Site Of Origin Research Articles

Plasticity in plant defense and the role of phytochemical dissimilarity in limiting specialist herbivory

Phytochemical diversity is an effective plant defensive attribute, but much more research has focused on genetic and environmental controls of specific defensive compounds than phytochemical diversity per se. Documenting plasticity in phytochemical richness and plant chemical composition as opposed to individual compounds is important for understanding plant defense. This study outlines a multi-site transplant experiment in Cerrado gallery forests in central Brazil, utilizing Piper arboreum (Piperaceae), a prevalent and widespread neotropical shrub. Clones from four distinct populations were planted either at their origin site or in a different forest. Secondary metabolite composition varied between populations initially and then changed after transplanting. Interestingly, clones with chemical profiles that were distinct from the populations where they were introduced experienced reduced specialist chrysomelid herbivory compared to clones that were more chemically similar to the existing P. arboreum populations where they were planted. Specialist Lepidoptera herbivory also declined in clones transplanted to a new forest, but this change could not be ascribed to chemical profiles. In contrast, generalist herbivory was unaffected by chemical dissimilarity and transplanting. This research adds to the expanding body of evidence suggesting that phytochemical diversity is a dynamic trait exerting unique effects on different herbivore guilds.

Multi-cancer early detection test in symptomatic patients referred for cancer investigation in England and Wales (SYMPLIFY): a large-scale, observational cohort study

Analysis of circulating tumour DNA could stratify cancer risk in symptomatic patients. We aimed to evaluate the performance of a methylation-based multicancer early detection (MCED) diagnostic test in symptomatic patients referred from primary care. We did a multicentre, prospective, observational study at National Health Service (NHS) hospital sites in England and Wales. Participants aged 18 or older referred with non-specific symptoms or symptoms potentially due to gynaecological, lung, or upper or lower gastrointestinal cancers were included and gave a blood sample when they attended for urgent investigation. Participants were excluded if they had a history of or had received treatment for an invasive or haematological malignancy diagnosed within the preceding 3 years, were taking cytotoxic or demethylating agents that might interfere with the test, or had participated in another study of a GRAIL MCED test. Patients were followed until diagnostic resolution or up to 9 months. Cell-free DNA was isolated and the MCED test performed blinded to the clinical outcome. MCED predictions were compared with the diagnosis obtained by standard care to establish the primary outcomes of overall positive and negative predictive value, sensitivity, and specificity. Outcomes were assessed in participants with a valid MCED test result and diagnostic resolution. SYMPLIFY is registered with ISRCTN (ISRCTN10226380) and has completed follow-up at all sites. 6238 participants were recruited between July 7 and Nov 30, 2021, across 44 hospital sites. 387 were excluded due to staff being unable to draw blood, sample errors, participant withdrawal, or identification of ineligibility after enrolment. Of 5851 clinically evaluable participants, 376 had no MCED test result and 14 had no information as to final diagnosis, resulting in 5461 included in the final cohort for analysis with an evaluable MCED test result and diagnostic outcome (368 [6·7%] with a cancer diagnosis and 5093 [93·3%] without a cancer diagnosis). The median age of participants was 61·9 years (IQR 53·4-73·0), 3609 (66·1%) were female and 1852 (33·9%) were male. The MCED test detected a cancer signal in 323 cases, in whom 244 cancer was diagnosed, yielding a positive predictive value of 75·5% (95% CI 70·5-80·1), negative predictive value of 97·6% (97·1-98·0), sensitivity of 66·3% (61·2-71·1), and specificity of 98·4% (98·1-98·8). Sensitivity increased with increasing age and cancer stage, from 24·2% (95% CI 16·0-34·1) in stage I to 95·3% (88·5-98·7) in stage IV. For cases in which a cancer signal was detected among patients with cancer, the MCED test's prediction of the site of origin was accurate in 85·2% (95% CI 79·8-89·3) of cases. Sensitivity 80·4% (95% CI 66·1-90·6) and negative predictive value 99·1% (98·2-99·6) were highest for patients with symptoms mandating investigation for upper gastrointestinal cancer. This first large-scale prospective evaluation of an MCED diagnostic test in a symptomatic population demonstrates the feasibility of using an MCED test to assist clinicians with decisions regarding urgency and route of referral from primary care. Our data provide the basis for a prospective, interventional study in patients presenting to primary care with non-specific signs and symptoms. GRAIL Bio UK.

Prognostic impact of morphology and duration of premature ventricular contractions in a population without structural heart disease.

