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1.
Article in English | MEDLINE | ID: mdl-38958945

ABSTRACT

BACKGROUND: The stromal microenvironment (SME) is integral to breast cancer (BC) biology, impacting metastatic proclivity and treatment response. Emerging data indicate that host factors may impact the SME, but the relationship between pre-diagnostic host factors and SME phenotype remains poorly characterized, particularly among women of African ancestry. METHODS: We conducted a case-only analysis involving 792 BC patients (17-84 years) from the Ghana Breast Health Study (GBHS). High-accuracy machine-learning algorithms were applied to standard H&E-stained images to characterize SME phenotypes (including percent tumor-associated connective tissue stroma, Ta-CTS (%), and tumor-associated stromal cellular density, Ta-SCD (%)). Associations between pre-diagnostic host factors and SME phenotypes were assessed in multivariable linear regression models. RESULTS: Decreasing Ta-CTS and increasing Ta-SCD were associated with aggressive, mostly high-grade tumors (p-value<0.001). Several pre-diagnostic host factors were associated with Ta-SCD independently of tumor characteristics. Compared with nulliparous women, parous women had higher levels of Ta-SCD [mean (standard deviation, SD) = 31.3% (7.6%) vs. 28.9% (7.1%); p-value=0.01]. Similarly, women with a positive family history of breast cancer had higher levels of Ta-SCD than those without family history [mean (SD) = 33.0% (7.5%)] vs. 30.9% (7.6%); p-value=0.03]. Conversely, increasing body size was associated with decreasing Ta-SCD [mean (SD) = 32.0% (7.4%), 31.3% (7.3%), and 29.0% (8.0%) for slight, average, and large body sizes, respectively, p-value=0.005]. CONCLUSIONS: Epidemiological risk factors were associated with varying degrees of stromal cellularity in tumors, independently of clinicopathological characteristics. IMPACT: The findings raise the possibility that epidemiological risk factors may partly influence tumor biology via the SME.

2.
Hum Pathol ; 2024 Jul 05.
Article in English | MEDLINE | ID: mdl-38972607

ABSTRACT

A fusion between tubulin polymerization-promoting protein (TPPP), a regulatory cytoskeletal gene, and the chromatin remodeling factor, bromodomain-containing protein 9 (BRD9), TPPP-BRD9 fusion has been found in rare cancer cases, including lung and gallbladder cancers (GBC). In this study, we investigated the histopathological features of 16 GBCs previously shown by RNA sequencing to harbor the TPPP-BRD9 fusion. Findings in the fusion-positive GBCs were compared with 645 GBC cases from the authors' database. Among the 16 TPPP-BRD9 fusion-positive GBC cases, most were females (F:M=7:1) of Chinese ethnicity (12/16), whereas the remaining cases were from Chile. The histopathological examination showed the following findings: 1) Intracholecystic neoplasm (ICN) in 7/15 (47% vs. 7% 645 reference GBCs, p<0.001), all with gastro-pancreatobiliary phenotype, often with clear cell change, and in the background of pyloric gland metaplasia and extensive high-grade dysplasia. 2) Neuroendocrine carcinoma (NEC): 3 cases (27% vs. 4.6% in the reference database, p=0.001) showed a sheet-like and nested/trabecular growth pattern of monotonous cells with salt-and-pepper chromatin characteristic of NECs. Two were large cell type, one had prominent clear cell features, a rare finding in GBNECs; the other one had relatively bland, well-differentiated morphology, and the remining case was small cell type. 3) Adenocarcinoma identified in 8 cases had a distinctive pattern characterized by widely separated small, round tubular units with relatively uniform nuclei in a fashion seen in mesonephric adenocarcinomas, including hobnail-like arrangement and apical snouts, reminiscent of tubular carcinomas of the breast in many areas. In some foci, the epithelium was attenuated, and glands were elongated, some with comma shapes, which along with the mucinous/necrotic intraluminal debris created a "syringoid" appearance. 4) Other occasional patterns included the cribriform, glomeruloid patterns, and metaplastic tubular-spindle cell pattern accompanied by hemorrhage. In conclusion, TPPP-BRD9 fusion-positive GBCs often develop through intracholecystic neoplasms (adenoma-carcinoma sequence) of gastro-pancreatobiliary lineage, appear more prone to form NEC and have a propensity to display clear cell change. Invasive adenocarcinomas arising in this setting often seem to display a distinctive appearance that we tentatively propose as the TPPP-BRD9 fusion-positive pattern of GBC.

