tbuckley/cabot-search huggingface dataset:
Micropapillary urothelial carcinoma (mpUC): A comparative analysis of oncologic outcomes compared to conventional urothelial carcinoma (CUC).
Authors: Leonidas Nikolaos Diamantopoulos, Ali Raza Khaki, Adam John Gadzinski, Brian Winters, Funda Vakar-Lopez, Maria S. Tretiakova, John L. Gore, George R. Schade, Sarah P. Psutka, Andrew Caleb Hsieh, John Kyung Lee, Todd Yezefski, Michael Thomas Schweizer, Heather H. Cheng, Evan Y. Yu, Daniel W. Lin, Robert B. Montgomery, Petros Grivas, Jonathan L. Wright
Journal: Journal of Clinical Oncology (2020)

459 Background: MpUC is a rare variant associated with adverse outcomes. We describe our institutional experience and compare clinicopathologic features and survival between patients with mpUC and CUC. Methods: Patients with mpUC or CUC at radical cystectomy (RC) or transurethral resection of bladder tumor were identified from a retrospective institutional RC database. Clinicopathologic/treatment data were extracted and compared using T-test and χ 2 test. Recurrence free survival (RFS) and overall survival (OS) from RC to first recurrence or death were estimated using the KM method. Factors identified as significant in univariable (UVA) Cox regression analysis for OS were included in multivariable analysis (MVA). Results: 64 consecutive patients with mpUC and 457 with CUC were identified (2003 - 2018); 36 (56%) and 188 (41%) received neoadjuvant chemotherapy (NAC). MpUC had higher incidence of pT3/4 (41% vs. 28%) or pN+ disease (39% vs. 17%), carcinoma in-situ (52% vs. 24%) and lymphovascular invasion (LVI, 39% vs. 16%) at RC, compared to CUC (all p &lt; 0.05). Rates of ypT0N0 after NAC were comparable between groups (25% vs. 35%, p = 0.26). Median follow-up was 62 months (95% CI 55.4 – 68.3). 5-year RFS was 24% (mpUC) vs. 58% (CUC), p = 0.001. 5-year OS was 40% (mpUC) vs. 69% (CUC), p = 0.001. MpUC histology was not independently associated with OS after adjusting for pT stage, node ratio (# nodes +/ # nodes removed) and ECOG status (Table). Conclusions: Patients with mpUC presented with advanced stage at RC, while they showed inferior RFS and OS, when compared to CUC. However, rates of pathologic response to NAC were comparable to CUC and mpUC was not associated with OS in MVA. Further studies are needed to define the optimal management of this variant. [Table: see text]
Acute hepatitis C infection among adults with HIV in the Netherlands between 2003 and 2016: a capture–recapture analysis for the 2013 to 2016 period
Authors: T. Sonia Boender, Eline Op de Coul, Joop Arends, Maria Prins, Marc van der Valk, Jan T.M. van der Meer, Birgit van Benthem, Peter Reiss, Colette Smit
Journal: Eurosurveillance (2020)

Background With regards to the global strategy towards eliminating viral hepatitis, reliable surveillance systems are essential to assess the national response for eliminating hepatitis C virus (HCV). Aim We aimed to assess the completeness of the two national registries with data on acute HCV infection in people with HIV, and estimated the number of acute HCV infections among adults (aged ≥ 18 years) with HIV in the Netherlands. Methods In this observational study, cases of HCV infection and reinfection among adults with a positive or unknown HIV-serostatus were identified from 2003 to 2016 in two national registries: the ATHENA cohort and the National Registry for Notifiable Diseases. For 2013–2016, cases were linked, and two-way capture–recapture analysis was carried out. Results During 2013–2016, there were an estimated 282 (95% confidence interval (CI): 264–301) acute HCV infections among adults with HIV. The addition of cases with an unknown HIV-serostatus increased the matches (from n = 107 to n = 129), and subsequently increased the estimated total: 330 (95%CI: 309–351). Under-reporting was estimated at 14–20%. Conclusion Under-reporting of acute HCV infection among people with HIV could partially be explained by an unknown HIV-serostatus, or by differences in HCV stage (acute or chronic) at first diagnosis. Surveillance data should ideally include both acute and chronic HCV infections, and enable to distinguish these as well as initial- and re-infections. National surveillance of acute HCV can be improved by increased notification of infections.
Offline: Facts are not enough
Authors: Richard Horton
Journal: The Lancet (2020)