Premature ventricular contractions (PVCs) are a common form of arrhythmia associated with an unfavorable prognosis in patients with structural heart disease. It is unclear whether PVCs site of origin and QRS-width has a prognostic significance in patients without structural heart disease. The aim of this study was to assess the prognostic importance of PVCs morphology and duration in this patient group. We included 511 consecutive patients without a history of previous heart disease. They were examined with echocardiography and exercise test with normal findings. We categorized the PVCs from a 12 lead ECG according to morphology and width of the QRS-complex and analyzed the outcome in terms of a composite endpoint of total mortality and cardiovascular morbidity. During a median follow-up time of 5.3 years, 19 patients (3.5%) died and 61 (11.3%) met the composite outcome. Patients with PVCs originating from the outflow tracts had a significantly lower risk for the composite outcome compared to patients with non-OT-PVCs. Similarly, patients with PVC originating from the right ventricle had a better outcome than patients with left ventricular PCVs. No difference in outcome depending on QRS-width during PVCs was noticed. In our cohort of consecutively included PVC patients without structural heart disease PVCs from the outflow tracts were associated with a better prognostic outcome than non-OT PVCs; the same was true for right ventricular PVCs when compared to left ventricular ones. The classification of the origin of the PVCs was based on 12-lead ECG morphology. QRS-width during PVC did not seem to have prognostic significance.

Ancient river fishing utensils in the northwest of the Iberian Peninsula: the Miño river basin between the 4th century BC and the 4th century AD

This paper presents a brief overview of fishing in Galicia during Antiquity on the basis of fishing equipment—in particular hooks and weights—recovered from several sites of indigenous origin (castros or hill forts) and newly-established Roman settlements around the basin of the Miño river. Although the topic has often passed unnoticed by archaeological research and suffers from a distinct lack of literature to guide future efforts, the more or less recent publication of papers dealing with this topic in depth has facilitated the study of the Galician record, which is supported by literary and iconographic sources as well as ethnographic documents. The latter have proved relevant in this context, as the world of fishing tends to hold on to traditions. The author sets out to establish a correlation between the remains of fishing implements found and the possible fishing gear they would have been attached to.

A rare case of bilateral pulse granuloma of maxilla

Pulse or hyaline ring granulomas are rare but are well-defined oral and extraoral lesions due to implantation of the cellulose moiety of plant foods in contrast starch components. Implantation could be through extraction sockets, deep periodontal pockets, associated with tumor growth, interdental areas of teeth, unfilled root canals, and grossly decayed teeth. These get rapidly digested and altered by host responses. It is Microscopic oral inflammatory lesion characterized by the presence of giant cells and hyaline rings. The features of pulse granuloma are not considered clinically distinctive and remain primarily microscopic. Extensive knowledge of abnormal sites of origin and clinical manifestations enables clinicians to recognize the diagnostic risks of confusing pulse granuloma with other entities.

Dopaminergic Dysfunction Is More Symmetric in Dementia with Lewy Bodies Compared to Parkinson's Disease.

The α-syn Origin site and Connectome model (SOC) proposes that α-synucleinopathies can be divided into two categories: the asymmetrical brain-first, and more symmetrical body-first Lewy body disease. We have hypothesized that most patients with dementia with Lewy bodies (DLB) belong to the body-first subtype, whereas patients with Parkinson's disease (PD) more often belong to the brain-first subtype. To compare asymmetry of striatal dopaminergic dysfunction in DLB and PD patients using [18F]-FE-PE2I positron emission tomography (PET). We analyzed [18F]-FE-PE2I PET data from 29 DLB patients and 76 PD patients who were identified retrospectively during a 5-year period at Dept. of Neurology, Aarhus University Hospital. Additionally, imaging data from 34 healthy controls was used for age-correction and visual comparison. PD patients showed significantly more asymmetry in specific binding ratios between the most and least affected putamen (p < 0.0001) and caudate (p = 0.003) compared to DLB patients. PD patients also had more severe degeneration in the putamen compared to the caudate in comparison to DLB patients (p < 0.0001) who had a more universal pattern of striatal degeneration. Patients with DLB show significantly more symmetric striatal degeneration on average compared to PD patients. These results support the hypothesis that DLB patients may be more likely to conform to the body-first subtype characterized by a symmetrical spread of pathology, whereas PD patients may be more likely to conform to the brain-first subtype with more lateralized initial propagation of pathology.