3.
bioRxiv ; 2024 Apr 03.
Article in English | MEDLINE | ID: mdl-38617360

ABSTRACT

APOBEC enzymes are part of the innate immunity and are responsible for restricting viruses and retroelements by deaminating cytosine residues1,2. Most solid tumors harbor different levels of somatic mutations attributed to the off-target activities of APOBEC3A (A3A) and/or APOBEC3B (A3B)3-6. However, how APOBEC3A/B enzymes shape the tumor evolution in the presence of exogenous mutagenic processes is largely unknown. Here, by combining deep whole-genome sequencing with multi-omics profiling of 309 lung cancers from smokers with detailed tobacco smoking information, we identify two subtypes defined by low (LAS) and high (HAS) APOBEC mutagenesis. LAS are enriched for A3B-like mutagenesis and KRAS mutations, whereas HAS for A3A-like mutagenesis and TP53 mutations. Unlike APOBEC3A, APOBEC3B expression is strongly associated with an upregulation of the base excision repair pathway. Hypermutation by unrepaired A3A and tobacco smoking mutagenesis combined with TP53-induced genomic instability can trigger senescence7, apoptosis8, and cell regeneration9, as indicated by high expression of pulmonary healing signaling pathway, stemness markers and distal cell-of-origin in HAS. The expected association of tobacco smoking variables (e.g., time to first cigarette) with genomic/epigenomic changes are not observed in HAS, a plausible consequence of frequent cell senescence or apoptosis. HAS have more neoantigens, slower clonal expansion, and older age at onset compared to LAS, particularly in heavy smokers, consistent with high proportions of newly generated, unmutated cells and frequent immuno-editing. These findings show how heterogeneity in mutational burden across co-occurring mutational processes and cell types contributes to tumor development, with important clinical implications.

4.
J Hand Surg Am ; 49(3): 212-221, 2024 Mar.
Article in English | MEDLINE | ID: mdl-38069954

ABSTRACT

PURPOSE: Despite modern advancements in the treatment of late stages of wrist joint degeneration, few reliable options exist for patients requiring motion-preserving reconstruction of their radiocarpal and midcarpal joints. Vascularized composite allotransplantation (VCA) could be considered an option for wrist reconstruction in the future. The goal of this study was to describe the relevant anatomy and design a potential surgical technique for wrist VCA. METHODS: Anatomic studies were performed on 17 human upper extremities. The arterial system of each cadaver was injected with latex dye or radiographic contrast. After injecting a contrast medium visible on a computerized tomography (CT) scan, the initial three specimens were examined using microCT. This confirmed joint vascular patency and allowed for the dissection of the other specimens that were injected with latex for the study of joint vascularization and the design of the wrist VCA. We then outlined a donor and recipient surgical technique for transplant based on recipient CT scans. Customized cutting guides were designed for the transplant procedure. After the procedure, we performed angiography of the VCA to determine the vascularity of the transplant. RESULTS: Using a combined volar and dorsal approach, we were able to perform a complete wrist VCA procedure. After the completed transplant procedure, angiographic imaging of the specimens demonstrated that the flap dissection and transplantation preserved the nutrient endosteal supply to the distal end of the radius and ulna, as well as to the carpal bones and the metacarpal bases. CONCLUSIONS: The dissection of the donor, recipient, and the entire vascularized joint transplant procedure served to illustrate the anatomical feasibility of the cadaveric surgical technique. This establishes an anatomic basis for the possibility of future human clinical applications. CLINICAL RELEVANCE: This study helps investigate the anatomical feasibility of a wrist VCA.


Subject(s)
Latex , Vascularized Composite Allotransplantation , Humans , Feasibility Studies , Wrist Joint/surgery , Contrast Media , Cadaver
6.
Plast Reconstr Surg Glob Open ; 11(8): e5212, 2023 Aug.
Article in English | MEDLINE | ID: mdl-37593694