We are in the midst of a struggle. A struggle for the soul of global health. On one side, the intelligent idealists. Those who sincerely believe that by describing the world in ever more refined and precise ways we will advance closer to an elusive truth. A truth that will unlock the extraordinary potential that is global health. The Global Burden of Disease is the divine apotheosis of intelligent idealists. And universal health coverage their Garden of Eden. On the other side of this struggle, the innocent cynics.
Mental Health Service Use and Psychopharmacological Treatment Following Psychotic Experiences in Preadolescence
Authors: Martin Køster Rimvall, Jim van Os, Frank Verhulst, Rasmus Trap Wolf, Janne Tidselbak Larsen, Lars Clemmensen, Anne Mette Skovgaard, Charlotte Ulrikka Rask, Pia Jeppesen
Journal: American Journal of Psychiatry (2020)

Objective: Psychotic experiences affect more than 10% of children and often co-occur with nonpsychotic mental disorders. However, longitudinal studies of the outcome of psychotic experiences based on unbiased information on mental health service use and psychotropic medications are scarce. The authors investigated whether psychotic experiences at ages 11–12 predicted a psychiatric diagnosis or treatment with psychotropic medications by ages 16–17. Methods: In a longitudinal register-based follow-up study of the Copenhagen Child Cohort 2000, a total of 1,632 children ages 11–12 were assessed for psychotic experiences in face-to-face interviews. The children were also assessed for mental disorders and IQ. National registries provided information on perinatal and sociodemographic characteristics, on psychiatric disorders diagnosed at child and adolescent mental health services, and on prescribed psychotropic medications through ages 16–17. Results: Among children who had not been previously diagnosed, and after adjustment for sociodemographic and perinatal adversities and IQ, psychotic experiences at ages 11–12 predicted receiving a psychiatric diagnosis in child and adolescent mental health services before ages 16–17 (adjusted hazard ratio=3.13, 95% CI=1.93, 5.07). The risk was increased if the child met criteria for a co-occurring mental disorder (not diagnosed in mental health settings) at baseline compared with no psychotic experiences or diagnosis at baseline (adjusted hazard ratio=7.85, 95% CI=3.94, 15.63), but having psychotic experiences alone still marked a significantly increased risk of later psychiatric diagnoses (adjusted hazard ratio=2.76, 95% CI=1.48, 5.13). Similar patterns were found for treatment with psychotropic medications. Conclusions: Psychotic experiences in childhood predict mental health service use and use of psychotropic medications during adolescence. The study findings provide strong evidence that psychotic experiences in preadolescence index a transdiagnostic vulnerability for diagnosed psychopathology in adolescence.
Does pathologic upstaging to PT3A portend a worsened prognosis when compared to non-upstaged PT3A renal cell carcinoma: Analysis of the National Cancer Database.
Authors: Devin Patel, Fady Ghali, Margaret Meagher, Aaron Bradshaw, Sunil Patel, Cathrine Keiner, Nathan Miller, Raksha Dutt, James Don Murphy, Ithaar Derweesh
Journal: Journal of Clinical Oncology (2020)

624 Background: Pathological T3a (pT3a) renal cell carcinoma (RCC) is often diagnosed at the time of final pathological analysis, though impact of lack pre-treatment detection on surgical outcomes is unclear. We sought to compare outcomes of pathologically upstaged pT3a RCC with pT3a RCC recognized clinically. Methods: We queried the National Cancer Database for incident cases of pT3a pN0/x pM0/x renal cell carcinoma (RCC) treated with radical (RN) or partial nephrectomy (PN) between 2009-2015. Tumors were staged using the AJCC staging system, 7th edition. Pathologically upstaged tumors were defined as those that had a clinical stage of T1 or T2. Non-upstaged tumors had a clinical stage of T3a. Multivariable Cox proportional hazards and Kaplan-Meier survival analysis were performed to study the impact of clinical to pathological upstaging in pT3a tumors on overall survival (OS) in patients treated with RN and PN. Results: A total of 19,538 pT3a tumors were identified of which 7,231 (37%) had concordant clinical stage (non-upstaged) and 12,307 (63%) had lower clinical stage (upstaged). Patients with upstaged tumors had longer time from diagnosis to surgery (31.5 vs. 23.8 days; p&lt;0.001), smaller tumor size (6.7 vs. 7.4 cm; p&lt;0.001), higher rates of treatment with partial nephrectomy (18% vs. 11%; p&lt;0.001), and higher rates of negative margins (92% vs. 89%; p&lt;0.001). On multivariate analysis, age (HR 1.06; p&lt;0.001), Charlson Comorbidity Index (HR 1.51; p=0.006) and positive margin status (HR 1.55; p&lt;0.001) were associated with worse OS. Pathological upstaging was an independent predictor of improved OS following both PN (HR 0.74; 95% CI 0.59-0.91; p=0.006) and RN (HR 0.87; 95% CI 0.82-0.93; p&lt;0.001). Kaplan-Meier analysis showed higher OS for tumors that were upstaged following both PN (5-year OS 73 vs. 70%; p=0.0083) and RN (5-year OS 67 vs. 64%; p&lt;0.001). Conclusions: Most pT3a RCC are pathologically upstaged. Pathological pT3a tumors that were correctly detected clinically were associated with worsened outcomes. While our findings require further confirmation, they call for consideration and refinement of risk stratification protocols in pT3a RCC.
Testosterone recovery as biomarker for overall and cause-specific survival in combined treated patients with high-risk and locally advanced prostate cancer.
Authors: Mathew Deek, Victoria Vaage, Knut H. Hole, Theodore L. DeWeese, Andreas Stensvold, Therese Seierstad, Phuoc T. Tran, Wolfgang Lilleby
Journal: Journal of Clinical Oncology (2020)

