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Background: Spread through air spaces (STAS) has been identified as an invasion pattern in non–small cell lung cancer (NSCLC). This study evaluated the association between tumor STAS and various clinicopathological parameters of NSCLC, with emphasis on the prognostic role of STAS. Methods: We evaluated 96 cases of NSCLC for STAS. STAS-positive cases were graded according to the distance between the edge of the primary tumor and the furthest STAS, in millimeters, or the number of alveoli separating STAS from the tumor. Results: STAS was observed in 33 patients (34.4%). In 28 cases, STAS was located in airspaces >3 alveoli away from the primary tumor. In 18 cases, STAS was found in airspaces > 2.5 mm away from the edge of the primary tumor. Morphologically, 18 cases of STAS demonstrated a solid nest pattern, eight showed a micropapillary cluster pattern, and seven exhibited a single-cell pattern. In multivariate analysis, only high tumor grade (p = .001) was independently associated with STAS in NSCLC. The presence of STAS (p = .047), lymphovascular invasion (p = .001), positive surgical margin (p = .021), adenocarcinoma histology (p = .020), and postoperative therapy (p = .049) showed a statistically significant lower overall survival (OS). However, multivariate analyses showed that STAS is not an independent predictor of OS in NSCLC. In addition, STAS-positive cases with an extension of >2.5 mm had significantly lower disease-free survival (DFS) (p = .018). Conclusions: The findings demonstrated that STAS is independently associated with a higher tumor grade and appears to have an adverse impact on OS and DFS in the examined subpopulation.

Background and Objectives: Human papillomavirus (HPV) was previously investigated in lung cancer with wide inter-geographic discrepancies. p16INK4a has been used as a surrogate for detecting high-risk HPV (HR-HPV) in some cancer types. This study assessed the evidence of HPV in non-small-cell lung cancer (NSCLC) among Jordanian patients, investigated the expression of p16INK4a, and evaluated its prognostic value and association with HPV status. Materials and Methods: The archived samples of 100 patients were used. HPV DNA detection was performed by real-time polymerase chain reaction (RT-PCR). p16INK4a expression was assessed by immunohistochemistry (IHC). The Eighth American Joint Committee on Cancer protocol (AJCC) of head and neck cancer criteria were applied to evaluate p16INK4a positivity considering a moderate/strong nuclear/cytoplasmic expression intensity with a distribution in ≥75% of cells as positive. Results: HPV DNA was detected in 5% of NSCLC cases. Three positive cases showed HR-HPV subtypes (16, 18, 52), and two cases showed the probable HR-HPV 26 subtype. p16INK4a expression was positive in 20 (20%) NSCLC cases. None of the HPV-positive tumors were positive for p16INK4a expression. A statistically significant association was identified between p16INK4a expression and the pathological stage (p = 0.029) but not with other variables. No survival impact of p16INK4a expression was detected in NSCLC cases as a group; however, it showed a statistically significant association with overall survival (OS) in squamous cell carcinoma (SqCC) cases (p = 0.033). Conclusions: This is the first study to assess HPV and p16INK4a expression in a Jordanian population. HPV positivity is rare in NSCLC among a Jordanian subpopulation. P16 INK4a reliability as a surrogate marker for HPV infection in lung cancer must be revisited.

Recent studies imply that psychological factors may actively contribute to the development of asthma. It is generally known that people with asthma frequently suffer from psychological illnesses. This association can make it challenging to reach asthma control. This study aimed to assess the prevalence of depression and anxiety among Jordanian adults with asthma, in addition to the link between asthma control levels and these psychological disorders. This cross-sectional study included 175 adults with asthma who visited the tertiary asthma clinic in three Jordanian Governmental hospitals. Sociodemographic data was collected directly from the patients who were assessed for their level of depression and anxiety using a self-administered questionnaire, the Hospital Anxiety and Depression Scale (HADS). Also, asthma control was assessed using the Asthma Control Test (ACT). The relation between the different sociodemographic variables and clinical data, particularly depression and anxiety and asthma control level, was assessed. Among 175 asthmatic patients, 60.57% had poor disease control, 8% had anxiety alone, 11.43% had depression alone, and 53.14% had anxiety plus depression. Poor asthma control was significantly associated with anxiety and depression ( ) and low levels of education ( ). Further, a lower level of education was also related to higher levels of anxiety and depression. Most of the assessed Jordanian patients with asthma had their disease poorly controlled. Anxiety and depression are common among the studied sample of adults with asthma, and they appear to affect the level of disease control, suggesting the possibility that addressing these psychological conditions could enhance asthma control levels.

