Advanced HIV disease and associated factors among young people aged 15-24 years at a tertiary hospital in Sierra Leone: a cross-sectional study.

BACKGROUND: Advanced HIV disease (AHD) in young people living with HIV (PLHIV) is an increasingly pressing public health issue in sub-Saharan Africa. Despite global progress in early HIV testing and reducing HIV-related deaths, many youths experience increased rates of HIV disease progression in sub-Saharan Africa. This study describes the burden, clinical manifestations, and factors for disease progression among young PLHIV aged 15 - 24 years seeking medical services at a major public hospital in Sierra Leone. METHODS: We performed a cross-sectional analysis of routinely collected data for PLHIV patients aged 15 to 24 seen at Connaught Hospital in Sierra Leone between September 2022 and March 2023. We estimated the proportion of AHD in young PLHIV and performed logistic regression modelling to explore predictors of AHD. The statistical significance level was set at 0.05 for all statistical tests. RESULTS: Of the 581 PLHIV that were reported, 238 (40.9%) were between the ages of 15 and 24 years, with a median age of 22 (20-24), and 151 (63.5%) were females. On review, 178 (74.8%) has initiated antiretroviral therapy regimen (ART); 117 (65.7%) were actively on ART for ≤ 6 months, while 114 (64%) had interruptions with their ART treatment. The overall prevalence of AHD was 41.6% (99/238); 46.7% (35/68) of young PLHIV at the HIV clinic, and 39.3% (64/163) of admission. Sex-Female (OR, 0.51; 95% CI, 0.28-0.94; p = 0.030), and Tertiary Education level (OR, 0.27; 95% CI, 0.10 - 0.78; p = 0.015) have significantly lower odds of AHD in the entire study population. While for inpatients, Age (young Adults) of PLHIV (OR, 1.23; 95% CI, 1.00-1.52; p = 0.047) had 1.23 times the odds of AHD compared to adolescents, and being female (OR, 0.27; 95% CI, 0.08-0.84; p = 0.024), Overweight-Body mass index (OR, 0.10; 95% CI, 0.01-0.77; p = 0.028), Tertiary Education level (OR, 0.08; 95% CI, 0.01-0.52; p = 0.008) have significantly lower odds of AHD. Common conditions reported for the AHD group in the medical wards are tuberculosis (13.58%), hepatitis B (6.13%), Kaposi sarcoma (3.07%), and oesophagal candidiasis (2.45%). CONCLUSION: We reported a high prevalence of advanced HIV among young patients in a tertiary Hospital in Sierra Leone. One in two young PLHIV aged 15 to 24 years reported AHD, emphasizing the need to strengthen public health measures that address access to and retention of HIV services.

Tape strips detect molecular alterations and cutaneous biomarkers in skin of patients with hidradenitis suppurativa.

BACKGROUND: Hidradenitis suppurativa (HS) has a high unmet need for better treatments. Biopsies are considered the gold standard for studying molecular alterations in skin. A reproducible, minimally invasive approach is needed for longitudinal monitoring in trials and in pediatric populations. OBJECTIVE: To determine whether skin tape strips can detect molecular alterations in HS and identify biomarkers of disease activity. METHODS: We performed RNA sequencing on tape strips collected from lesional and healthy-appearing (nonlesional) HS skin (n = 22) and healthy controls (n = 21). We correlated the expression of skin biomarkers between tape strips and a previously published gene-signature of HS biopsies. RESULTS: Tape strips detected upregulation of known HS biomarkers (eg, Interleukin[IL]-17A) in nonlesional and/or lesional skin and also identified novel clinically actionable targets, including OX40 and JAK3. The expression of Th17 and tumor necrosis factor-α pathways were highly correlated between tape strips and biopsies. HS clinical severity was significantly associated with expression of biomarkers (eg tumor necrosis factor-α , IL-17 A/F, OX40, JAK1-3, IL-4R) in HS lesional and/or nonlesional skin. LIMITATIONS: Sample size. Tape stripping is limited in depth. CONCLUSION: This study validates tape strips as a minimally-invasive approach to identify cutaneous biomarkers in HS. This provides a novel avenue for monitoring treatment efficacy and a potential step toward individualized therapy in HS.