188 Background: Androgen deprivation therapy (ADT) can cause considerable toxicity and may influence outcome. The study assessed the impact of testosterone recovery (TR) on survival after ADT and definitive radiotherapy in two independent cohorts. Methods: Two hundred and forty-four patients (high risk JHH cohort N=106, T1c-T3N0M0 [A], locally advanced OUH cohort N=138, T1c-T4N0-1M0 [B]) with adenocarcinoma of the prostate were included in this retrospective analysis. Short and long-term ADT was given (median 12 months A, 24 months B, respectively,) and along with conformal external beam radiation 76-80 Gy given to the prostate in cohort A, 74 Gy prescribed in cohort B and 46-50 Gy to the whole pelvis. Testosterone levels were measured at the end of ADT and at biochemical relapse. TR was defined as ≥ 9 nmol/L. Kaplan Meier plots were generated for overall survival (OS) and cause-specific survival (CSS) stratified by TR, in addition to patient characteristics median time to TR and FU were calculated. Results: The median age in the A cohort was 66.7 years and 64.7 years in the B group. FU was 6 years for A and 8 years in B. Patients in group A received median ADT of 12 months and 24 months in group B. The median time to TR was 1.6 yr in A and 2.5 yrs in B, respectively. Patients in group A stratified to TR showed no difference in overall survival (p=0.92)), on contrary, patients in group B showed improved overall survival depending on TR (Fig. 1, KM plot, 10 year OS 75.3% vs 59.9% p=0.034). CSS was seemed to trend towards improvement with TR for cohort A (p=0.19) and was improved in cohort B (p=0.022). The Univariate ADT length, age, and RT dose was associated with time to TR, but on multivariate analysis only longer ADT time (p = 0.03) was significantly associated with time to TR. Conclusions: TR was associated with improved OS in patients with unfavorable locally advanced disease a finding not seen in patients with high-risk disease.
Enzymes C1r and C1s may show progression of a type of skin cancer called keratinocyte‐derived cutaneous squamous cell carcinoma
Authors: P. Riihilä, K. Viiklepp, L. Nissinen, M. Farshchian, M. Kallajoki, A. Kivisaari, S. Meri, J. Peltonen, S. Peltonen, V.‐M. Kähäri
Journal: British Journal of Dermatology (2020)

The incidence of skin cancers is increasing worldwide. The epidermis is the surface layer of the skin and the main cell type is the keratinocyte. Keratinocyte-derived cutaneous squamous cell carcinoma (cSCC) is the most common metastatic (meaning it can spread) skin cancer and it is responsible for 20% of skin cancer related deaths. The main risk factor for cSCC includes long term exposure to sun ultraviolet radiation. The progression of cSCC is as follows: it starts in a premalignant form (not yet cancerous) called actinic keratosis (AK), then becomes locally restricted cSCC, then cSCC in situ (cSCCIS), and eventually becomes invasive and metastatic cSCC. This research, from Finland, aimed to find biomarkers (chemicals in the body which act as signs of a disease) which could predict the progression and aggressiveness of cSCC. The authors found significantly elevated levels of mRNA (messenger molecules) for enzymes called C1r and C1s (which play a role in our immune system), in cSCC cells and tumors compared to normal epidermal keratinocytes and normal skin, respectively. Abundant expression of C1r and C1s by tumor cells was detected in invasive cSCCs and in an aggressive form of cSCC (recessive dystrophic epidermolysis bullosa-associated cSCC), whereas the expression of C1r and C1s was lower in cSCCIS, actinic keratosis, and normal skin tissue samples. The roles of C1r and C1s in cSCC cells were investigated by knocking down (reducing) the expression of C1r and C1s, and through complex methods, this was shown to potentially suppress growth of cSCC tumours. These results provide evidence that tumor cell-derived C1r and C1s play a part in the progression of cSCC and identify them as biomarkers and possible treatment targets in cSCC. This is a summary of the study: Tumour-cell-derived complement components C1r and C1s promote growth of cutaneous squamous cell carcinoma
Co-ordinate epigenetic silencing of a cluster of 3p22 genes flanking MLH1 in sporadic microsatellite unstable colorectal cancer.
Authors: Megan Hitchins, Vita Ap Lin, Andrew Buckle, Kayfong Cheong, Nimita Halani, Chau-To Kwok, Deborah Packham, Catherine Suter, Alan Meagher, Susan Clark, Nicholas Hawkins, Robyn Ward
Journal: Cancer Research (2007)