ABSTRACT

Free flap surgery for limb salvage has become the surgical standard for reconstruction of bone and soft tissue with success rates and flap survivals of 94%-95%. The soft tissue defect dictates the technique of coverage. In many cases, multiple techniques of soft tissue coverage are necessary, ranging from myocutaneous and fasciocutaneous free flaps to split-thickness skin grafts (STSGs). It has been shown that fasciocutaneous free flaps are not inferior to muscle flaps in treatment of lower leg limb salvage. Although a complete flap loss is rare, it is not uncommon to have partial flap necrosis, wound dehiscence, or secondary soft tissue defects, necessitating further minor reconstruction, which we call "touch up" skin grafts. In many of these secondary procedures, split thickness skin grafts are sufficient. We have been using the skin portion of the fasciocutaneous free flap as a donor site for harvesting STSGs for quite some time without disadvantages. We believe that minimizing additional donor site morbidity is of great importance. The free tissue transfer is insensate and readily available at the site of injury, making prepping and draping simple as well as cosmetically acceptable, as the transferred free tissue, unfortunately, is rarely a perfect fit. The associated pain, discomfort, and scar of an additional donor site can be avoided. In our case series, we did not experience any flap loss, infections, or complications. Thus, harvesting an STSG from a fasciocutaneous free flap seems to be a feasible option to be considered in limb salvage.

7.
Breast Cancer Res ; 25(1): 97, 2023 08 15.
Article in English | MEDLINE | ID: mdl-37582731

ABSTRACT

BACKGROUND: Emerging data indicate that variations in quantitative epithelial and stromal tissue composition and their relative abundance in benign breast biopsies independently impact risk of future invasive breast cancer. To gain further insights into breast cancer etiopathogenesis, we investigated associations between epidemiological factors and quantitative tissue composition metrics of the normal breast. METHODS: The study participants were 4108 healthy women ages 18-75 years who voluntarily donated breast tissue to the US-based Susan G. Komen Tissue Bank (KTB; 2008-2019). Using high-accuracy machine learning algorithms, we quantified the percentage of epithelial, stromal, adipose, and fibroglandular tissue, as well as the proportion of fibroglandular tissue that is epithelium relative to stroma (i.e., epithelium-to-stroma proportion, ESP) on digitized hematoxylin and eosin (H&E)-stained normal breast biopsy specimens. Data on epidemiological factors were obtained from participants using a detailed questionnaire administered at the time of tissue donation. Associations between epidemiological factors and square root transformed tissue metrics were investigated using multivariable linear regression models. RESULTS: With increasing age, the amount of stromal, epithelial, and fibroglandular tissue declined and adipose tissue increased, while that of ESP demonstrated a bimodal pattern. Several epidemiological factors were associated with individual tissue composition metrics, impacting ESP as a result. Compared with premenopausal women, postmenopausal women had lower ESP [ß (95% Confidence Interval (CI)) = -0.28 (- 0.43, - 0.13); P < 0.001] with ESP peaks at 30-40 years and 60-70 years among pre- and postmenopausal women, respectively. Pregnancy [ß (95%CI) vs nulligravid = 0.19 (0.08, 0.30); P < 0.001] and increasing number of live births (P-trend < 0.001) were positively associated with ESP, while breastfeeding was inversely associated with ESP [ß (95%CI) vs no breastfeeding = -0.15 (- 0.29, - 0.01); P = 0.036]. A positive family history of breast cancer (FHBC) [ß (95%CI) vs no FHBC = 0.14 (0.02-0.26); P = 0.02], being overweight or obese [ß (95%CI) vs normal weight = 0.18 (0.06-0.30); P = 0.004 and 0.32 (0.21-0.44); P < 0.001, respectively], and Black race [ß (95%CI) vs White = 0.12 (- 0.005, 0.25); P = 0.06] were positively associated with ESP. CONCLUSION: Our findings revealed that cumulative exposure to etiological factors over the lifespan impacts normal breast tissue composition metrics, individually or jointly, to alter their dynamic equilibrium, with potential implications for breast cancer susceptibility and tumor etiologic heterogeneity.


Subject(s)
Breast Neoplasms , Pregnancy , Female , Humans , Breast Neoplasms/epidemiology , Breast Neoplasms/etiology , Breast Neoplasms/pathology , Benchmarking , Risk Factors , Breast/pathology , Obesity/pathology , Life Style
8.
Ann Plast Surg ; 91(1): 109-116, 2023 07 01.
Article in English | MEDLINE | ID: mdl-37450869