Laser capture microdissection provides a novel molecular profile of human primary cutaneous melanoma.

Melanoma accounts for the majority of skin cancer-related mortality, highlighting the need to better understand melanoma initiation and progression. In-depth molecular analysis of neoplastic melanocytes in whole tissue biopsies may be diluted by inflammatory infiltration, which may obscure gene signatures specific to neoplastic cells. Thus, a method is needed to precisely uncover molecular changes specific to tumor cells from a limited sample of primary melanomas. Here, we performed laser capture microdissection (LCM) and gene expression profiling of patient-derived frozen sections of pigmented lesions and primary cutaneous melanoma. Compared to bulk tissue analysis, analysis of LCM-derived samples identified 9528 additional differentially expressed genes (DEGs) including melanocyte-specific genes like PMEL and TYR, with enriched of pathways related to cell proliferation. LCM methodology also identified potentially targetable kinases specific to melanoma cells that were not detected by bulk tissue analysis. Taken together, our data demonstrate that there are marked differences in gene expression profiles depending on the method of sample isolation. We found that LCM captured higher expression of melanoma-related genes while whole tissue biopsy identified a wider range of inflammatory markers. Taken together, our data demonstrate that LCM is a valid approach to identify melanoma-specific changes using a relatively small amount of primary patient-derived melanoma sample.

International Dermatology Outcome Measures (IDEOM) - Report from the 2022 Annual Meeting.

BACKGROUND: The International Dermatology Outcome Measures (IDEOM) is a non-profit organization dedicated to the advancement of evidence-based, consensus-driven outcome measures in dermatological diseases. Researchers and stakeholders from various backgrounds collaborate to develop these objective benchmark metrics to further advance treatment and management of dermatological conditions. SUMMARY: The 2022 IDEOM Annual Meeting was held on June 17-18, 2022. Leaders and stakeholders from the hidradenitis suppurativa, acne, vitiligo, actinic keratosis, alopecia areata, itch, cutaneous lymphoma, and psoriatic disease workgroups discussed the progress of their respective outcome-measures research. This report summarizes each workgroup's updates from 2022 and their next steps as established during the 2022 IDEOM Annual Meeting. J Drugs Dermatol. 2023;22(12):1153-1159 doi:10.36849/JDD.7615.

Prevalence and factors associated with advanced HIV disease among young people aged 15 - 24 years in a national referral hospital in Sierra Leone: A cross-sectional study.

Background: Advanced HIV in young people living with HIV is an increasingly pressing public health issue in sub-Saharan Africa. Despite global progress in early HIV testing and reducing HIV-related deaths, many young people with HIV continue to experience HIV disease progression in sub-Saharan Africa. This study provides an overview of the prevalence, clinical manifestations, and factors associated with advanced HIV in young people seeking medical services in a major hospital in Sierra Leone. Methods: We used a cross-sectional design to collect data from HIV patients aged 15 to 24 years at a major hospital in Sierra Leone between September 2022 and March 2023. Advanced HIV was defined as (i) CD4+ below 200 cells/mm3 or (ii) WHO clinical stage 3 or 4. Logistic regression models determined the association between observable independent characteristics and advanced HIV. The statistical significance level was set at 0.05 for all statistical tests. Results: About 40% (231/574) of patients were recruited; 70.6% (163/231) were inpatients, and 29.4% (68/231) were outpatients. The mean age was approximately 21.6 years (SD ±2.43). The overall prevalence of advanced HIV was 42.9% (99/231), 51.5% (35/68) of outpatients, and 39.3% (64/163) of inpatients. Age of inpatients (OR, 1.23; 95% CI, 1.00-1.52; p= 0.047) was associated with a higher risk. Female sex (OR, 0.51; 95% CI, 0.28-0.94; p= 0.030), higher education (OR, 0.27; 95% CI, 0.10 - 0.78; p= 0.015), and Body Mass (OR, 0.10; 95% CI, 0.01-0.77; p= 0.028) were at lower risk of advance HIV. Common conditions diagnosed in this population are tuberculosis (13.58%), hepatitis B (6.13%), Kaposi sarcoma (3.07%), and esophageal candidiasis (2.45%). Conclusion: We reported a high prevalence of advanced HIV among young patients in a referral Hospital in Sierra Leone. This emphasises the need to strengthen public health measures and policies that address challenges of access to HIV services.

