Summary We assessed differences in the patterns of expression of matrix metalloproteases and their inhibitors (tissue inhibitors of metalloproteases) in ductal carcinoma in situ alone and admixed ...with invasive ductal carcinomas (n = 40), as well as in pure invasive ductal carcinomas (n = 40), immunohistochemically and using tissue arrays. The invasive ductal carcinoma components showed higher expression of matrix metalloprotease–9 and –13 than did the admixed ductal carcinoma in situ, whereas stromal fibroblasts of the invasive components showed higher expression of matrix metalloprotease–2, –7, –9, –13, and –14 and tissue inhibitor of metalloprotease–1 and –3 than did fibroblasts around the neoplastic ducts of the admixed ductal carcinoma in situ. Expression of matrix metalloprotease–14 and tissue inhibitor of metalloprotease–3 was significantly higher in the mononuclear inflammatory cells of the invasive components. By contrast, matrix metalloprotease–1 expression was significantly higher in stromal cells of the ductal carcinoma in situ admixed with invasive ductal carcinoma. The pure invasive ductal carcinomas had significantly higher expression of matrix metalloprotease–1, –9, –11, and –14 and tissue inhibitor of metalloprotease–1 and –3 than the invasive ductal carcinomas admixed with ductal carcinoma in situ. Our findings indicate a significant association of matrix metalloprotease expression by the periductal stromal cells of the ductal carcinoma in situ component of mixed tumors and the occurrence of distant metastasis. Our data suggest that the molecular matrix metalloprotease/tissue inhibitor of metalloprotease profile can contribute to better characterization of early breast carcinomas.
Summary To analyze the expression and prognostic value of matrix metalloproteases and their tissue inhibitors in luminal A and basal-like breast carcinomas, an immunohistochemical study was performed ...on cancer specimens from 93 randomly selected patients with invasive primary ductal tumors of the breast (46 with and 47 without distant metastasis) and with luminal A (n = 48) (ER+, HER2−) or basal-like (HER2−, ER−, PgR−) (n = 45) lesions. Luminal B cases were too few to analyze. Specimens were also studied using tissue microarrays and specific antibodies against matrix metalloproteases 1, 2, 7, 9, 11, 13, and 14 and tissue inhibitors 1, 2, and 3. There were no significant differences in matrix metalloprotease or tissue inhibitor expression in the 2 phenotypes of tumors. In basal-like carcinomas, high scores for matrix metalloproteases 9 and 11 were significantly associated with a high distant metastasis rate. Likewise, data showed associations between matrix metalloprotease/tissue inhibitor expression by either stromal fibroblasts or mononuclear inflammatory cells and distant relapse-free survival in both tumor phenotypes. In addition, in infiltrating luminal A and basal-like tumors, we identified a prometastatic phenotype of mononuclear inflammatory cells, showing a high matrix metalloprotease/tissue inhibitor molecular profile. Expression of matrix metalloproteases and tissue inhibitors is related to the characteristics of breast tumor cells. As prognostic factors in breast carcinomas of both luminal A and basal-like phenotypes, our results point to the importance of the expression of matrix metalloproteases and tissue inhibitors by the stromal cells.
Abstract Myosin has raised an interest in cancer research because of its role in tumor progression. The aim of this study was to investigate the expression and clinical relevance of myosin in ...colorectal cancer (CC). Myosin was detected in CC tumors with recurrence using matrix-assisted laser desorption/ionization time-of-flight analysis. An immunohistochemical study was performed using tissue arrays and specific antibodies against myosin heavy chain. Determinations on cancer specimens from 91 patients with resectable CCs were performed. The minimum follow-up period was of 12.5 years for these patients without tumor recurrence. Western blot and real-time polymerase chain reaction analysis were also performed. Samples of carcinomas with recurrence showed an increased expression of myosin. Tumors with high myosin expression by tumor cell were significantly associated with higher probability of metastasis. Our results suggest that myosin expression in CCs is associated with tumor progression and metastasis development. Therefore, myosin tumor expression may contribute to an improved prognostic evaluation in patients with CC.