Neoadjuvant chemotherapy (NAC) is a frequently utilized approach to treat locally advanced breast cancer, but, unfortunately, a subset of tumors fails to undergo complete pathological response. Apoptosis and therapy-induced senescence (TIS) are both cell stress mechanisms but their exact role in mediating the pathological response to NAC is not fully elucidated. We investigated the change in expression of PAMIP1 , the gene encoding for the pro-apoptotic protein, NOXA, following NAC in two breast cancer gene datasets, and the change in NOXA protein expression in response to NAC in 55 matched patient samples (pre- and post-NAC). PAMIP1 expression significantly declined in post-NAC in the two sets, and in our cohort, 75% of the samples exhibited a downregulation in NOXA post-NAC. Matched samples that showed a decline in NOXA post-NAC were examined for TIS based on a signature of downregulated expression of Lamin-B1 and Ki-67 and increased p16 INK4a , and the majority exhibited a decrease in Lamin B1 (66%) and Ki-67 (80%), and increased p16 INK4a (49%). Since our cohort consisted of patients that did not develop complete pathological response, such findings have clinical implications on the role of TIS and NOXA downregulation in mediating suboptimal responses to the currently established NAC.

Background Oncogene-Induced Senescence (OIS) is a form of senescence that occurs as a consequence of oncogenic overstimulation and possibly infection by oncogenic viruses. Whether senescence plays a role in the pathogenesis of cervical cancer (CC) is not well understood. Moreover, whether cervical epithelial cells that are part of the premalignant cervical intraepithelial neoplasia (CIN), exhibit markers of OIS in Human Papillomavirus (HPV)-infected tissue, has not been investigated. Methods We utilized a set of patient-derived premalignant and malignant tissue samples to investigate the protein (Ki67 and Lamin B1) and gene ( TP53 , IL1A , CCL2 , and MMP9 ) expression of several OIS-associated biomarkers using immunohistochemistry (IHC) and qRT-PCR, respectively. Furthermore, we characterized the HPV status of all tissue samples. Results Most of the CC samples (34/37) were positive for HPV, mainly HPV-16 which was observed in 62.2% of the CC samples. Among CINs, HPV infection was found in 60.2% of the 32 samples with HPV-16 as the dominant genotype in 58.5% of the CINs. IHC analysis revealed a significant increase in the expression levels of both Ki67 and Lamin B1 proteins in CC tissue compared to CIN. On average, 93% of tumor cells were positive for Ki67 in comparison to only 25% of premalignant cells in CIN samples. Similarly, Lamin B1 expression was observed in 89% of tumor cells in malignant tissue on average, compared to 60% in CIN samples. Importantly, Lamin B1 expression was elevated in nonmalignant cervical tissue suggesting that its downregulation is more predominant in the premalignant state. Furthermore, RT-PCR revealed a significant decrease in the expression of TP53 , IL1a , CCL2 , and MMP9 markers in CC samples compared to CINs. Specifically, 84% of CC samples showed reduced TP53 expression, 90% showed reduced IL1a expression, 74% showed reduced CCL2 expression, and 76% showed reduced MMP9 expression when compared with their premalignant baseline. Infection of HPV was confirmed in 61% of the tumor tissues while only 25% of the CINs were positive for HPV. Conclusion This work shall provide an opportunity to further examine the role of OIS in the process of HPV-driven CC development.