Natural gas odorants: A scoping review of health effects.

PURPOSE OF REVIEW: Organosulfur compounds are intentionally added to natural gas as malodorants with the intent of short-term nasal inhalation to aid in leak detection. Regulatory exposure limits have not been established for all commonly used natural gas odorants, and recent community-level exposure events and growing evidence of indoor natural gas leakage have raised concerns associated with natural gas odorant exposures. We conducted a scoping review of peer-reviewed scientific publications on human exposures and animal toxicological studies of natural gas odorants to assess toxicological profiles, exposure potential, health effects and regulatory guidelines associated with commonly used natural gas odorants. RECENT FINDINGS: We identified only 22 studies which met inclusion criteria for full review. Overall, there is limited evidence of both transient nonspecific health symptoms and clinically diagnosed causative neurotoxic effects associated with prolonged odorant exposures. Across seven community-level exposure events and two occupational case reports, consistent symptom patterns included: headache, ocular irritation, nose and throat irritation, respiratory complaints such as shortness of breath and asthma attacks, and skin irritation and rash. Of these, respiratory inflammation and asthma exacerbations are the most debilitating, whereas the high prevalence of ocular and dermatologic symptoms suggest a non-inhalation route of exposure. The limited evidence available raises the possibility that organosulfur odorants may pose health risks at exposures much lower than presently understood, though additional dose-response studies are needed to disentangle specific toxicologic effects from nonspecific responses to noxious organosulfur odors. Numerous recommendations are provided including more transparent and prescriptive natural gas odorant use practices.

A case of acute tubulointerstitial nephritis following administration of the Oxford-AstraZeneca COVID-19 vaccine: a case report.

BACKGROUND: More than 4 billion doses of the Coronavirus disease (COVID-19) vaccine have been administered worldwide but the relationship between the different vaccines and the development of renal disease is unknown. We present a case of tubulointerstitial nephritis following administration of the Oxford-AstraZeneca COVID-19 vaccine. CASE PRESENTATION: A previously fit and well 51-year-old female presented on 27th May 2021 with a one-month history of weight loss, fatigue, nausea, and a metallic taste. She had an acute kidney injury with a creatinine of 484 umol/L. She was on no regular medications and denied taking any over-the-counter or alternative medicines. She had received her first dose of the Oxford-AstraZeneca vaccine on 23rd March 2021 and her second dose on 20th May 2021. A renal biopsy was performed the following day. The 19 glomeruli appeared normal to light microscopy but the tubulointerstitial compartment contained a dense inflammatory infiltrate including many eosinophils. There was widespread acute tubular injury with tubulitis, but no established or longstanding atrophy. A diagnosis was made of an acute tubulointerstitial nephritis. She was commenced on oral prednisolone and her renal function improved. She did not require renal replacement therapy at any time. CONCLUSIONS: To our knowledge, this was the first described case of acute tubulointerstitial nephritis following administration of the Oxford-AstraZeneca COVID-19 vaccine, although a number of cases have emerged more recently. In our case the patient was very fit and well, had no previous past medical history and had not taken any recent prescribed, over-the-counter or alternative medications. The absence of these provoking factors in our case makes the vaccine the most likely explanation for the development of tubulointerstitial nephritis although the pathophysiology behind this remains unknown. Given the unprecedented number of vaccinations being delivered around the world, nephrologists should be aware of this possible link although more research into the topic is required.

Gelatin-containing porous polycaprolactone PolyHIPEs as substrates for 3D breast cancer cell culture and vascular infiltration.