LB-207  Somatically acquired biallelic methylation of the MLH1 promoter and accompanying transcriptional silencing occurs in most sporadic colorectal cancers exhibiting microsatellite instability due to failed DNA mismatch repair function. Long-range epigenetic silencing of contiguous genes has recently been found on chromosome 2q14 in colorectal cancer. We hypothesized that epigenetic silencing of MLH1 could occur on a regional scale affecting additional genes within 3p22, rather than as a focal event. We found concordant CpG island hypermethylation and transcriptional inactivation of MLH1 with a specific cluster of flanking genes spanning >1Mb in primary microsatellite unstable colorectal cancers, which included additional tumour suppressor genes. This hypermethylated region was interspersed with genes that escaped methylation, but were nevertheless also transcriptionally repressed. Epigenetic silencing of the >1Mb cluster was observed in a proportion of adenomas, suggesting this event occurs early in the neoplastic process. The microsatellite unstable RKO cell line also demonstrated this regional pattern of hypermethylation and gene silencing. However, treatment of RKO cells with methyltransferase and histone deacetylase inhibitors reactivated genes within the affected region, further demonstrating that epigenetic suppression encompassing MLH1 occurs on a regional scale within 3p22. Two genes adjacent to the cluster that are not usually expressed in the colonic tissues were methylated in both microsatellite stable and unstable cancers, adenomas, and at low levels in normal colonic mucosa from older individuals, suggesting this may be related to patterns of tissue expression. Our findings indicate that epigenetic inactivation of MLH1 occurs by a mechanism of long-range epigenetic silencing in the majority of sporadic colorectal tumours that exhibit microsatellite instability. Concordant epigenetic silencing of a cluster of 3p22 genes including MLH1 and additional tumour suppressors may contribute to the initiation of colorectal carcinogenesis, or drive its progression.
Impact of MRI on outcomes in active surveillance (AS) for localized prostate cancer in a hospital registry.
Authors: Praful Ravi, Neil E. Martin, Quoc-Dien Trinh, Grace Shaw, Mark Pomerantz, Mark A. Preston, Manuel Pedregal, Mary-Ellen Taplin, Adam S. Kibel, Christopher Sweeney
Journal: Journal of Clinical Oncology (2020)

