Site Of Origin Research Articles

Biomarker-Driven Oncology Clinical Trials: Novel Designs in the Era of Precision Medicine

Oncology drug development historically has followed a path of sequential phase I, II, and III clinical trials using traditional trial designs, with the goal of achieving regulatory approval. These studies are often conducted with inclusion criteria that limit enrollment to a single tumor type or tumor site of origin, excluding other patients who might also respond. Increased use of precision medicine targeting biomarkers or specific oncogenic mutations has led to novel clinical trial designs that can evaluate these therapies in a less limited fashion. Master protocols such as basket trials, umbrella trials, and platform trials can, for example, evaluate histology-specific therapies targeting a common oncogenic mutation across multiple tumor types or screen for the presence of multiple different biomarkers rather than a single one. In other cases, they can lead to more rapid evaluation of a drug and evaluate targeted therapies in tumor types for which they are not yet currently indicated. As the use of complex biomarker-based master protocols increases, advanced practitioners must understand these novel trial designs, their advantages and disadvantages, and how their use may advance drug development and maximize the clinical benefits of molecular precision therapy.

Continual learning strategies for cancer-independent detection of lymph node metastases.

Recently, large, high-quality public datasets have led to the development of convolutional neural networks that can detect lymph node metastases of breast cancer at the level of expert pathologists. Many cancers, regardless of the site of origin, can metastasize to lymph nodes. However, collecting and annotating high-volume, high-quality datasets for every cancer type is challenging. In this paper we investigate how to leverage existing high-quality datasets most efficiently in multi-task settings for closely related tasks. Specifically, we will explore different training and domain adaptation strategies, including prevention of catastrophic forgetting, for breast, colon and head-and-neck cancer metastasis detection in lymph nodes. Our results show state-of-the-art performance on colon and head-and-neck cancer metastasis detection tasks. We show the effectiveness of adaptation of networks from one cancer type to another to obtain multi-task metastasis detection networks. Furthermore, we show that leveraging existing high-quality datasets can significantly boost performance on new target tasks and that catastrophic forgetting can be effectively mitigated.Last, we compare different mitigation strategies.

VP-Preposing and Constituency “Paradox”

English VP-preposing allows VP modifiers to remain on the right (John said he would arrive on Tuesday, and arrive he did, on Tuesday). The classic analysis of this invokes VP constituency, claiming that the modifiers are right-adjoined to VP and stranded by movement of a smaller VP ([VP arrive] he did [VP [VP arrive] on Tuesday]). This article proposes a radically different view based on the copy theory of movement (Chomsky 1993), wherein moved items leave a copy in their site of origin. I propose that VP-preposing always involves movement of the maximal VP with possible/impossible argument/modifier “strandings” representing possible/impossible pronunciations of the original copy. This proposal allows a straightforward analysis of “paradox” examples in which VP-preposing constituency appears to clash with c-command requirements. It also raises the possibility of eliminating adjunction entirely in the analysis of modifiers.

Choanal polyps: Variant sites of origin

Choanal polyps: Variant sites of origin

Parkinson's Disease, SARS-CoV-2, and Frailty: Is There a Vicious Cycle Related to Hypovitaminosis D?

The literature has long established the association between aging and frailty, with emerging evidence pointing to a relationship between frailty and SARS-CoV-2 contagion. The possible neurological consequences of SARS-CoV-2 infection, associated with physical and cognitive frailty, could lead to a worsening of Parkinson's disease (PD) in infected patients or-more rarely-to an increase in the Parkinsonian symptomatology. A possible link between those clinical pictures could be identified in vitamin D deficiency, while the whole process would appear to be associated with alterations in the microbiota-intestine-brain axis that fall within the α-Synuclein Origin site and Connectome (SOC) model, and allow for the identification of a body-first PD and a brain-first PD. The model of care for this condition must consider intrinsic and extrinsic variables so that care by a multidisciplinary team can be successfully predicted. A multidimensional screening protocol specifically designed to identify people at risk or in the early stages of the disease should begin with the investigation of indices of frailty and microbiota-intestine-brain axis alterations, with a new focus on cases of hypovitaminosis D.

Morphological Study of the Thebesian Valve in Fresh Autopsied Adult Human Hearts.