Tumour survival and growth are reliant on angiogenesis, the formation of new blood vessels, to facilitate nutrient and waste exchange and, importantly, provide a route for metastasis from a primary to a secondary site. Whilst current models can ensure the transport and exchange of nutrients and waste via diffusion over distances greater than 200 µm, many lack sufficient vasculature capable of recapitulating the tumour microenvironment and, thus, metastasis. In this study, we utilise gelatin-containing polymerised high internal phase emulsion (polyHIPE) templated polycaprolactone-methacrylate (PCL-M) scaffolds to fabricate a composite material to support the 3D culture of MDA-MB-231 breast cancer cells and vascular ingrowth. Firstly, we investigated the effect of gelatin within the scaffolds on the mechanical and chemical properties using compression testing and FTIR spectroscopy, respectively. Initial in vitro assessment of cell metabolic activity and vascular endothelial growth factor expression demonstrated that gelatin-containing PCL-M polyHIPEs are capable of supporting 3D breast cancer cell growth. We then utilised the chick chorioallantoic membrane (CAM) assay to assess the angiogenic potential of cell-seeded gelatin-containing PCL-M polyHIPEs, and vascular ingrowth within cell-seeded, surfactant and gelatin-containing scaffolds was investigated via histological staining. Overall, our study proposes a promising composite material to fabricate a substrate to support the 3D culture of cancer cells and vascular ingrowth.

Characteristics of procalcitonin in hospitalized COVID-19 patients and clinical outcomes of antibiotic use stratified by procalcitonin levels.

We examined the characteristics of pro-calcitonin (PCT) in hospitalized COVID-19 patients (cohort 1) and clinical outcomes of antibiotic use stratified by PCT in non-critically ill patients without bacterial co-infection (cohort 2). Retrospective reviews were performed in adult, hospitalized COVID-19 patients during March-May 2020. For cohort 1, we excluded hospital transfers, renal disease and extra-pulmonary infection without isolated pathogen(s). For cohort 2, we further excluded microbiologically confirmed infection, 'do not resuscitate ± do not intubate' status, and intensive care unit (ICU). For cohort 1, PCT was compared between absent/low-suspicion and proven bacterial co-infections. Factors associated with elevated PCT and sensitivity/specificity/PPV/NPV of PCT cutoffs for identifying bacterial co-infections were explored. For cohort 2, clinical outcomes including mechanical ventilation within 5 days (MV5) were compared between the antibiotic and non-antibiotic groups stratified by PCT ≥ 0.25 µg/L. Nine hundred and twenty four non-ICU and 103 ICU patients were included (cohort 1). The median PCT was higher in proven vs. absent/low-suspicion of bacterial co-infection. Elevated PCT was significantly associated with proven bacterial co-infection, ICU status and oxygen requirement. For PCT ≥ 0.25 µg/L, sensitivity/specificity/PPV/NPV were 69/65/6.5/98% (non-ICU) and 75/33/8.6/94% (ICU). For cohort 2, 756/1305 (58%) patients were included. Baseline characteristics were balanced between the antibiotic and non-antibiotic groups except PCT ≥ 0.25 µg/L (antibiotic:non-antibiotic = 59%:24%) and tocilizumab use (antibiotic:non-antibiotic = 5%:2%). 23% (PCT < 0.25 µg/L) and 58% (PCT ≥ 0.25 µg/L) received antibiotics. Antibiotic group had significantly higher rates of MV5. COVID-19 severity inferred from ICU status and oxygen requirement as well as the presence of bacterial co-infections were associated with elevated PCT. PCT showed poor PPV and high NPV for proven bacterial co-infections. The use of antibiotics did not show improved clinical outcomes in COVID-19 patients with PCT ≥ 0.25 µg/L outside of ICU when bacterial co-infections are of low suspicion.

Inherited PD-1 deficiency underlies tuberculosis and autoimmunity in a child.

The pathophysiology of adverse events following programmed cell death protein 1 (PD-1) blockade, including tuberculosis (TB) and autoimmunity, remains poorly characterized. We studied a patient with inherited PD-1 deficiency and TB who died of pulmonary autoimmunity. The patient's leukocytes did not express PD-1 or respond to PD-1-mediated suppression. The patient's lymphocytes produced only small amounts of interferon (IFN)-γ upon mycobacterial stimuli, similarly to patients with inborn errors of IFN-γ production who are vulnerable to TB. This phenotype resulted from a combined depletion of Vδ2+ γδ T, mucosal-associated invariant T and CD56bright natural killer lymphocytes and dysfunction of other T lymphocyte subsets. Moreover, the patient displayed hepatosplenomegaly and an expansion of total, activated and RORγT+ CD4-CD8- double-negative αß T cells, similar to patients with STAT3 gain-of-function mutations who display lymphoproliferative autoimmunity. This phenotype resulted from excessive amounts of STAT3-activating cytokines interleukin (IL)-6 and IL-23 produced by activated T lymphocytes and monocytes, and the STAT3-dependent expression of RORγT by activated T lymphocytes. Our work highlights the indispensable role of human PD-1 in governing both antimycobacterial immunity and self-tolerance, while identifying potentially actionable molecular targets for the diagnostic and therapeutic management of TB and autoimmunity in patients on PD-1 blockade.