On the Evolutionary History of Philometridae (Nematoda: Dracunculoidea): Integrative Taxonomy Reveals Evidence of Character Diversification and Host–Parasite Cophylogenetic Patterns

(1) Background: Integrative taxonomy has been important in the comprehension of relationships among nematode parasites. Philometridae is a highly diverse family of these organisms, but poorly-known regarding genetic characterization and evolution. An integrative taxonomic analysis was performed to improve the knowledge of the evolutionary history of Philometridae. (2) Methods: Phylogenies were reconstructed based on genetic sequences alone and integrated with morphological/life history traits, which were phylogenetically mapped. The host–parasite cophylogeny was evaluated. (3) Results: Previously unpublished 28S rDNA sequences are given for some species. The phylogeny from this marker, although limited by data scarcity, showed similar patterns as that from 18S rDNA. Clades shared common features related to the structure of the esophagus and of the tail in males (especially the gubernaculum), site of infection, habitat, host taxa and geographic origin; most of these features were phylogenetically informative. The integrative phylogeny was better resolved. A cophylogenetic signal was present mainly in clades of freshwater species. (4) Conclusions: The speciation process in Philometridae is not unique or uniform; host capture, host–parasite co-evolution and allopatric (especially in freshwater) events may be occurring simultaneously in different lineages, places and times. Cases of plesiomorphy retention probably occur. Evolutionary convergence of poorly-informative characters is suggested, even though they are important for species diagnosis.

A Case Report on Brachytherapy in Extremity Soft Tissue Sarcoma (STS)

STS represents a heterogenous group of malignancies with varying pathological grades, sites of origin and histologies. In the olden days, treatment consisted of resections and amputation which led to significant detriment in quality of life(QoL) and structural functions . Here we present a case of 49 year old patients who came with complaints of painless, progressive swelling in the right upper arm. He underwent WLE followed by intraoperative brachytherapy catheter application. He was then planned for HDR brachytherapy 34 Gy in 10 fractions 4 days following surgery. He tolerated the treatment well, the surgical scar healed by primary intention with no complication during or after the procedure. It can be concluded that brachytherapy in soft tissue sarcoma is a feasible option and an effective modality in the treatment of extremity soft tissue sarcoma with adequate local control.

Utility of artificial intelligence-based genomic classification of occult malignancies in clinical practice.

3065 Background: Occult primary malignancies (OPM) are a significant clinical problem, representing 3 to 5% of advanced cancers. Patients with OPM have a worse prognosis and fewer treatment options than when the primary site of origin of cancer can be confidently identified. Novel artificial intelligence-based genomic classification of occult malignancies has been validated for clinical use by previous studies, but reports of clinical utility have not yet been published. We report our experience of consecutive cases where a commercial AI-based genomic classifier was used in routine practice at a high-volume community cancer center. Methods: Malignancies with uncertain pathological classification or site of origin were subjected to molecular profiling and AI-based genomic classification (GPSai) capable of recognizing a set of 115 distinct primary tumor sites and histology classes. Molecular profiling consisted of whole exome and whole transcriptome sequencing of FFPE tumor samples along with other predictive biomarkers assays performed by a commercial laboratory (Caris Life Sciences). The identification of targetable mutations was reported, but variants of unknown significance were excluded when reporting genomic alterations. Results: From 1,316 patients between October 2021-November 2022, we analyzed 70 (5.3%) patients with OPM, including 44 (62.9%) females and 26 (37.1%) males, with 34 (48.6%) being 65 or older. GPSai classification was ordered for 73 samples from 70 patients, which resulted in the classification of 33 (45.2%) tumors, inconclusive results in 36 (49.3%), and insufficient tissue quantity in 4 (5.5%). Of the 33 cases with a GPSai classification, the putative pathology diagnosis was concordant in 26 (78.8%) and discordant in 7 (21.2%) cases. We investigated discordance between the GPSai and pathological diagnoses in discordant cases . The pathological classification was favored over GPSai in all 7 discordant cases. Of the 36 cases that could not be confidently assigned a classification, 14 (38.9%) possessed potentially actionable alterations . 23 of the 36 had no presumptive site of origin. Of these, 10 of 23 (43.5%) were PD-L1 positive, 4 of 23 (17.4%) had a high TMB, and 1 of 23 (4.4%) had MMR deficiency. Additionally, based on molecular profile and examination of RNA expression levels, 2 cases were able to be classified with subsequent IHC confirmation. Based on the results from genomic testing, 55.7% of patients (39 of 70) had FDA-approved treatment options. Conclusions: Over a third of patients with OPM were able to be assigned a cancer diagnosis concordant with diagnoses by pathologists. Of those which could not be classified, targetable biomarkers were commonly found. AI-based genomic classification of occult primaries is useful in clinical practice to help discern the site of origin and identify treatment options.

Molecular classification of cancer site of origin and lineage.