Background The coronary sinus (CS) and its tributaries have been used to perform various electrophysiological and cardiac interventional procedures which require cannulation.The Thebesian valve (TV) guarding the coronary sinus orifice (CSO) exhibits morphological variations which might make cannulation unsuccessful leading to the failure of invasive cardiac procedures.This study aimed to analyze in detail themorphological features of the TV infreshautopsiedhuman hearts which were representative of the adult population of this region owing to its practical implications in invasive cardiac procedures. Methodology This was a cross-sectional, descriptive study conducted in the Department of Anatomy in collaboration with the Department of Forensic Medicine and Toxicology at Jawaharlal Institute of Postgraduate Medical Education and Research, Puducherry. A total of 104 fresh adult heart specimens were collected during the autopsy. The CSO was located, and the characteristic shape, composition, position, and extent of coverage of the CSO by the TV were observed and analyzed. Results The TV was present in 65% of heart specimens.The most common shape was remnant (33%), and the most common site of origin was inferior (63%).The valve composition was thin and membranous in 63% of heart specimens.In 7% of heart specimens, the TV covered more than 75% of the CSO diameter, of which in 4% of heart specimens, the CSO was completely closed and found to be obstructive. Conclusions This study highlights the variability in the morphological structure of the TV in adult human hearts and its potential implications in unsuccessful CS cannulation and failure of invasive cardiac procedures.Thus, prior imaging of the TV should be an integral part of CS cannulation procedures to avoid unsuccessful cannulation and complications related to repeated forceful cannulation.

Sinus rhythm electrocardiographic abnormalities, sites of origin, and ablation outcomes of ventricular premature depolarizations initiating ventricular fibrillation

BackgroundVentricular fibrillation (VF) can be initiated by ventricular premature depolarizations (VPDs) in the absence of obvious structural abnormalities. ObjectiveThe purpose of this study was to determine the prevalence of 12-lead electrocardiographic (ECG) sinus rhythm reduced QRS amplitude, QRS fractionation (QRSf), and early repolarization (ER) pattern, and the outcome of catheter ablation and VPD anatomic distribution in patients with VPDs initiating VF. MethodsWe compared a cohort with no apparent structural heart disease and VPDs initiating VF (group 1; n = 42) to a reference cohort (group 2; n = 61) of patients with no structural heart disease and symptomatic unifocal VPDs. ResultsA reduced QRS amplitude (<0.55 mV) in aVF (59% vs 10%; P <.001), QRSf in ≥2 contiguous leads (50% vs 16%; P <.001), and ER pattern (21.4% vs 1.6%; P = .01) were more common in group 1 than in group 2. At least 1 abnormal ECG finding was present in 34 group 1 patients (81%) vs 17 group 2 patients (28%) (P <.001). VPD origin included right ventricular and left ventricular distal Purkinje system and moderator band/papillary muscles in 83% of group 1 patients vs 18% of group 2 patients (P <.001). VF was eliminated with a single ablation procedure in 77% of group 1 patients with at least 2 years of follow-up. ConclusionA reduced QRS amplitude (<0.55 mV) in aVF, QRSf in ≥2 contiguous leads, and/or an ER pattern are frequently observed in patients with VPDs initiating VF. VPDs initiating VF typically originate from the distal Purkinje system and papillary muscles and can be successfully eliminated with catheter ablation.

Utility of cardiac imaging in patients with ventricular tachycardia

Ventricular tachycardia (VT) is a life-threatening arrhythmia that may be idiopathic or result from structural heart disease. Cardiac imaging is critical in the diagnostic workup and risk stratification of patients with VT. Data gained from cardiac imaging provides information on likely mechanisms and sites of origin, as well as risk of intervention. Pre-procedural imaging can be used to plan access route(s) and identify patients where post-procedural intensive care may be required. Integration of cardiac imaging into electroanatomical mapping systems during catheter ablation procedures can facilitate the optimal approach, reduce radiation dose, and may improve clinical outcomes. Intraprocedural imaging helps guide catheter position, target substrate, and identify complications early. This review summarises the contemporary imaging modalities used in patients with VT, and their uses both pre-procedurally and intra-procedurally.