Evaluation of PNU-159682 antibody drug conjugates (ADCs).

PNU-159682 is a highly potent secondary metabolite of nemorubicin belonging to the anthracycline class of natural products. Due to its extremely high potency and only partially understood mechanism of action, it was deemed an interesting starting point for the development of a new suite of linker drugs for antibody drug conjugates (ADCs). Structure activity relationships were explored on the small molecule which led to six linker drugs being developed for conjugation to antibodies. Herein we describe the synthesis of novel PNU-159682 derivatives and the subsequent linker drugs as well as the corresponding biological evaluations of the small molecules and ADCs.

Diagnostic and management considerations in the modern patient with AIDS: a case of concurrent disseminated Kaposi sarcoma and colesional Cryptococcus neoformans.

In the era of highly active antiretroviral therapy (HAART), disseminated Kaposi sarcoma (KS) has become much rarer in the USA. We report a case of a 34-year-old man with KS of the skin, oropharynx, lung and rectum. Within the same lung nodule, we discovered significant burden of colesional Cryptococcus neoformans, in the context of a positive asymptomatic cryptococcal antigenemia, which was a previously unreported occurrence. The gold standard of treatment for KS continues to be HAART. The role of chemotherapy is still controversial. In addition, a cryptococcal antigen screen-and-treat approach with fluconazole is still not routinely recommended in the USA to prevent serious meningeal disease despite recent studies showing efficacy and applicability. We discuss both issues here and the outcome of our patient. We also present the patient's own unique perspective in dealing with the ramifications of these diagnoses.

Population allocation at the housing unit level: estimates around underground natural gas storage wells in PA, OH, NY, WV, MI, and CA.

BACKGROUND: Spatially accurate population data are critical for determining health impacts from many known risk factors. However, the utility of the increasing spatial resolution of disease mapping and environmental exposures is limited by the lack of receptor population data at similar sub-census block spatial scales. METHODS: Here we apply an innovative method (Population Allocation by Occupied Domicile Estimation - ABODE) to disaggregate U.S. Census populations by allocating an average person per household to geospatially-identified residential housing units (RHU). We considered two possible sources of RHU location data: address point locations and building footprint centroids. We compared the performance of ABODE with the common proportional population allocation (PPA) method for estimating the nighttime residential populations within 200 m radii and setback areas (100 - 300 ft) around active underground natural gas storage (UGS) wells (n = 9834) in six U.S. states. RESULTS: Address location data generally outperformed building footprint data in predicting total counts of census residential housing units, with correlations ranging from 0.67 to 0.81 at the census block level. Using residentially-sited addresses only, ABODE estimated upwards of 20,000 physical households with between 48,126 and 53,250 people living within 200 m of active UGS wells - likely encompassing the size of a proposed UGS Wellhead Safety Zone. Across the 9834 active wells assessed, ABODE estimated between 5074 and 10,198 more people living in these areas compare to PPA, and the difference was significant at the individual well level (p = < 0.0001). By either population estimation method, OH exhibits a substantial degree of hyperlocal land use conflict between populations and UGS wells - more so than other states assessed. In some rare cases, population estimates differed by more than 100 people for the small 200 m2 well-areas. ABODE's explicit accounting of physical households confirmed over 50% of PPA predictions as false positives indicated by non-zero predictions in areas absent physical RHUs. CONCLUSIONS: Compared to PPA - in allocating identical population data at sub-census block spatial scales -ABODE provides a more precise population at risk (PAR) estimate with higher confidence estimates of populations at greatest risk. 65% of UGS wells occupy residential urban and suburban areas indicating the unique land use conflicts presented by UGS systems that likely continue to experience population encroachment. Overall, ABODE confirms tens of thousands of homes and residents are likely located within the proposed UGS Wellhead Safety Zone - and in some cases within state's oil and gas well surface setback distances - of active UGS wells.