The use of L protein coupled magnetic particles for the concentration and purification of immunoglobulin M (mIgM) monoclonal antibodies against Taenia solium was evaluated. Three concentration ...methods and different elution times were evaluated and the ratio of particles to the ratio of mIgM was optimized. It is demonstrated that: 1) with the use of magnetic particles, a previous concentration of mIgM is not required, which reduces the manipulation of the antibodies and improves the recovery, 2) the use of a binding buffer can be omitted, since the pH of most cell culture supernatants are neutral, and 3) longer elution times (~ 45 minutes) are needed to increase recovery to a level greater than 80%. The study demonstrates that the use of L protein-coupled magnetic particles is a simple and efficient tool for mIgM concentration and purification.
Chronic cough can be triggered by respiratory and non-respiratory tract illnesses originating mainly from the upper and lower airways, and the GI tract (ie, reflux). Recent findings suggest it can ...also be a prominent feature in obstructive sleep apnea (OSA), laryngeal hyperresponsiveness, and COVID-19. The classification of chronic cough is constantly updated but lacks clear definition. Epidemiological data on the prevalence of chronic cough are informative but highly variable. The underlying mechanism of chronic cough is a neurogenic inflammation of the cough reflex which becomes hypersensitive, thus the term hypersensitive cough reflex (HCR). A current challenge is to decipher how various infectious and inflammatory airway diseases and esophageal reflux, among others, modulate HCR.
The World Allergy Organization/Allergic Rhinitis and its Impact on Asthma (WAO/ARIA) Joint Committee on Chronic Cough reviewed the current literature on classification, epidemiology, presenting features, and mechanistic pathways of chronic cough in airway- and reflux-related cough phenotypes, OSA, and COVID-19. The interplay of cough reflex sensitivity with other pathogenic mechanisms inherent to airway and reflux-related inflammatory conditions was also analyzed.
Currently, it is difficult to clearly ascertain true prevalence rates in epidemiological studies of chronic cough phenotypes. This is likely due to lack of standardized objective measures needed for cough classification and frequent coexistence of multi-organ cough origins. Notwithstanding, we emphasize the important role of HCR as a mechanistic trigger in airway- and reflux-related cough phenotypes. Other concomitant mechanisms can also modulate HCR, including type2/Th1/Th2 inflammation, presence or absence of deep inspiration-bronchoprotective reflex (lower airways), tissue remodeling, and likely cough plasticity, among others.
Summary Background Most patients with chronic lymphocytic leukaemia or small lymphocytic lymphoma relapse after initial therapy. Bendamustine plus rituximab is often used in the relapsed or ...refractory setting. We assessed the efficacy and safety of adding ibrutinib, an oral covalent inhibitor of Bruton's tyrosine kinase (BTK), to bendamustine plus rituximab in patients with previously treated chronic lymphocytic leukaemia or small lymphocytic lymphoma. Methods The HELIOS trial was an international, double-blind, placebo-controlled, phase 3 study in adult patients (≥18 years of age) who had active chronic lymphocytic leukaemia or small lymphocytic lymphoma with measurable lymph node disease (>1·5 cm) by CT scan, and had relapsed or refractory disease following one or more previous lines of systemic therapy consisting of at least two cycles of a chemotherapy-containing regimen, an Eastern Cooperative Oncology Group (ECOG) performance status of 0–1, and adequate bone marrow, liver, and kidney function. Patients with del(17p) were excluded because of known poor response to bendamustine plus rituximab. Patients who had received previous treatment with ibrutinib or other BTK inhibitors, refractory disease or relapse within 24 months with a previous bendamustine-containing regimen, or haemopoietic stem-cell transplant were also excluded. Patients were randomly assigned (1:1) by a web-based system to receive bendamustine plus rituximab given in cycles of 4 weeks' duration (bendamustine: 70 mg/m2 intravenously on days 2–3 in cycle 1, and days 1–2 in cycles 2–6; rituximab: 375 mg/m2 on day 1 of cycle 1, and 500 mg/m2 on day 1 of cycles 2–6 for a maximum of six cycles) with either ibrutinib (420 mg daily orally) or placebo until disease progression or unacceptable toxicity. Patients were stratified according to whether they were refractory to purine analogues and by number of previous lines of therapy. The primary endpoint was independent review committee (IRC)-assessed progression-free survival. Crossover to ibrutinib was permitted for patients in the placebo group with IRC-confirmed