280 Background: MRI is increasingly used in follow-up of men undergoing AS for localized prostate cancer. Large cohorts predating the MRI era have shown that the risk of disease progression or stopping an AS protocol is ~20-30% at 5 years, but the impact of MRI on outcomes in AS is unclear. Methods: We studied men who initiated AS at Dana-Farber Cancer Institute between 2001-2017 for Gleason 6 prostate cancer diagnosed on transrectal ultrasound-guided biopsy, and who underwent a prostate MRI as part of their AS protocol. Progression on AS was defined as finding Gleason ≥7 cancer on repeat biopsy or at radical prostatectomy. Early MRI was defined as one performed within 1 year of diagnosis. Results: A total of 148 men were identified from a prospective IRB-approved database. Median PSA at diagnosis was 4.8 (range 0.7-14.3), median number of positive biopsy cores was 1 (1-7), median maximal core involvement by cancer was 10% (1-65), and most men (87%) had T1c disease. Overall, 54 (36%) progressed on AS over a median follow-up of 5.6 years (95% CI 5.1-6.0), with the majority (n=44, 81%) progressing at repeat biopsy; the 5-year progression rate was 32% (25-41). There were no major differences in baseline clinicopathologic characteristics between men undergoing early (n=103, 70%) or delayed (n=45, 30%) MRI, but men who had an early MRI underwent fewer subsequent biopsies (median 2 vs. 3, p=0.010) and more targeted biopsies (47% vs. 36, p=0.212). Men who underwent early MRI had a higher rate of progression compared to those who had a delayed MRI (5-year rate 43% [33-55] vs. 12% [5-26], log-rank p=0.001). However, when immortal time bias was accounted for by considering MRI receipt as a time-dependent covariate, early MRI was not associated with progression (HR=0.74 [0.50-1.09], p=0.129). Conclusions: The 5-year progression rate on AS was ~30% in the MRI era, a rate similar to that reported in series that predate the adoption of MRI. A higher rate of progression was seen in men undergoing MRI within 1 year of diagnosis, but MRI timing did not influence risk of progression when accounting for the time interval before an MRI was performed. Longer follow-up is needed to determine the impact of MRI on cancer-specific survival in men undergoing AS.
Allergenicity and Safety Profile of Depigmented-Polymerized Phleum pratense Extract for Use in Allergen-Specific Immunotherapy Treatments
Authors: Janice Layhadi, Raquel Moya Lobo, Rebecca Parkin, Madison Lenormand, Gemma Vila, Jeronimo Carnes, Mohamed Shamji
Journal: Journal of Allergy and Clinical Immunology (2020)
Efficacy of Lanadelumab in Hereditary Angioedema Patients With and Without Prior Long-Term Prophylaxis Use: Interim Results From the HELP Open-Label Extension Study
Authors: Kim Paes, Timothy Craig, Jonathan Bernstein, Hilary Longhurst, Emel Aygoren-Pursun, Christina Nurse, Bruce Zuraw, Joshua Jacobs
Journal: Journal of Allergy and Clinical Immunology (2020)
Patient-reported outcomes (PRO) from a phase I/II dose-escalation study of fractionated dose 177Lu-PSMA-617 for progressive metastatic castration-resistant prostate cancer (mCRPC).
Authors: Panagiotis J. Vlachostergios, Sukanya Goswami, Muhammad Junaid Niaz, Charlene Thomas, Paul J. Christos, Joseph Osborne, Shankar Vallabhajosula, Ana M. Molina, Cora N. Sternberg, Sharon Singh, Angela Tan, Amie Patel, David M. Nanus, Neil Harrison Bander, Scott T. Tagawa
Journal: Journal of Clinical Oncology (2020)

45 Background: We performed the 1st dose-escalation study of PSMA-targeted radionuclide therapy with 177 Lu-PSMA-617. Using dose-fractionation, we intended to deliver a dose-intense regimen designed to minimize radioresistance due to repopulation. Radionuclide therapy may be able to treat symptoms due to tumor and therefore may be associated with improvement in PRO. Methods: Inclusion: progressive mCRPC following potent AR-pathway inhibitor (ARPI, e.g. abi/enza) and taxane (or unfit/refuse chemo) without limit of # prior therapies, adequate organ function, ECOG performance status 0-2, without preselection for PSMA expression. Treatment was a single cycle of fractionated dose 177 Lu-PSMA-617 on D1 and D15 (7.4 to 22 GBq in phase 1; 22.2 GBq in phase 2). PRO tools included FACT-P and BPI-SF at baseline and follow up. Results: 44 men with median age 69 (range 55-91), median PSA 182.97 (range 0.89-5541) were treated. 93% with bone, 45% nodal, 18% lung, 9% liver, 9% other visceral metastases. 55% with at least 1 prior chemo regimen, 52% &gt;2 prior ARPI, 27% with Ra223, 30% sip-T, 5% 177 Lu-J591. 59.1% with &gt;50% PSA decline (66.7% at 22.2 GBq, n=21), median overall survival 16 months (95% CI 11-NR). High grade (Gr) toxicity was rare with 6.8% Gr 3 anemia and 2.3% Gr 3 platelets. Gr 1/2 treatment-emergent AE’s include 81.8% with pain flare, 61.4% xerostomia, 29.5% fatigue, 25% platelets, 25% anemia, 25% pain, 15.5% nausea. FACT-P scores tended to improve in all categories by D22 (1 week later), with overall FACT-P scores improving by mean of 8.9 points (p=0.07) at D22 and remaining improved at 12 wks. All BPI scores also improved, with BPI overall severity score improving by mean of 3.0 at D22 (p=0.008) and remained better than baseline at 12 wks. There was no clear association with any AE and PRO changes, but those with PSA decline tended to have improved pain scores (p=0.1). Conclusions: A single cycle of up to 22.2 GBq of 177 Lu-PSMA-617 is safe with fractionated (D1 &amp; D15) dosing, with encouraging early efficacy signals in a population unselected for PSMA expression and improved quality of life and pain scores by validated PRO instruments. Clinical trial information: NCT03042468.