Increased use of cross-sectional imaging for follow-up does not improve post-recurrence survival of surgically treated initially localized R.C.C.: results from a European multicenter database (R.E.C.U.R.).

Objective: Modality and frequency of image-based renal cell carcinoma (R.C.C.) follow-up strategies are based on risk of recurrence. Using the R.E.C.U.R.-database, frequency of imaging was studied in regard to prognostic risk groups. Furthermore, it was investigated whether imaging modality utilized in contemporary follow-up were associated with outcome after detection of recurrence. Moreover, outcome was compared based on whether the assessment of potential curability was a pre-defined set of criteria's (per-protocol) or stated by the investigator. Materials and methods: Consecutive non-metastatic R.C.C. patients (n = 1,612) treated with curative intent at 12 institutes across eight European countries between 2006 and 2011 were included. Leibovich or U.I.S.S. risk group, recurrence characteristics, imaging modality, frequency and survival were recorded. Primary endpoints were overall survival (O.S.) after detection of recurrence and frequency of features associated with favourable outcome (non-symptomatic recurrences and detection within the follow-up-programme). Results: Recurrence occurred in 336 patients. Within low, intermediate and high risk for recurrence groups, the frequency of follow-up imaging was highest in the early phase of follow-up and decreased significantly over time (p < 0.001). However, neither the image modality for detection nor ≥ 50% cross-sectional imaging during follow-up were associated with improved O.S. after recurrence. Differences between per protocol and investigator based assessment of curability did not translate into differences in O.S. Conclusions: As expected, the frequency of imaging was highest during early follow-up. Cross-sectional imaging use for detection of recurrences following surgery for localized R.C.C. did not improve O.S. post-recurrence. Prospective studies are needed to determine the value of imaging in follow-up.

Long-term Outcomes of Follow-up for Initially Localised Clear Cell Renal Cell Carcinoma: RECUR Database Analysis.

BACKGROUND: Optimal follow-up (FU) strategy to detect potentially curable (PC) recurrences after treatment of localised clear cell renal cell carcinoma (ccRCC) is unclear. This study retrospectively analysed a large international database to determine recurrence patterns and overall survival (OS), as part of a wider project to issue recommendations on FU protocols. OBJECTIVE: To analyse associations between RCC recurrences in patients with ccRCC, their risk group stratifications, treatments, and subsequent outcomes. DESIGN, SETTING, AND PARTICIPANTS: Nonmetastatic ccRCC patients treated with curative intent between 1 January 2006 and 31 December 2011, with at least 4 yr of FU, were included. Patient, tumour and recurrence characteristics, Leibovich score, and management and survival data were recorded. Isolated local, solitary, and oligometastatic (three or fewer lesions at a single site) recurrences were considered PC, while all others were probably incurable (PI). INTERVENTION: Primarily curative surgical treatment of ccRCC while at recurrence detection metastasectomy, systemic therapy, best supportive care, or observation. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Incidence, time to recurrence (TTR), and OS were measured. Competing risk analysis, Kaplan-Meier, and Cox regression models were used. RESULTS AND LIMITATION: Of 1265 patients with ccRCC, 286 had a recurrence, with 131 being PC and 155 PI. Five-year cumulative risks of recurrence for low- (n=53), intermediate- (n=105), and high-risk (n=128) patients were, respectively, 7.2%, 23.2%, and 61.6%, of whom 52.8%, 37.1%, and 30.5% were PC, respectively. Median TTR was 25.0 for PC patients versus 17.3 mo for PI patients (p=0.004). Median OS was longer in PC compared with that in PI patients (p<0.001). Competing risk analysis showed highest risk of ccRCC-related death in younger and high-risk patients. Limitations were no data on comorbidities, retrospective cohort, and insufficient data excluding 12% of cohort. CONCLUSIONS: Low-risk group recurrences are rare and develop later. Treatment of recurrences with curative intent is disappointing, especially in high-risk patients. An age- and risk score-dependent FU approach is suggested. PATIENT SUMMARY: We analysed data from eight European countries, and found that the incidence of the kidney cancer recurrence and patient survival correlated with clinical factors known to predict cancer recurrence reliably and age. We conclude that these factors should be used to design follow-up strategies.