The right atrial auricle—Worthy of a new look

IntroductionThe right atrium is the least well studied cardiac chamber. Even less is known about the right atrial appendage (RAA). Recently, the RAA has been shown to be the site of numerous and diverse pathological processes. Furthermore, the RAA can also be the site of origin of atrial fibrillation with obvious implications for ablation procedures. No standard method of transthoracic echocardiography (TTE) for imaging of the RAA can be found in current literature, despite numerous reports for transesophageal echocardiography (TEE). Purpose of this studyThe purpose of this study was to determine if a reliable transthoracic window could be found for consistent and reliable imaging of the RAA. Method30 patients (15 men and 15 women) were included into this study. All patients were placed in the left lateral decubitus position and echocardiography was performed with a Vivid E9 ultrasound system (GE Healthcare). The RAA was visualized by tilting the probe infero-medially from the standard apical four chamber view. ResultsThe RAA was visualized in all 30 patients. The RAA followed a consistent upwards and leftwards path anterior to the aortic root. ConclusionTTE is a valid method of imaging of the RAA.

Vestibular, Central, and Non-Vestibular Etiologies of Vertigo and Disequilibrium: A Rural Hospital-Based Cross-Sectional Comparative Analysis.

Vertigo/dizziness is defined as disturbed postural awareness and could range from a feeling of sensation of spinning of self or surrounding. Dizziness or disturbed postural awareness is a common presentation in varying age groups. Vertigo has varied clinical presentations. Classically, there are four vertigo syndromes: vertigo, imbalance/disequilibrium, presyncope/lightheadedness, and psychogenic dizziness. The present study was conducted to examine the various etiologies involved in these syndromes and to help unmask the overlaps between them. This study also aimed to further classify the etiologies underlying these vertigo syndromes and overlaps into peripheral or vestibular, central, and non-vestibular. This would help develop a comprehensive management protocol for vertigo of any origin. A prospective observational cross-sectional study was undertaken in a rural hospital in Central India. We studied patients with giddiness and categorized them into vertigo syndromes according to the site of origin of vertigo. We also compared overlaps in the presentation of vertigo. Out of the 80 patients that were studied, vertigo with disequilibrium was observed in 72.50% of the patients. Non-vestibular vertigo of cervicogenic origin was the common cause of vertigo seen in 36.25% of the patients occurring alone or in association with vestibular vertigo. Among patients with overlaps, vestibular vertigo with non-vestibular vertigo was the most common etiology observed in 89.65% of the patients with overlaps. The syndrome of "vertigo with disequilibrium" was the commonest presentation in the patients studied, followed by "vertigo syndrome" as an isolated symptom, not associated with "disequilibrium."Ours is probably the first study to report this observation of overlaps of two syndromes, with diagnostic implications.

Anatomical Reconstruction of Extensive Inferomedial Blow-Out Fractures Involving the Inferomedial Orbital Strut Using a Single Fan-shaped Titanium-Reinforced Porous Polyethylene Plate.

Extensive inferomedial blow-out fractures involving the inferomedial orbit strut frequently result in severe ophthalmic complications. Therefore, anatomical reconstruction is essential but is still technically challenging. Thus, the authors have used a novel technique using a combination of single fan-shaped titanium-reinforced porous polyethylene (TR-PPE) implants and a bidirectionally extended transconjunctival approach. Herein, the authors describe our surgical technique and discuss its effectiveness. First, the transconjunctival approach was performed and was subsequently extended medially using the transcaruncular approach and laterally using lateral blepharotomy. After the origin of the inferior oblique muscle was identified, a trimmed fan-shaped TR-PPE implant was inserted into the orbital floor. It was subsequently rotated and bent at the site of origin of the IO muscle and moved upward to cover the superior bony ledge of the medial wall. Finally, the implant was fixed to the orbital rim. Anatomical orbital reconstruction was confirmed by a computed tomographic scan. The preoperative diplopia in 19 patients, resolved within 1 week in 16 patients and in 3 to 6 months in the remaining 3 patients. Preoperative enophthalmos >2mm in all patients improved to <2mm in 67 patients and 3mm in 2 patients (>7mm preoperatively). The postoperative course was uneventful, and no severe complications were observed. The authors believe that the placement of a fan-shaped TR-PEE implant into the orbit through the bidirectionally extended transconjunctival approach could be a viable option for the anatomical reconstruction of extensive inferomedial blow-out fractures involving the inferomedial orbital strut.

Therapeutic advances in leiomyosarcoma.