3116 Background: Histopathologic assessment has been the primary modality for the diagnosis of human cancers since the 19th century, and to this day remains the mainstay of diagnosis, risk stratification and staging. While the field has made significant advances, the “art of pathology” relies heavily on subjective visual inspection, with significant levels of inter-observer variability and sometimes uncertainty in diagnosis. Advances in next-generation sequencing have ushered in new molecular diagnostic frameworks that can improve accuracy, critical in deciding treatment. Methods: We utilized machine learning (XGBoost) and developed comprehensive molecular classifiers for cancer site of origin (22 classes i.e. breast, prostate, lung, etc.) and cancer lineage (8 classes i.e. adenocarcinoma, squamous cell carcinoma, etc.) to augment traditional histopathologic assessment. These models were trained on a total of 8,249 tumor samples. We then evaluated performance using a large independent validation cohort consisting of 10,376 samples. While 8,886 of these were primary tumors from 97 different datasets, uniquely we also assessed performance in 1,490 metastatic tumors from 17 datasets. Pathologic diagnosis of metastatic tumors can be more difficult due to de-differentiation, but metastatic samples for molecular profiling are difficult to obtain and were only rarely included in previous efforts. Results: After model training, we locked the site of origin and lineage expression-based models and next evaluated performance on our independent validation cohort. Overall accuracy was 92.5% for cancer site of origin and 97.2% for cancer lineage on validation. Accuracy among primary site samples was higher than for metastatic samples (93.4%, and 86.8% for cancer site of origin, respectively; 97.5% and 95.7% for cancer lineage, respectively). However, accuracy jumped to an astounding 98-99% for both site of origin and lineage in both primary and metastatic samples where the signatures were highly confident, encompassing the majority of cases. Our unique approach in evaluating site of origin and lineage separately allowed us to identify a lineage differentiation score that was associated with small cell lung and neuroendocrine prostate tumors (AUC 0.955 and 0.833, respectively), as well as worse survival across most evaluable tumor types. Conclusions: To our knowledge, this is the largest and most comprehensive validation of platform-independent site of origin/lineage classifiers to date. Our approach can be applied to any existing research or commercial RNA-seq assay, and provides an objective and quantifiable confidence measurement that is correlated with accuracy. This allows for nuanced interpretation of high vs. low confidence predictions, which can complement and potentially even help guide traditional histopathologic assessment in cancer research, clinical trial design, and ultimately clinical practice.

Hydraulic safety and growth rather than climate of origin influence survival in desert shrubs and trees

The species-poor woodlands in arid regions are particularly vulnerable to climate change induced plant die-off. Searching for species suitable to replant in these areas is an effective way to prevent further expansion of land desertification. Good knowledge of drought resistance of species is critical for current replanting efforts, however, the related plant survival mechanisms in the process of restoration remain limited. Here, we tested the dominant drivers of plant survival in relation to climate factors, growth characteristics and functional traits including hydraulics and gas exchange across 35 multiple shrub and tree woody species in a common garden at the Tengger Desert, northwest China. We found a wide range of hydraulic thresholds among these desert species, with relatively high hydraulic safety and low xylem hydraulic conductivity. Pant survival was largely determined by hydraulic safety and growth status, but was not affected by the climate of the species’ site of origin. Shrubs and trees diverged in hydraulic and growth characteristics, while no difference between native and introduced species was found. Our results highlight the critical roles of hydraulic safety and growth on determining the survival and drought adaptation during desert vegetation development, which provide a new insight into ecological restoration in arid regions under changing climate conditions.

Trends in ovarian cancer incidence and incidence-based mortality: A 15-year population-based analysis.