Intensive Imaging-based Follow-up of Surgically Treated Localised Renal Cell Carcinoma Does Not Improve Post-recurrence Survival: Results from a European Multicentre Database (RECUR).

The optimal follow-up (FU) strategy for patients treated for localised renal cell carcinoma (RCC) remains unclear. Using the RECUR database, we studied imaging intensity utilised in contemporary FU to evaluate its association with outcome after detection of disease recurrence. Consecutive patients with nonmetastatic RCC (n=1612) treated with curative intent at 12 institutes across eight European countries between 2006 and 2011 were included. Recurrence occurred in 336 patients. Cross-sectional (computed tomography, magnetic resonance imaging) and conventional (chest X-ray, ultrasound) methods were used in 47% and 53%, respectively. More intensive FU imaging (more than twofold) than recommended by the European Association of Urology (EAU) was not associated with improved overall survival (OS) after recurrence. Overall, per patient treated for recurrence remaining alive with no evidence of disease, the number of FU images needed was 542, and 697 for high-risk patients. The study results suggest that use of more imaging during FU than that recommended in the 2017 EAU guidelines is unlikely to improve OS after recurrence. Prospective studies are needed to design optimal FU strategies for the future. PATIENT SUMMARY: After curative treatment for localised kidney cancer, follow-up is necessary to detect any recurrence. This study illustrates that increasing the imaging frequency during follow-up, even to double the number of follow-up imaging procedures recommended by the European Association of Urology guidelines, does not translate into improved survival for those with recurrence.

Status of nucleolar channel systems in uterine secretions accurately reflects their prevalence-a marker for the window of implantation-in simultaneously obtained endometrial biopsies.

OBJECTIVE: To assess whether nucleolar channel systems (NCSs) can be detected in exfoliated endometrial epithelial cells (EECs) of uterine secretions and whether such noninvasively determined NCS status is associated with significant NCS prevalence in simultaneously obtained endometrial biopsies. DESIGN: Prospective study (December 2015-February 2017). SETTING: University-affiliated and private fertility clinics. PATIENT(S): Luteal-phase patients of reproductive age requiring endometrial biopsy for medical indications. INTERVENTION(S): Uterine secretion aspiration before endometrial biopsy. Cells in uterine secretions were spun onto slides and fixed. NCSs were identified and quantified in cells and paraffin-embedded tissue sections by indirect immunofluorescence. MAIN OUTCOME MEASURE(S): Comparison of NCS status of uterine secretions with NCS prevalence in biopsies. Based on NCS detection, uterine secretions were assigned a status of NCS-positive (n = 15) or NCS-negative (n = 7). NCS prevalence in biopsies was expressed as a percentage of NCSs per EECs. RESULT(S): NCSs can be detected in exfoliated EECs of uterine secretions. Median NCS prevalence in endometrial biopsies from patients with NCS-positive secretions was 41.9% (interquartile range [IQR], 21.1-53.9) versus 2.0% (IQR, 0-6.9) when secretions were NCS-negative. The NCS status of secretions identified a significant difference in NCS prevalence of simultaneously obtained biopsies. CONCLUSION(S): NCS status of secretions accurately reflects NCS prevalence of biopsies, a marker for the implantation window. As secretion aspiration is compatible with same-day ET, our study provides proof of principle for a minimally invasive approach to determine endometrial receptivity for timing frozen ET.

A PTK7-targeted antibody-drug conjugate reduces tumor-initiating cells and induces sustained tumor regressions.