ABSTRACT

BACKGROUND: Neuroma-induced neuropathic pain is associated with loss of function and reduced quality of life. No consistently effective standard-of-care treatment has been defined. Neurocap, a bioresorbable nerve capping device, has been designed to isolate the nerve stump from surrounding tissues to reduce development of symptomatic end-neuromas. METHODS: Patients with peripheral symptomatic end-neuromas were included in a prospective, multicenter, single-arm design. Data were collected presurgery up till 24 months postsurgery. Eligible patients with neuromas were identified based on blocks using anesthetic. Intervention included surgical excision and capping of the transected proximal nerve end with the Neurocap. Main outcome measures were pain, function, recurrence of symptomatic neuroma, use of analgesics, and adverse events. RESULTS: In total, 73 patients with 50 upper-extremity and 23 lower-extremity end-neuromas were enrolled. End-neuromas were predominately located in the digits and lower leg. Statistical power of the study outcomes was preserved by 46 of 73 patients completing 24-month follow-up. The mean VAS-Pain score at baseline was 70.2 ± 17.8 (scale 0-100) and decreased significantly to 31 ± 32.5 (P < 0.001). Function significantly improved over time. The recurrence rate of confirmed symptomatic neuroma was low (2 of 98 capped nerves). Adverse event rate was low and included pain and infection; there were no unexpected device-related adverse events. Most patients reported lower use of nonsteroidal anti-inflammatory drugs, opioids, and antineuropathic medications at last follow-up compared with baseline. CONCLUSIONS: End-neuroma treatment with excision and capping resulted in long-term significant reduction in reported pain, disability, and analgesic medication use. Adverse event rate was low.


Subject(s)
Neuralgia , Neuroma , Humans , Prospective Studies , Quality of Life , Absorbable Implants , Neuroma/surgery , Neuralgia/etiology , Neuralgia/surgery
9.
J Glaucoma ; 32(10): 815-819, 2023 10 01.
Article in English | MEDLINE | ID: mdl-37523638

ABSTRACT

PRCIS: Physicians were most likely to recommend primary medical therapy upon diagnosis of glaucoma. Laser therapy was underutilized where they were available. Physicians were more likely to recommend surgery in severe glaucoma, laser therapy in mild glaucoma, while recommendation of medical therapy did not depend on glaucoma severity. PURPOSE: To characterize treatment patterns for newly diagnosed glaucoma in sub-Saharan Africa (SSA). METHODS: This was a multicenter cross-sectional study of adults newly diagnosed with glaucoma at 27 eye care centers in 10 African countries. In addition to demographic and clinical data, physician treatment recommendations (medication, laser, surgery, or no treatment) were recorded. Statistical analyses were performed using STATA version 14.0. RESULTS: Data from 1201 patients were analyzed. Physicians were most likely to recommend primary medical therapy upon diagnosis of glaucoma (69.4%), with laser (13.2%), surgery (14.9%), and no treatment (2.5%) recommended to the remaining patients. All sites had medical therapy available and most (25/27, 92.6%) could provide surgical treatment; only 16/27 (59.3%) sites offered laser, and at these sites, 30.8% of eyes were recommended to undergo primary laser procedures. As glaucoma severity increased, the laser was recommended less, surgery more, and medications unchanged. Patient acceptance of medical therapy was 99.1%, laser 88.3%, and surgery 69.3%. CONCLUSIONS: Medical therapy for first-line glaucoma management is preferred by most physicians in SSA (69%). Laser therapy may be underutilized at centers where it is available. These findings underscore the need for comparative studies of glaucoma treatments in SSA to inform the development of evidence-based treatment guidelines and of programs to reduce glaucoma blindness in SSA. Strategic approaches to glaucoma therapy in SSA must address the question of whether medical therapy is the most optimal first-line approach in this setting.


Subject(s)
Glaucoma , Laser Therapy , Adult , Humans , Intraocular Pressure , Cross-Sectional Studies , Glaucoma/therapy , Glaucoma/surgery , Africa South of the Sahara/epidemiology
10.
Cancer Prev Res (Phila) ; 16(10): 561-570, 2023 10 02.
Article in English | MEDLINE | ID: mdl-37477495