Background and Objectives: Multiple sclerosis (MS) is a chronic autoimmune disease of the central nervous system with rising prevalence in the Middle East. Real-world comparative data on disease-modifying therapies from this region remain limited. This retrospective study compared the clinical outcomes and tolerability of fingolimod and interferon beta-1a (IFN-β1a) among patients with relapsing–remitting multiple sclerosis treated at a large public referral hospital in Jordan. Materials and Methods: All eligible RRMS patients received fingolimod or IFN-β1a at a single tertiary hospital. The annualized relapse rate (ARR), Expanded Disability Status Scale (EDSS) scores, and adverse effect frequencies were analyzed using descriptive and inferential statistics. A full-cohort inclusion approach was applied instead of sample-size calculation, as all available cases at Al-Basheer Hospital (Amman, Jordan) were included. Results: Fingolimod-treated patients showed a significantly higher ARR than those on IFN-β1a (0.51 vs. 0.26, p = 0.016), an association likely influenced by treatment sequencing and baseline disease activity. EDSS distributions were similar between treatment groups, with most patients demonstrating mild disability (EDSS ≤ 3.5). IFN-β1a was linked to injection site reactions, while fingolimod was better tolerated. Conclusions: The higher observed relapse rate among fingolimod-treated patients possibly reflects treatment sequencing and underlying disease severity rather than pharmacologic efficacy, as fingolimod was commonly prescribed as an escalation therapy. These findings highlight the importance of individualized treatment selection and underscore the need for prospective studies incorporating standardized baseline disease activity measures to better inform multiple sclerosis care in Jordan and the wider Middle Eastern region.

Background Human epidermal growth factor receptor 2 (HER2), a promising therapeutic target, can be mutated, amplified, or overexpressed in different malignancies, including non-small cell lung cancer (NSCLC). Although these alterations showed adverse prognostic effects in many cancers, their clinical significance in NSCLC is controversial. This study primarily assessed the prevalence of HER2 protein expression in NSCLC among Jordanian patients. In addition, the possible association between HER2 protein expression and clinicopathological variables was evaluated. Methods A total of 100 surgically resected NSCLC cases treated at King Hussein Cancer Center (KHCC) between 2009 and 2021 were examined for HER2 protein expression using immunohistochemistry (IHC). The American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP) guidelines for breast cancer were applied to interpret the results with a final score ranging from 0 to 3+, considering a score of 3 + as overexpression. Additionally, a separate subset of patients was tested for HER2 gene mutation. Fisher’s exact test was used to assess the association between HER2 scores and the other variables. Kaplan-Meier method was used to calculate survival. Results Of the 100 cases, Her2 overexpression (score 3+) was detected in 2 cases (2%), score 2 + in 10 cases (10%), score 1 + in 12 cases (12%), and score 0 in 76 cases (76%). The two positive cases were one adenocarcinoma and one squamous cell carcinoma; both patients were elderly male smokers. No significant association was identified between Her2 expression and age, gender, smoking, histological subtype, grade, stage, tumor size, and lymph node status. Our findings also showed no association between Her2 expression and survival; however, advanced tumor stages and positive lymph node metastasis were significantly associated with poor overall survival. All cases tested for the Her2 mutation were negative. Conclusions Her2 overexpression is uncommon in NSCLC among the Jordanian population. However, when the same scoring criteria are used, the rates are similar to other results found in Asian cohorts. Due to our study’s relatively small sample size, a larger one is required to investigate the prognostic value and the molecular associations between the different Her2 alterations.