Leiomyosarcoma is an aggressive mesenchymal malignancy and represents one of the most common subtypes of soft tissue sarcomas. It is characterized by significant disease heterogeneity with variable sites of origin and diverse genomic profiles. As a result, the treatment of advanced leiomyosarcoma is challenging. First-line therapy for metastatic and/or unresectable leiomyosarcoma includes anthracycline or gemcitabine based regimens, which provide a median progression-free survival time of about 5 months and overall survival time between 14-16 months. Effective later-line therapies are limited. Molecular profiling has enhanced our knowledge of the pathophysiology driving leiomyosarcoma, providing potential targets for treatment. In this review, we explore recent advances in our understanding of leiomyosarcoma tumor biology and implications for novel therapeutics. We describe the development of clinical trials based on such findings and discuss available published results. To date, the most promising approaches for advanced leiomyosarcoma include targeting DNA damage repair pathways and aberrant metabolism associated with oncogenesis, as well as novel chemotherapy combinations. This review highlights the recent progress made in the treatment of advanced leiomyosarcoma. Ongoing progress is contingent upon further development of clinical trials based on molecular findings, with careful consideration for clinical trial design, strong academic collaborations, and prospective correlative analyses.

Drought erodes mountain plant community resistance to novel species under a warming climate

ABSTRACT Warming in mountain regions is projected to occur three times faster than the global average. Recently, a small number of observational studies have reported species loss in mountain plant communities and have explored mechanisms facilitating the colonization by novel species. We monitored translocated mountain plant communities and their novel competitor interactions following five years of exposure to downslope climates. We found increasing species turnover under two future climate scenarios with time. Local loss of native species was followed by the colonization by novel species after a severe drought year in the third year after translocation. Here, the assumed mechanism facilitating novel species colonization in mountain communities is direct environmental filtering. We find a time lag between the local loss of native species and the colonization by novel species, which can be explained by interacting climate stressors—that is, warming and drought—pushing communities across a threshold of resistance to colonization. Interestingly, despite significant changes in species identity and strong colonization by novel species, the proportional contribution of plant functional groups to aboveground biomass stayed stable across both sites of origin and over time. Our study provides experimental evidence of local species loss in mountain plant communities prone to severe climatic change, revealing abrupt threshold dynamics.

Clinical outcomes of sinonasal inverted papilloma: a retrospective analysis of 139 cases.

Sinonasal inverted papilloma has a high tendency for recurrence, local bone destruction and risk of malignant transformation. Therefore, complete resection of the tumour is required, and close follow up is essential. This article describes the clinical outcomes, recurrence rate and malignant transformation rate of sinonasal inverted papilloma. In this study, 139 patients diagnosed with sinonasal inverted papilloma in our hospital from December 2010 to May 2022 were retrospectively analysed. All patients underwent endoscopic surgery. Sinonasal inverted papilloma occurred more often in males than in females. The mean age of patients with sinonasal inverted papilloma was 67.3 ± 5.7 years at diagnosis. The most prevalent site of origin was the maxillary sinus (50.4 per cent). The recurrence rate was 5.75 per cent, and the malignant transformation rate was 6.5 per cent. All patients in this study underwent endoscopic surgery. Meticulous resection and regular long-term follow ups are crucial to reducing sinonasal inverted papilloma recurrence after surgery.

Clinicopathological Spectrum of Benign Skin Adnexal Tumors in the Pakistani Population: A Single-Center Study.

Background Skin adnexal tumors (SATs) are categorized per the site of origin, for example, hair follicles, sebaceous glands, and sweat glands. In our population, there is limited information related to the clinicopathological characteristics of these tumors. Management and prognosis depend largely upon the morphological type of the tumor. In this study, we assessed the disease spectrum and most prevalent subtypes of benign SATs. Methodology An analysis of 565 cases was conducted in this cross-sectional study between January 2018 and December 2022, using a non-probability consecutive sampling approach. Patient age, gender, site of involvement, and diagnosis were documented according to the fourth edition of the WHO Classification of Skin Tumors published in 2018. Data were entered and analyzed using SPSS Version 26.0 (IBM Corp., Armonk, NY). Results Our study had 565 patients, out of which 271 (47.9%) were males and 294 (52.1%) were females. The mean age was 40.97±19.3 years (range, 2-100 years). Anatomical site variations were as follows, head and neck (n=336, 59.4%), extremities (n=124, 22%), trunk (n=84, 14.9%), and genital areas (n=21, 3.7%). The most common histological subtypes of benign SATs were sweat gland origin (n=350, 62.0%), followed by hair follicle origin (n=161, 28.5 %), and sebaceous gland origin (n=54, 9.5%). Conclusion Sweat gland tumors were the most prevalent class of benign SATs in our study, in which hidradenoma and poroma were the most frequent subtypes. Hair follicle origin was the second most prevalent class of tumors with pilomatricoma being the most frequent. Sebaceous tumors were overall uncommon; nevus sebaceous of Jadasshon was the most common tumor in this class.