ABSTRACT

FGFR3 and PIK3CA are among the most frequently mutated genes in bladder tumors. We hypothesized that recurrent mutations in these genes might be caused by common carcinogenic exposures such as smoking and other factors. We analyzed 2,816 bladder tumors with available data on FGFR3 and/or PIK3CA mutations, focusing on the most recurrent mutations detected in ≥10% of tumors. Compared to tumors with other FGFR3/PIK3CA mutations, FGFR3-Y375C was more common in tumors from smokers than never-smokers (P = 0.009), while several APOBEC-type driver mutations were enriched in never-smokers: FGFR3-S249C (P = 0.013) and PIK3CA-E542K/PIK3CA-E545K (P = 0.009). To explore possible causes of these APOBEC-type mutations, we analyzed RNA sequencing (RNA-seq) data from 798 bladder tumors and detected several viruses, with BK polyomavirus (BKPyV) being the most common. We then performed IHC staining for polyomavirus (PyV) Large T-antigen (LTAg) in an independent set of 211 bladder tumors. Overall, by RNA-seq or IHC-LTAg, we detected PyV in 26 out of 1,010 bladder tumors with significantly higher detection (P = 4.4 × 10-5), 25 of 554 (4.5%) in non-muscle-invasive bladder cancers (NMIBC) versus 1 of 456 (0.2%) of muscle-invasive bladder cancers (MIBC). In the NMIBC subset, the FGFR3/PIK3CA APOBEC-type driver mutations were detected in 94.7% (18/19) of PyV-positive versus 68.3% (259/379) of PyV-negative tumors (P = 0.011). BKPyV tumor positivity in the NMIBC subset with FGFR3- or PIK3CA-mutated tumors was also associated with a higher risk of progression to MIBC (P = 0.019). In conclusion, our results support smoking and BKPyV infection as risk factors contributing to bladder tumorigenesis in the general patient population through distinct molecular mechanisms. PREVENTION RELEVANCE: Tobacco smoking likely causes one of the most common mutations in bladder tumors (FGFR3-Y375C), while viral infections might contribute to three others (FGFR3-S249C, PIK3CA-E542K, and PIK3CA-E545K). Understanding the causes of these mutations may lead to new prevention and treatment strategies, such as viral screening and vaccination.


Subject(s)
Urinary Bladder Neoplasms , Virus Diseases , Humans , Urinary Bladder Neoplasms/genetics , Urinary Bladder Neoplasms/pathology , Mutation , Urinary Bladder/pathology , Class I Phosphatidylinositol 3-Kinases/genetics
11.
Res Sq ; 2023 Apr 14.
Article in English | MEDLINE | ID: mdl-37090574

ABSTRACT

Background: Emerging data suggest that beyond the neoplastic parenchyma, the stromal microenvironment (SME) impacts tumor biology, including aggressiveness, metastatic potential, and response to treatment. However, the epidemiological determinants of SME biology remain poorly understood, more so among women of African ancestry who are disproportionately affected by aggressive breast cancer phenotypes. Methods: Within the Ghana Breast Health Study, a population-based case-control study in Ghana, we applied high-accuracy machine-learning algorithms to characterize biologically-relevant SME phenotypes, including tumor-stroma ratio (TSR (%); a metric of connective tissue stroma to tumor ratio) and tumor-associated stromal cellular density (Ta-SCD (%); a tissue biomarker that is reminiscent of chronic inflammation and wound repair response in breast cancer), on digitized H&E-stained sections from 792 breast cancer patients aged 17-84 years. Kruskal-Wallis tests and multivariable linear regression models were used to test associations between established breast cancer risk factors, tumor characteristics, and SME phenotypes. Results: Decreasing TSR and increasing Ta-SCD were strongly associated with aggressive, mostly high grade tumors (p-value < 0.001). Several etiologic factors were associated with Ta-SCD, but not TSR. Compared with nulliparous women [mean (standard deviation) = 28.9% (7.1%)], parous women [mean (standard deviation) = 31.3% (7.6%)] had statistically significantly higher levels of Ta-SCD (p-value = 0.01). Similarly, women with a positive family history of breast cancer [FHBC; mean (standard deviation) = 33.0% (7.5%)] had higher levels of Ta-SCD than those with no FHBC [mean (standard deviation) = 30.9% (7.6%); p-value = 0.01]. Conversely, increasing body size was associated with decreasing Ta-SCD [mean (standard deviation) = 32.0% (7.4%), 31.3% (7.3%), and 29.0% (8.0%) for slight, moderate, and large body sizes, respectively, p-value = 0.005]. These associations persisted and remained statistically significantly associated with Ta-SCD in mutually-adjusted multivariable linear regression models (p-value < 0.05). With the exception of body size, which was differentially associated with Ta-SCD by grade levels (p-heterogeneity = 0.04), associations between risk factors and Ta-SCD were not modified by tumor characteristics. Conclusions: Our findings raise the possibility that epidemiological factors may act via the SME to impact both risk and biology of breast cancers in this population, underscoring the need for more population-based research into the role of SME in multi-state breast carcinogenesis.