5570 Background: The predicted incidence and incidence-based mortality (IBM) of ovarian cancer (OC) in 2023 is lower than prior years. OC encompasses a range of heterogeneous cancers with subtypes categorized on histology and site of origin. Given differences in survival and treatment paradigms, we aim to characterize trends in OC incidence and IBM based on histology and site of origin to determine what factors are responsible for the decline. Methods: Patients with OC from 2000-2019 were identified from the US Surveillance, Epidemiology, and End Results 17 registry database. Using ICD-O-3 codes, patients with epithelial, stromal, and germ cell cancers of the ovary, fallopian tube, and peritoneum were included. Incidence and IBM were reported as age-adjusted rates and stratified by cancer subtype. Using Joinpoint 4.9.1.0, we characterized piecewise log-linear time trends to identify inflection points in the rates’ annual percentage change (APC). Results: The incidence of epithelial OC decreased significantly from 2004-2019 (APC -1.24%). When stratified by disease stage, this trend was seen in distant disease (APC -2.11%) and unknown/unstaged disease (APC -3.40%); however, there was a significant increase in incidence of local disease (APC +0.83%). There was no significant change in the incidence of germ cell and stromal OC from 2004-2019 in all stages. (APC -0.30% and +0.33%). Among all OC subtypes, there was a significant decline in incidence from 2000-2019 (APC -1.57%) with a sharper decline from 2015-2019 (APC -3.41%). Among all cancer subtypes, the incidence trended down from 2000-2019, with a significant decline from 2015-2019 (APC -2.37%). Similar trends are observed in IBM. Among all stages of epithelial OC, there was a significant decrease in IBM from 2006-2019 (APC -2.02%). When stratified by disease stage, there was a decline in IBM in local disease (APC -7.19%, 2014-2019) and distant disease (APC -2.44%, 2010-2019). There were no changes in IBM of germ cell and stromal OC from 2004-2019 (APC +0.78% and -0.20%). Among all cancers, IBM significantly decreased from 2006-2019 (APC -2.28%). When stratified by disease stage, there was no change among local disease and an increase in regional disease from 2006-2019 with the increase from 2006-2010 (APC +14.35%) compared to 2010-2019 (APC +1.45%). Conversely, there was a significant decrease in IBM for distant disease (APC -2.51% from 2010-2019) and unknown/unstaged disease (APC -3.27% from 2006-2019). Conclusions: There has been an overall decline in incidence and IBM of OC over a 15-year period, primarily driven by the epithelial histology. Over the past 20 years, OC has been increasingly diagnosed at earlier stages with a corresponding improvement in survival. While stage migration and improved survival may contribute to these trends, they do not entirely explain them. As new treatments become available, the incidence and IBM of OC may further decline.

Clinical trial enrollment in a Hispanic-majority NCI-designated cancer center: The Mays Cancer Center experience over 10 years.

e18551 Background: There is a perpetual lack of representation in clinical trial enrollment among minorities. In 2013, the former Cancer Therapy and Research Center (CTRC) at the University of Texas Health Science Center at San Antonio implemented the Minority Accrual Plan (MAP) to address the challenge of deliberately enrolling minority subjects in clinical trials (CT). The objective of the present study was to describe the racial and ethnic minority representation in CT conducted, at the now Mays Cancer Center (MCC), from years 2012-2021. The MCC is an NCI designated cancer center, that serves a Hispanic (HI) enriched catchment area of 5.1 million people of South Texas. Methods: This is a descriptive analysis of patients enrolled in CT at the MCC from years (y) 2012 to 2021. Patients were enrolled in either interventional treatment (IT), interventional non-treatment (INT), or non-interventional/observational (NI) CT. Variables analyzed included ethnicity, payment class, disease site, and county of origin. Results: We identified a total of 14661 patients with various tumor types who were enrolled in CT at the MCC. A total of 7019 patients (48%) were HI, 6590 patients (45%) were Non-Hispanics (NH), and 1062 (7%) patients did not report ethnicity data. The majority of patients were enrolled on NI (67%), followed by INT (18%) and IT (15%) CT. Overall, the highest enrolled disease sites were genitourinary (40%), breast (11%) and pediatric (7%) cancers. Most patients were self-pay (27%) or had Medicare (27%), whereas 19% of patients had commercial insurance and 7% had CareLink. Enrollment of HI has fluctuated over the years; 4333 HI patients were enrolled from 2012-2016, this decreased to 2686 in the following 2017-2021 period. Overall, 26% of patients were from rural locations, while 74% were from urban locations. The number of rural CT participants was greater in Val Verde (298), Kerr (272), Uvalde (163), and Frio (103) counties. Conclusions: HI continue to be disproportionately enrolled in CT. In 2012, and prior to the implementation of the MAP, 45% of the patients enrolled in clinical trials were HI. In the past 10 years, over 7000 HI patients have participated in CT, even though there have been some fluctuations in accruals rates over the past years, such as in the 2017-2021 period where the COVID-19 pandemic affected enrollment rates. This study validates the notion that better, and perhaps different approaches are needed to improve minority enrollment in CT. Finally, we conclude that the uniqueness of our geographic location did not positively impact HI enrollments. [Table: see text]

Clinicopathological features and treatment patterns of patients with cancer of unknown primary site (CUP): Mayo Clinic experience.

