ survival status and creating individualized treatment plans

The value of routine measurement of serum calcitonin on insufficient, indeterminate, and suspicious thyroid nodule cytology

Routine calcitonin measurement in patients with nodular thyroid disease is rather controversial. The aim of this study was to evaluate the contribution of serum calcitonin measurement in the diagnostic evaluation of thyroid nodules with insufficient, indeterminate, or suspicious cytology. Out of 1668 patients who underwent thyroidectomy with the diagnosis of nodular thyroid disease and were screened, 873 patients with insufficient, indeterminate, or suspicious fine needle aspiration biopsy results were included in the study. From the total number of patients in this study, 10 (1.1%) were diagnosed as medullary thyroid cancer (MTC) using histopathology. The calcitonin level was detected to be above the assay-specific cut-off in 23 (2.6%) patients ranging between 6.5 - 4450 pg/mL. While hypercalcitoninemia was detected in all 10 MTC patients, a false positive elevation of serum calcitonin was detected in 13 patients (1.5%). Of the MTC group, 7 patients had cytology results that were suspicious for malignancy (Bethesda V), one patient’s cytology showed atypia of undetermined significance (Bethesda III) and two patient’s cytology results were suspicious for follicular neoplasm (Bethesda IV). Among the cases with non-diagnostic cytology (Bethesda I), none of the patients were diagnosed with MTC. In conclusion, routine serum calcitonin measurement can be performed in selected cases rather than in all nodular thyroid patients. While it is reasonable to perform routine calcitonin measurement in patients with Bethesda IV and Bethesda V, this measurement was not useful in Bethesda I patients. In Bethesda III patients, patient-based decisions can be made according to their calcitonin measurement. &nbsp

Three-dimensional telomere profiles in papillary thyroid cancer variants: A pilot study

Besides the two main histologic types of papillary thyroid carcinoma (PTC), the classical PTC (CL-PTC) and the follicular variant PTC (FV-PTC), several other variants are described. The encapsulated FV-PTC variant was recently reclassified as noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) due to its similarities to benign lesions. Specific molecular signatures, however, are still unavailable. It is well known that improper DNA repair of dysfunctional telomeres may cause telomere-related genome instability. The mechanisms involved in the damaged telomere repair processing may lead to detrimental outcomes, altering the three-dimensional (3D) nuclear telomere and genome organization in cancer cells. This pilot study aimed to evaluate whether a specific 3D nuclear telomere architecture might characterize NIFTP, potentially distinguishing it from other PTC histologic variants. Our findings demonstrate that 3D telomere profiles of CL-PTC and FV-PTC were different from NIFTP and that NIFTP more closely resembles follicular thyroid adenoma (FTA). NIFTP has longer telomeres than CL-PTC and FV-PTC samples, and the telomere length of NIFTP overlaps with that of the FTA histotype. In contrast, there was no association between BRAF expression and telomere length in all tested samples. These preliminary findings reinforce the view that NIFTP is closer to non-malignant thyroid nodules and confirm that PTC features short telomeres

Audiological and vestibular evaluations in vitiligo patients

The aim of this paper was to investigate audiological abnormalities and potential vestibular injury in a sample of vitiligo subjects. Thirty-five patients with non-segmental vitiligo (NSV) were enrolled in the study. They underwent pure tonal audiometry (PTA), vestibular Fitzgerald-Hallpike caloric test, C-VEM, and O-VEMP testing.  The χ2 test and multiple regression analysis were performed. At PTA, 69% of patients presented with bilateral hearing loss, 8% monaural hearing loss, and 23% normal values. Bilateral caloric stimulations were performed and demonstrated that 14% of patients had a monolateral and 9% had a bilateral pathological response. VEMPs analysis showed that  20% of patients had no O-VEMPs response and 3% had no C-VEMPs response. Comparison between the normal values of healthy subjects and NSV patients showed an alteration of VEMPs in 44%. Multiple regression showed no statistical differences. We propose a specific diagnostic protocol employing PTA, bithermal caloric tests, C-VEMP, and O-VEMP testing to evaluate audio-vestibular damage. Our data were concordant with the anatomic-physiological melanocytic distribution and their possible degeneration linked with NSV.&nbsp