Disease relapse after treatment is common in triple-negative breast cancer (TNBC), ovarian cancer (OVCA), and non-small cell lung cancer (NSCLC). Therapies that target tumor-initiating cells (TICs) should improve patient survival by eliminating the cells that can drive tumor recurrence and metastasis. We demonstrate that protein tyrosine kinase 7 (PTK7), a highly conserved but catalytically inactive receptor tyrosine kinase in the Wnt signaling pathway, is enriched on TICs in low-passage TNBC, OVCA, and NSCLC patient-derived xenografts (PDXs). To deliver a potent anticancer drug to PTK7-expressing TICs, we generated a targeted antibody-drug conjugate (ADC) composed of a humanized anti-PTK7 monoclonal antibody, a cleavable valine-citrulline-based linker, and Aur0101, an auristatin microtubule inhibitor. The PTK7-targeted ADC induced sustained tumor regressions and outperformed standard-of-care chemotherapy. Moreover, the ADC specifically reduced the frequency of TICs, as determined by serial transplantation experiments. In addition to reducing the TIC frequency, the PTK7-targeted ADC may have additional antitumor mechanisms of action, including the inhibition of angiogenesis and the stimulation of immune cells. Together, these preclinical data demonstrate the potential for the PTK7-targeted ADC to improve the long-term survival of cancer patients.

A DLL3-targeted antibody-drug conjugate eradicates high-grade pulmonary neuroendocrine tumor-initiating cells in vivo.

The high-grade pulmonary neuroendocrine tumors, small cell lung cancer (SCLC) and large cell neuroendocrine carcinoma (LCNEC), remain among the most deadly malignancies. Therapies that effectively target and kill tumor-initiating cells (TICs) in these cancers should translate to improved patient survival. Patient-derived xenograft (PDX) tumors serve as excellent models to study tumor biology and characterize TICs. Increased expression of delta-like 3 (DLL3) was discovered in SCLC and LCNEC PDX tumors and confirmed in primary SCLC and LCNEC tumors. DLL3 protein is expressed on the surface of tumor cells but not in normal adult tissues. A DLL3-targeted antibody-drug conjugate (ADC), SC16LD6.5, comprised of a humanized anti-DLL3 monoclonal antibody conjugated to a DNA-damaging pyrrolobenzodiazepine (PBD) dimer toxin, induced durable tumor regression in vivo across multiple PDX models. Serial transplantation experiments executed with limiting dilutions of cells provided functional evidence confirming that the lack of tumor recurrence after SC16LD6.5 exposure resulted from effective targeting of DLL3-expressing TICs. In vivo efficacy correlated with DLL3 expression, and responses were observed in PDX models initiated from patients with both limited and extensive-stage disease and were independent of their sensitivity to standard-of-care chemotherapy regimens. SC16LD6.5 effectively targets and eradicates DLL3-expressing TICs in SCLC and LCNEC PDX tumors and is a promising first-in-class ADC for the treatment of high-grade pulmonary neuroendocrine tumors.

Patient-derived xenografts, the cancer stem cell paradigm, and cancer pathobiology in the 21st century.

Cancer is a heterogeneous disease manifest in many forms. Tumor histopathology can differ significantly among patients and cellular heterogeneity within tumors is common. A primary goal of cancer biologists is to better understand tumorigenesis and cancer progression; however, the complex nature of tumors has posed a substantial challenge to unlocking cancer's secrets. The cancer stem cell (CSC) paradigm for the pathobiology of solid tumors appropriately acknowledges phenotypic and functional tumor cell heterogeneity observed in solid tumors and accounts for the disconnect between drug approval based on response and the general inability of approved therapies to meaningfully impact survival due to their failure to eradicate these most important of cellular targets. First proposed to exist decades ago, CSC have only recently begun to be precisely identified due to technical advancements that facilitate identification, isolation, and interrogation of distinct tumor cell subpopulations with differing ability to form and perpetuate tumors. Precise identification of CSC populations and the complete hierarchy of cells within solid tumors will facilitate more accurate characterization of patient subtypes and ultimately contribute to more personalized and effective therapies. Rapid advancement in the understanding of tumor biology as it exists in patients requires cooperation among institutions, surgeons, pathologists, cancer biologists and patients alike, primarily because this translational research is best done with patient-derived tissue grown in the xenograft setting as patient-derived xenografts. This review calls for a broader change in the approaches taken to study cancer pathobiology, highlights what implications the CSC paradigm has for pathologists and cancer biologists alike, and calls for greater collaboration between institutions, physicians and scientists in order to more rapidly advance our collective understanding of cancer.