e18803 Background: CUPs are a heterogeneous group of metastatic cancers for which a standardized diagnostic work-up fails to identify the site of origin at the time of diagnosis. CUP accounts for 3%-5% of all cancer diagnoses worldwide, and the natural history of patient with CUP differs from that of patients (pts) with cancer with known primary tumor. Here we report and summarize the clinical features of patients with CUP treated at Mayo Clinic. Methods: Retrospective study of patients treated at Mayo Clinic Rochester MN from 2010 to 2021. Patient demographics, tumor-related variables, treatment-related variables, and clinical data were extracted. Descriptive statistics were used, and all data were analyzed by the SPSS version 22.0 software (SPSS, Chicago, IL, United States). Results: From a total of 214 pts, 207 pts were included, as primary tumor site was identified in 7 patients after initial evaluation. The pts in this study were predominantly white (87%) of female (50.2%) gender with a mean age of 63 (SD: 13) without history of smoking (51%) and either private or public insurance (82.6%). The predominant histology was adenocarcinoma (30%), followed by neuroendocrine neoplasms (27%), and carcinoma NOS (not otherwise specified) (25%). The most prevalent grade in this cohort was grade III with poorly differentiated tumor cells. All pts had diagnostic imaging and the most used imaging modalities included CT (81.2%), and PET-CT (43.5%). In our cohort, the 3 most common sites of metastases included lymph nodes (57.5%), liver (37.8%), lung (34.3%), and bone (23.7%); and in 64% of pts, there was a specific presentation pattern including liver-predominant (24.6%), lymph node-predominant (24.6%), bone-predominant (7.7%), and peritoneal carcinomatosis (7.7%). The majority of pts received systemic therapy (69%) as first line of therapy and the most frequent first line regimens included platinum-doublet (26.5%), gemcitabine-based regimen (20.7%), 5FU-based regimens (18%) and somatostatin analogs (16.7%); whereas salvage radiation and ablation were offered to 11% of pts and surgery to 17%. The median follow-up time was 22 months (IQR: 45) with a median survival time of 23 months and the 3-year cumulative survival rate was 30%. Conclusions: The heterogenous nature of CUPs and lack of specific immunohistochemical signature prevents primary tissue of origin diagnoses in CUP pts. Without the identification of a primary origin site, treatment is restricted to generic chemotherapy with limited benefit as demonstrated in this cohort.

Prognostic value of total tumor volume with 68Ga DOTATOC PET/CT in predicting response to 177-Lu-DOTATOC treatment in metastatic well-differentiated neuroendocrine tumors (NETs).

e16248 Background: PET/CT with somatostatin analogues (68 Ga DOTATOC) is essential for decision-making prior to treatment with [177Lu–Dota0–Tyr3]–Octreotate (177Lu-DOTATOC), there are biological characteristics in this type of neoplasms that allow predicting the response to therapy, the tumor burden is one of the most important variables, however its estimation with conventional imaging tools is limited, currently there are reconstruction algorithms based on artificial intelligence that allow estimating the tumor burden using molecular imaging studies with 68 Ga DOTATOC, aim of this work is to determine the value of the total tumor load with this radiotracer as a predictor of overall survival in patients treated with 177Lu DOTATOC. Methods: 45 patients (11 men and 34 women) with an average age of 57.2 (range 47.2 to 66.5) with histopathological and immunohistochemical diagnosis of well-differentiated neuroendocrine tumors (NETs) in the period from 2015 to 2021 who received therapy with (177Lu-DOTATOC) and who had a baseline 68Ga DOTATOC PET to calculate total tumor volume (TVV) and semiquantitative uptake values were retrospectively included. Results: The mean follow-up was 29.3 +/- 6 months. Using ROC curves, a cut-off point of 100 cm3 was determined to differentiate responding and non-responding patients. The difference in the overall survival curves between both groups was statistically significant (470 days vs. 180 days) with p=0.07. The main sites of origin of the primary tumor were pancreas (n=24), lung (n=11), small intestine (n=7) and liver (n=3). The mean tumor volume was 305.8 cm3 (+/- 272). The organs with the highest uptake values were pancreas with SUVmax of 27.9 (range 10.1-42.4), rectum with SUVmax 26.5 (10.7-42.3) and liver with SUVmax of 22.1 (14.4-31.7), these uptake values did not have any type of relation to patient survival. Regarding therapy with 177 Lu DOTATOC, 8 received 14.8 Gbq (400mCi), 12; 22.2 GBq (600mCi) and 25; 29.6 GBq (800 mCi), no serious adverse effect or kidney function impairment was demonstrated after 177Lu DOTATOC therapy. No grade 3 or 4 haematological toxicity was identified. Conclusions: PET/CT with 68 Ga-DOTATOC is routinely used in the management of patients with neuroendocrine tumors and also allows categorizing patients according to their tumor volume to predict overall survival in patients treated with 177 Lu-DOTATOC, thus in such a way that it could be considered as an easily accessible and widely available prognostic imaging biomarker.

Molecular tumor profiling and therapy selection in advanced gynecological cancers: A retrospective cohort analysis from the Australian Molecular Screening and Therapeutics (MoST) Program.