disease progression. Analysis was by intention-to-treat and is continuing for further long-term follow-up. The trial is registered with ClinicalTrials.gov , number NCT01611090. Findings Between Sept 19, 2012, and Jan 21, 2014, 578 eligible patients were randomly assigned to ibrutinib or placebo in combination with bendamustine plus rituximab (289 in each group). The primary endpoint was met at the preplanned interim analysis (March 10, 2015). At a median follow-up of 17 months (IQR 13·7–20·7), progression-free survival was significantly improved in the ibrutinib group compared with the placebo group (not reached in the ibrutinib group (95% CI not evaluable) vs 13·3 months (11·3–13·9) in the placebo group (hazard ratio HR 0·203, 95% CI 0·150–0·276; p<0·0001). IRC-assessed progression-free survival at 18 months was 79% (95% CI 73–83) in the ibrutinib group and 24% (18–31) in the placebo group (HR 0·203, 95% CI 0·150–0·276; p<0·0001). The most frequent all-grade adverse events were neutropenia and nausea. 222 (77%) of 287 patients in the ibrutinib group and 212 (74%) of 287 patients in the placebo group reported grade 3–4 events; the most common grade 3–4 adverse events in both groups were neutropenia (154 54% in the ibrutinib group vs 145 51% in the placebo group) and thrombocytopenia (43 15% in each group). A safety profile similar to that previously reported with ibrutinib and bendamustine plus rituximab individually was noted. Interpretation In patients eligible for bendamustine plus rituximab, the addition of ibrutinib to this regimen results in significant improvements in outcome with no new safety signals identified from the combination and a manageable safety profile. Funding Janssen Research & Development.
To evaluate the long-term safety and efficacy of posterior chamber collagen copolymer phakic intraocular lens (pIOL) implantation to correct myopia.
Fernández-Vega Ophthalmological Institute, Oviedo, ...Spain.
Cohort study.
Uncorrected (UDVA) and corrected (CDVA) distance visual acuities, refraction, pIOL vault, endothelial cell loss, and adverse events were evaluated for 5 years after implantation of the Visian Implantable Collamer Lens pIOL for moderate to high myopia.
The mean spherical equivalent (188 eyes) decreased from -11.17 diopters (D) ± 3.40 (SD) preoperatively to -0.88 ± 0.72 D 5 years postoperatively. The mean change in refraction from 1 month to 5 years was -0.65 ± 0.65 D. The mean UDVA and CDVA (Snellen decimal) were 0.69 ± 0.26 and 0.83 ± 0.15, respectively. The mean safety and efficacy indices were 1.27 ± 0.33 and 0.89 ± 0.35, respectively. No eye lost more than 2 lines of visual acuity; 70% achieved 0.80 or better CDVA. Three eyes (1.6%) developed late anterior subcapsular cataract that was clinically significant in 1 case, leading to pIOL removal and phacoemulsification. Of the 3 eyes (1.6%) with a mild transient increase in intraocular pressure (up to 27 mm Hg), none required a second surgical procedure or prolonged topical medication. The total endothelial cell loss (considered cumulatively at consecutive intervals through 5 years) was 7.7%. There was a tendency toward decreased pIOL vault decrease over time. No vision-threatening complications occurred.
Implantation of the collagen copolymer pIOL for moderate to high myopia was safe and effective and provided long-term predictable, stable refractive results.
Chronic cough management necessitates a clear integrated care pathway approach. Primary care physicians initially encounter the majority of chronic cough patients, yet their role in proper management ...can prove challenging due to limited access to advanced diagnostic testing. A multidisciplinary approach involving otolaryngologists and chest physicians, allergists, and gastroenterologists, among others, is central to the optimal diagnosis and treatment of conditions which underly or worsen cough. These include infectious and inflammatory, upper and lower airway pathologies, or gastro-esophageal reflux. Despite the wide armamentarium of ancillary testing conducted in cough multidisciplinary care, such management can improve cough but seldom resolves it completely. This can be due partly to the limited data on the role of tests (eg, spirometry, exhaled nitric oxide), as well as classical pharmacotherapy conducted in multidisciplinary specialties for chronic cough. Other important factors include presence of multiple concomitant cough trigger mechanisms and the central neuronal complexity of chronic cough. Subsequent management conducted by cough specialists aims at control of cough refractory to prior interventions and includes cough-specific behavioral counseling and pharmacotherapy with neuromodulators, among others. Preliminary data on the role of neuromodulators in a proof-of-concept manner are encouraging but lack strong evidence on efficacy and safety.