Long noncoding RNA RP11-70C1.3 confers chemoresistance of breast cancer cells through miR-6736-3p/NRP-1 axis

Chemoresistance remains a major obstacle for improving the clinical outcome of patients with breast cancer. Recently, long noncoding RNAs (lncRNAs) have been implicated in breast cancer chemoresistance. However, the function and underlying mechanism are still largely unknown. Using lncRNA microarray, we identified 122 upregulated and 475 downregulated lncRNAs that might be related to the breast cancer chemoresistance. Among them, RP11-70C1.3 was one of the most highly expressed lncRNAs. In breast cancer patients, high RP11-70C1.3 expression predicted poor prognosis. Knockdown of RP11-70C1.3 inhibited the multidrug resistance of breast cancer cells in vitro and in vivo. Further investigations revealed that RP11-70C1.3 functioned as a competing endogenous RNA (ceRNA) for miR-6736-3p to increase NRP-1 expression. Notably, the rescue experiments showed that both miR-6736-3p inhibitor and NRP-1 overexpression could partly reverse the suppressive influence of RP11-70C1.3 knockdown on breast cancer chemoresistance. In conclusion, our study indicated that lncRNA RP11-70C1.3 regulated NRP-1 expression by sponging miR-6736-3p to confer chemoresistance of breast cancer cells. RP11-70C1.3 might be a potential therapeutic target in enhancing the clinical efficacy of chemotherapy in breast cancer

Trop-2 protein as a therapeutic target: A focused review on Trop-2-based antibody-drug conjugates and their predictive biomarkers

Antibody-drug conjugates (ADCs) represent a new class of highly potent antineoplastic drugs built by attaching a small molecule of an anticancer drug (payload) or another therapeutic agent to an antibody recognizing an epitope on the targeted cells. Trophoblast cell-surface antigen-2 (Trop-2) was originally described in trophoblasts and fetal tissues, but subsequently, its overexpression has been demonstrated in various solid malignancies. Sacituzumab govitecan, a conjugate of anti-Trop-2 antibody and SN-38 payload (an active metabolite of irinotecan), is the first in the class that has been clinically validated and approved by the Food and Drug Administration for the treatment of metastatic triple-negative breast (2020) and urothelial carcinomas (2021). In the current review, we summarize and critically appraise the most recent advances with Sacituzumab govitecan, emphasizing the predictive biomarker analysis

Intravenous immunoglobulin: A potential treatment for the post-acute sequelae of SARS-Cov-2 infection?

Following the recovery from an initial infection with SARS-CoV-2, a recent meta-analysis of almost 1 million patients worldwide suggested that an estimated 43% of patients had experienced a variety of sequelae [1].  Furthermore, numerous studies indicate that patients can develop somatic, musculoskeletal, neuropsychiatric, cardiovascular, dermatologic, renal, hepatic and gastrointestinal manifestations that are heterogeneous and vary in intensity and duration (for up to 12 months) [2,3]. The CDC has defined this phenomenon as “long-term symptoms that might be experienced weeks to months after primary infection with SARS-CoV-2, the virus that causes COVID-19 [4]” and proposed designations for this syndrome have included long covid, long chronic covid syndrome, chronic covid, post-COVID-19 syndrome, post-acute covid-19 syndrome and long – haulers [5]. On Feb. 23, 2021, Dr. Francis Collins indicated that the persistent symptoms that occur in patients after recovery from the initial infection could be designated, post-acute sequelae of SARS-CoV-2 (PASC), which we will use in this article. Currently, there is no clear or agreed upon definition or diagnostic criteria for PASC. PASC is most likely a post-infectious illness similar to that reported by patients that had long - term sequelae that persisted for up to 14 months after infection with SARS-CoV-1 or the Middle Eastern respiratory SARS virus (MERS) [6].  Read more in PDF: https://www.bjbms.org/ojs/index.php/bjbms/article/view/6901/243