5526 Background: Gynecological (gyne) cancers are highly diverse with distinct sites of origin and histological subtypes that can limit development of evidence-based therapies. Comprehensive genomic profiling (CGP) has an increasing role in characterizing clinically relevant molecular subsets and in identifying actionable biomarkers with potential to guide therapy selection. Methods: MoST (ACTRN12616000908437) is an Australia-wide precision oncology program for adult patients (pts) with advanced cancers and limited treatment options. Tumor specimens are analysed by CGP and genomic results tiered by the level of evidence supporting matched therapies (https://topograph.info). Pts are followed for subsequent treatment and survival. Here, we present data for the MoST gyne cancer cohort. Results: Between Sept 2016 and Oct 2022, 533 gyne tumors were sequenced, with included pts having a minimum 4 months (mo) follow-up. Key histotypes included: ovarian serous (n=162) and non-serous (n=46) epithelial tumors; uterine carcinomas (n=99) and sarcomas (n=108); cervical carcinomas (n=51); germ cell and sex-cord stromal tumors (n=18); carcinosarcomas (n=33); and vulva/vaginal tumors (n=16). The median number of reported variants was 3 (IQR 2-5) and tumor mutational burden 3.1 mut/Mb (IQR 1.3—5.5, Range 0—284); 9 (2%) tumors were microsatellite unstable; and 22 (4%) had high level loss-of-heterozygosity (confirmed on validated genome-wide assays). The most common pathways involved in this pan-gyne cohort were: p53 (n=287, 54%), PI3K/AKT (n=227, 43%), cell cycle (n=182, 34%), and mitogen-activated protein kinase (n=91, 17%). Pathogenic mutations in BRCA1/2 were identified in 29 tumors (5%; 18 in ovarian serous cancers), whereas 81 tumors (15%) had alterations in other homologous recombination genes, most commonly uterine sarcomas (n=32, 30%). Actionable genomic biomarkers matched to a clinically active treatment (TOPOGRAPH tier 1-3) were identified in 207 (39%) tumors. In 19 pts (3.5%) who received Tier 1-3 matched therapy after CGP, a trend towards longer survival was observed (median OS 22.3 mo, 95% CI 17.3 to not reached) compared to those receiving unmatched therapy (n=65, median OS 14.9 mo, 10.2 to 22.1, p=0.052) following CGP. No OS difference was seen in pts who received matched investigational therapy (Tier 3B/4, n=31, median OS 17.0 mo, 8.1 to NR) versus only unmatched therapy (n=118, median OS 14.0 mo, 11.3 to 22.5; HR 0.97, 0.57 to 1.64; p=0.91). Conclusions: CGP identified actionable genomic results in nearly half of advanced gyne cancers, with enrichment in particular histotypes that supports testing above current standard of care. Trends in prolonged OS with subsequent matched therapies may be better realized with earlier testing and improved drug/clinical trial access.

Bladder Postoperative Spindle Cell Nodule: Malignant Mimicry in the Postoperative Setting

Bladder Postoperative Spindle Cell Nodule: Malignant Mimicry in the Postoperative Setting

Genomic landscape of cancer of unknown primary site (CUP): Mayo Clinic experience.

e18807 Background: CUP represents both a diagnostic and a management challenge. Despite improvements through sophisticated imaging modalities, specific and sensitive testing using immunohistochemistry, a concrete determination of the site of origin of the primary tumor can still be a diagnostic challenge Hereby, we described the genomic landscape of patients with CUP treated at our institution. Methods: Retrospective study of patients with CUP treated at Mayo Clinic Rochester MN from 2010 to 2021. Next generation sequencing (NGS) information was abstracted, and alterations were ranked into different levels of actionability following the Onco KB framework. All data were analyzed by the SPSS version 22.0 software (SPSS, Chicago, IL, United States). Results: From a total of 214 patients, we identified 67 (32%) patients in whom NGS was performed. Among patients with available NGS the median age was 64 years (range: 35-86) and 51% were female. the most prevalent histology included adenocarcinoma (39%), carcinoma NOS (31%), and neuroendocrine tumors (12%). NGS on tumor (t-NGS) was available in 56 (84 %) patients, circulating tumor NGS (b-NGS) was available in 12 (18%) patients, and only 1 patient had both testing available. Among the 56 patients with available t-NGS, MSI-high was detected in 9 patients, whereas among the 12 patients with available b-NGS, MSI-high was detected in 8 patients; yielding an MSI-high detection rate of 16% and 67% for t-NGS and b-NGS. In this cohort, there were a total of 474 genomic alterations detected from which 103 (22 %) were able to be ranked into one therapeutic level following the OncoKB framework. Genomic alterations were most observed among patients with carcinoma (n = 50, 48.53%) adenocarcinoma (n = 33, 32.03 %), squamous cell carcinoma (n = 3, 2.91 %) and neuroendocrine tumor (n = 2, 1.94%). Following the OncoKB framework, 39-level 1 genomic alterations were detected in a total of 14 genes. The most common level 1 genomic alterations comprised the BRCA2 (20.51%), NF1 ATM (17.95%) and HER2/NEU (ERBB2) (15.38%) genes. Therapeutic level 2 included 51 genomic alterations in 13 genes of which KRAS (17.65%), BRAF (15.69%), and BRCA2 (15.69%) were the most prevalent mutated genes. Additionally, level R comprised 13 genomic alterations in the following genes: KRAS (69.23) NRAS (23.08%) and PDGFRA (7.69%). Conclusions: CUP are malignancies rich in potentially actionable alterations, and NGS of tissue and blood samples can inform systemic therapy decisions. Alteration-specific targeted therapy may be an option for a substantial proportion of patients. NGS of tumor tissue or blood should be considered for all patients with CUP.