The World Allergy Organization (WAO)/Allergic Rhinitis and its Impact on Asthma (ARIA) Joint Committee on Chronic Cough reviewed the recent literature on management of chronic cough in primary, multidisciplinary, and cough-specialty care. Knowledge gaps in diagnostic testing, classical and neuromodulator pharmacotherapy, in addition to behavioral therapy of chronic cough were also analyzed.
This third part of the WAO/ARIA consensus on chronic cough suggests a management algorithm of chronic cough in an integrated care pathway approach. Insights into the inherent limitations of multidisciplinary cough diagnostic testing, efficacy and safety of currently available antitussive pharmacotherapy, or the recently recognized behavioral therapy, can significantly improve the standards of care in patients with chronic cough.
RET Fusion Testing in Patients With NSCLC: The RETING Study Conde, Esther; Hernandez, Susana; Rodriguez Carrillo, Jose Luis ...
JTO clinical and research reports,
April 2024, 2024-Apr, 2024-04-00, 20240401, 2024-04-01, Letnik:
5, Številka:
4
Journal Article
Recenzirano
Odprti dostop
RET inhibitors with impressive overall response rates are now available for patients with NSCLC, yet the identification of RET fusions remains a difficult challenge. Most guidelines encourage the ...upfront use of next-generation sequencing (NGS), or alternatively, fluorescence in situ hybridization (FISH) or reverse transcriptase-polymerase chain reaction (RT-PCR) when NGS is not possible or available. Taken together, the suboptimal performance of single-analyte assays to detect RET fusions, although consistent with the notion of encouraging universal NGS, is currently widening some of the clinical practice gaps in the implementation of predictive biomarkers in patients with advanced NSCLC.
This situation prompted us to evaluate several RET assays in a large multicenter cohort of RET fusion–positive NSCLC (n = 38) to obtain real-world data. In addition to RNA-based NGS (the criterion standard method), all positive specimens underwent break-apart RET FISH with two different assays and were also tested by an RT-PCR assay.
The most common RET partners were KIF5B (78.9%), followed by CCDC6 (15.8%). The two RET NGS-positive but FISH-negative samples contained a KIF5B(15)-RET(12) fusion. The three RET fusions not identified with RT-PCR were AKAP13(35)-RET(12), KIF5B(24)-RET(9) and KIF5B(24)-RET(11). All three false-negative RT-PCR cases were FISH-positive, exhibited a typical break-apart pattern, and contained a very high number of positive tumor cells with both FISH assays. Signet ring cells, psammoma bodies, and pleomorphic features were frequently observed (in 34.2%, 39.5%, and 39.5% of tumors, respectively).
In-depth knowledge of the advantages and disadvantages of the different RET testing methodologies could help clinical and molecular tumor boards implement and maintain sensible algorithms for the rapid and effective detection of RET fusions in patients with NSCLC. The likelihood of RET false-negative results with both FISH and RT-PCR reinforces the need for upfront NGS in patients with NSCLC.
The most common subtype of colon cancer is colorectal adenocarcinoma. Compared with other subtypes, such as signet-ring and mucinous, colorectal adenocarcinoma has been found to have lower rates of ...metastasis. Approximately 20% of colorectal cancer cases present with metastatic disease on initial evaluation. The most common locations for metastasis are the liver, lung, peritoneum, bone, and extra-regional lymph nodes. Metastatic disease to the skeletal muscle, however, is considerably rare. We present a clinical case of a 52-year-old female found to have a cystic iliopsoas muscle metastasis from rectosigmoid adenocarcinoma, initially classified as an infected fluid collection.
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