Local environment drives rapid shifts in composition and phylogenetic clustering of seagrass microbiomes

Plant microbiomes depend on environmental conditions, stochasticity, host species, and genotype identity. Eelgrass (Zostera marina) is a unique system for plant–microbe interactions as a marine angiosperm growing in a physiologically-challenging environment with anoxic sediment, periodic exposure to air at low tide, and fluctuations in water clarity and flow. We tested the influence of host origin versus environment on eelgrass microbiome composition by transplanting 768 plants among four sites within Bodega Harbor, CA. Over three months following transplantation, we sampled microbial communities monthly on leaves and roots and sequenced the V4–V5 region of the 16S rRNA gene to assess community composition. The main driver of leaf and root microbiome composition was destination site; more modest effects of host origin site did not last longer than one month. Community phylogenetic analyses suggested that environmental filtering structures these communities, but the strength and nature of this filtering varies among sites and over time and roots and leaves show opposing gradients in clustering along a temperature gradient. We demonstrate that local environmental differences create rapid shifts in associated microbial community composition with potential functional implications for rapid host acclimation under shifting environmental conditions.

C-reactive protein - My perspective on its first half century, 1930-1982.

C-reactive protein (CRP) was discovered in 1930 in the sera of patients during the acute phase of pneumococcal pneumonia and was so named because it bound to the C-polysaccharide of the pneumococcal cell wall. During the next half century many questions raised by this discovery were answered. Phosphorylcholine was found to be the moiety of the C-polysaccharide to which CRP bound. The molecular structure of CRP was elucidated: five identical subunits arranged in cyclic symmetry, giving rise to the term pentraxin. Initially felt to be not normally present in the blood, CRP was found to be a component of normal serum in trace amounts. Its site of origin was determined to be the hepatocyte. It became clear that the presumed humoral mediator responsible for CRP induction was of leukocytic origin. Binding of CRP to its ligand activated the complement system, one of the important effector mechanisms of innate immunity. CRP was found to stimulate phagocytosis of some bacterial species via binding to Fc receptors and was found to be protective in vivo against the pneumococcus in mice. It appeared likely that a related function of CRP was clearance of necrotic tissue. CRP was recognized as being a highly evolutionary conserved molecule. Its discovery during the acute phase of pneumococcal pneumonia led to its being dubbed an acute phase protein. What we today call "the acute phase response", refers to the large number of behavioral, physiologic, biochemical, and nutritional changes that occur during inflammatory states.

Ablation of Focal Intramural Outflow Tract Ventricular Arrhythmias.

Most idiopathic ventricular arrhythmias (VAs) originate from the outflow tract (OT) region and can be targeted with ablation either from the endocardial aspect of the right and left ventricular outflow tracts or from the aortic sinuses of Valsalva. It is important to exclude scar in patients with OT VAs. In some patients, the site of origin may be intramural. Ablation of intramural OT VAs can be challenging to map and ablate due to deep intramural sites of origin. The coronary venous branches may permit mapping and ablation of intramural OT VAs.

ADULT INTUSSUSCEPTION SECONDARY TO GASTROINTESTINAL LIPOMA – A CASE SERIES

Adult intussusceptions are a rare entity, accounting for 1-5% of all intussusceptions. The etiopathology and management varies largely as opposed to pediatric intussusceptions. While, the pathology is most commonly idiopathic in children, there usually is a structural abnormality in adults, which acts as a lead point. Consequently, the management also differs - while it is conservative in children, the management is usually surgical in adults. Moreover, the pathology precipitating intussusception also differs depending on the site of origin. In this case series, we report three cases of gastro intestinal lipomas who presented with intussusception and their management at our institution

Percutaneous Epicardial Ablation of Ventricular Arrhythmias Arising from the Left Ventricular Summit.

The left ventricular summit (LVS) is the highest point of the left ventricular epicardium, and ventricular arrhythmias originating from this area accounts for 10% to 15% of idiopathic outflow tract ventricular arrhythmias. Direct epicardial ablation of outflow tract ventricular arrhythmias arising from the LVS is successful only in a minority of patients because of close proximity to the coronary artery or thick epicardial fat. Therefore, alternative strategies should be prioritized before performing epicardial approach. When performed, electrocardiogram characteristics suggestive of the site of origin to be the accessible area within the LVS needs be evaluated to avoid ineffective epicardial approach.