Associations between memory strategies performance and CSF biomarkers: A new approach for the early intervention in MCI

AbstractBackgroundDiagnostic research criteria for Alzheimer’s Disease (AD) recommend the cerebrospinal fluid (CSF) as a sensible and validated biomarker to improve the accuracy of the prognosis regarding progression to dementia for people with mild cognitive impairment (MCI). Also, it has been established that episodic memory failure is a proxy for AD, while executive functions impairment could be leading to other types of dementia. One of the tests designed to simultaneously evaluate these cognitive functions with high sensitivity and specificity to discriminate between neurocognitive disorders is the Test of Memory Strategies (TMS). The main goals of the present study were 1) to assess the correlations between TMS and CSF markers (i.e., Aβ42, t‐tau, and p‐tau) in a sample of MCI patients, and 2) to provide additional validation for TMS as a clinical tool for Alzheimer’s Disease (AD) early detection.Method135 participants were recruited from a multicenter international study in Poland and Spain, but only 47 were selected (Mean age: 68.58 ± 10.03). The sample was split according to the Erlangen Score Diagnostic Algorithm (ESA) into: CSF ‐ (n = 11) and CSF + (n = 36). Correlations analyses between the five TMS word‐list conditions and CSF biomarkers were conducted, and analysis of covariance (ANCOVA) was performed to define the effect on ESA classification in the sample, using the site of origin of the participants as covariable.ResultsSignificant associations between the TMS‐3 condition and Aβ42, t‐tau, and p‐tau were observed for the whole sample. Also, the CSF‐ obtained a higher cognitive performance in the TMS‐3 than the possible AD group (CSF+).ConclusionsOur results revealed that combining CSF biomarker measures and TMS scores could contribute to a better characterization and a more precise approach to AD. Furthermore, considering that the TMS‐3 condition is mostly associated with executive functions, future interventions should focus on this cognitive construct and how it could affect the patient’s ability to encode and organize the information in memory.

Assessment of halophyte plant phenotypic responses under heavy metals pollution. Implications for monitoring and phytoremediation

While phytoremediation is a highly valued practice to address local pollution problems, the use of early biomarkers of stress is useful for monitoring environments since they allow us to take measures before deleterious effects are irreversible. In this framework the goals are: to evaluate the pattern of leaf shape variation of Limonium brasiliense plants related to a metal soil gradient in the San Antonio salt marsh; to assess whether seeds from sites with different pollution levels show the same pattern of leaf shape variations under optimal growing conditions; and to compare the growth, the Pb accumulation pattern, and the leaf shape variation pattern of plants germinated from seeds originated in sites with different pollution levels in response to an experimental Pb rise. The results obtained from leaves collected in the field showed that the leaf shape changed depending on the soil metal levels. Plants germinated from seeds collected at the different sites expressed all the variation in leaf shape independently of the origin site, and the mean shape of each site was close to the consensus. Instead, when looking for the leaf shape components that maximize the differences between the sites from a growth experiment exposed to an increase in Pb in the irrigation solution, the pattern of variation found in the field disappeared. That is, only plants from the polluted site did not show variations in leaf shape in response to Pb additions. Finally, Pb accumulation in the roots was highest in plants germinated from seeds from the site where the soil pollution is greater. That suggests that seeds of L. brasiliense from polluted sites are better to use in phytoremediation practices, specifically to stabilize Pb in its roots whilst plants from the non-polluted site are better to detect pollutant soils using the leaf shape as an early biomarker.