Objective: The effect of the cGAS/STING pathway on antitumor immunity and its connection to senescence in vivo necessitates further investigation. Introduction: Cellular senescence and its secretory phenotype (the SASP) are implicated in modulating the immune microenvironment of cancer possibly through the cGAS/STING pathway. Methods: Gene expression data from paired colon cancer and adjacent non-malignant mucosa (98 patients, n = 196 samples; 65 patients, n = 130 samples) were analyzed for cGAS/STING and a senescence signature. Immunohistochemistry assessed cGAS/STING protein expression in 124 colorectal samples. Results: Approximately one-quarter of patients displayed senescence profiles in both gene sets, yet without significantly correlating with cGAS/STING expression. Notably, cGAS expression was higher than STING in tumor tissue compared to non-malignant colonic mucosa. Protein analysis showed 83% positive cGAS expression and 39% positive STING expression, with discrepancies in expression patterns. Additionally, 15% of samples lacked both markers, while 35% exhibited positive staining for both. No significant correlations were found between cGAS/STING status and tumor stage, patient age, lymphovascular invasion, or lymph node involvement. Conclusions: Our findings demonstrate significant senescence marker expression in colorectal cancer samples but with no correlation with cGAS/STING.

Deletion of CDKN2A occurs in 50% of glioblastomas (GBM), and IFNA locus deletion in 25%. These genes reside closely on chromosome 9. We investigated whether CDKN2A and IFNA were co-deleted within the same heterogeneous tumour and their prognostic implications. We assessed CDKN2A and IFNA14 deletions in 45 glioma samples using an in-house three-colour FISH probe. We examined the correlation between p16 INK4a protein expression (via IHC) and CDKN2A deletion along with the impact of these genomic events on patient survival. FISH analyses demonstrated that grades II and III had either wildtype (wt) or amplified CDKN2A / IFNA14 , whilst 44% of GBMs harboured homozygous deletions of both genes. Cores with CDKN2A homozygous deletion ( n  = 11) were negative for p16 INK4a . Twenty p16 INK4a positive samples lacked CDKN2A deletion with some of cells showing negative p16 INK4a . There was heterogeneity in IFNA14/CDKN2A ploidy within each GBM. Survival analyses of primary GBMs suggested a positive association between increased p16 INK4a and longer survival; this persisted when considering CDKN2A/IFNA14 status. Furthermore, wt (intact) CDKN2A/IFNA14 were found to be associated with longer survival in recurrent GBMs. Our data suggest that co-deletion of CDKN2A/IFNA14 in GBM negatively correlates with survival and CDKN2A -wt status correlated with longer survival, and with second surgery, itself a marker for improved patient outcomes.

Cancers arising from germline DNA mismatch repair deficiency or polymerase proofreading deficiency (MMRD and PPD) in children harbour the highest mutational and microsatellite insertion–deletion (MS-indel) burden in humans. MMRD and PPD cancers are commonly lethal due to the inherent resistance to chemo-irradiation. Although immune checkpoint inhibitors (ICIs) have failed to benefit children in previous studies, we hypothesized that hypermutation caused by MMRD and PPD will improve outcomes following ICI treatment in these patients. Using an international consortium registry study, we report on the ICI treatment of 45 progressive or recurrent tumors from 38 patients. Durable objective responses were observed in most patients, culminating in a 3 year survival of 41.4%. High mutation burden predicted response for ultra-hypermutant cancers (>100 mutations per Mb) enriched for combined MMRD + PPD, while MS-indels predicted response in MMRD tumors with lower mutation burden (10–100 mutations per Mb). Furthermore, both mechanisms were associated with increased immune infiltration even in ‘immunologically cold’ tumors such as gliomas, contributing to the favorable response. Pseudo-progression (flare) was common and was associated with immune activation in the tumor microenvironment and systemically. Furthermore, patients with flare who continued ICI treatment achieved durable responses. This study demonstrates improved survival for patients with tumors not previously known to respond to ICI treatment, including central nervous system and synchronous cancers, and identifies the dual roles of mutation burden and MS-indels in predicting sustained response to immunotherapy. Hypermutation and microsatellite burden determine responses and long-term survival following PD-1 blockade in children and young adults with refractory cancers resulting from germline DNA replication repair deficiency.