12.
Breast Cancer Res ; 24(1): 86, 2022 12 05.
Article in English | MEDLINE | ID: mdl-36471360

ABSTRACT

BACKGROUND: Terminal duct lobular units (TDLUs) are the structures in the breast that give rise to most breast cancers. Previous work has shown that TDLU involution is inversely associated with TDLU metrics, such as TDLU count/100mm2, TDLU span (µm), and number of acini/TDLU, and that these metrics may be elevated in the normal breast tissue of women diagnosed with triple-negative (TN) compared with luminal A breast tumors. It is unknown whether this relationship exists in Black women, who have the highest incidence of TN breast cancer and the highest overall breast cancer mortality rate. We examined relationships between TDLU metrics and breast cancer molecular subtype among breast cancer cases in the Black Women's Health Study (BWHS). METHODS: We assessed quantitative TDLU metrics (TDLU count/100mm2, TDLU span (µm), and number of acini/TDLU) in digitized 247 hematoxylin and eosin-stained adjacent normal tissue sections from 223 BWHS breast cancer cases, including 65 triple negative (TN) cancers (estrogen receptor (ER) negative, progesterone receptor (PR) negative, human epidermal growth factor-2 (HER2) negative) and 158 luminal A cancers (ER positive, HER2 negative). We evaluated associations of least square mean TDLU metrics adjusted for age and body mass index (BMI) with patient and clinical characteristics. In logistic regression models, we evaluated associations between TDLU metrics and breast cancer subtype, adjusting for age, BMI, and tumor size. RESULTS: Older age and higher BMI were associated with lower TDLU metrics and larger tumor size and lymph node invasion with higher TDLU metrics. The odds of TN compared with luminal A breast cancer increased with increasing tertiles of TDLU metrics, with odds ratios (95% confidence intervals) for tertile 3 versus tertile 1 of 2.18 (0.99, 4.79), 2.77 (1.07, 7.16), and 1.77 (0.79, 3.98) for TDLU count, TDLU span, and acini count/TDLU, respectively. CONCLUSION: Associations of TDLU metrics with breast cancer subtypes in the BWHS are consistent with previous studies of White and Asian women, demonstrating reduced TDLU involution in TN compared with luminal A breast cancers. Further investigation is needed to understand the factors that influence TDLU involution and the mechanisms that mediate TDLU involution and breast cancer subtype.


Subject(s)
Breast Neoplasms , Mammary Glands, Human , Triple Negative Breast Neoplasms , Female , Humans , Breast Neoplasms/pathology , Mammary Glands, Human/pathology , Receptor, ErbB-2 , Receptors, Progesterone , Risk Factors , Triple Negative Breast Neoplasms/epidemiology , Triple Negative Breast Neoplasms/pathology , Women's Health
13.
J Glaucoma ; 31(9): 717-723, 2022 09 01.
Article in English | MEDLINE | ID: mdl-35758429

ABSTRACT

PRCIS: The initial presentation of glaucoma varies meaningfully across SSA. A comprehensive strategy with regional customization based on local differences is needed to reduce glaucoma blindness in SSA. PURPOSE: To explore regional variations in the presentation of newly diagnosed glaucoma in Sub Saharan Africa (SSA). METHODOLOGY: This was a multicenter, cross-sectional study in which newly diagnosed, consecutive, glaucoma patients aged older than or equal to 18 years were recruited from 27 eye clinics in 10 countries throughout SSA. Demographic and ophthalmic examination data were collected. Glaucoma severity was based on optic nerve head and visual field assessment. Statistical analyses were performed using STATA version 14.0. RESULTS: Among 1214 enrolled patients with newly diagnosed glaucoma from Western, Eastern, and Southern Africa, the overall mean (SD) age was 59.9 (17.1) years. More than half of all patients (716/1178; 60.8%) presented with severe glaucoma in the worse eye, and one-third (36.9%) had severe glaucoma in both eyes. Primary open angle glaucoma was the commonest form of glaucoma in all regions (77.4%). A family history of blindness (260/1204, 21.6%) was common. Patients from Western Africa had lower mean presenting intraocular pressure (26.4 [11.1] mm Hg, P <0.001), but had worse glaucoma in the better eye based on mean cup-disc ratio (0.8; P <0.001) and mean visual field mean deviation [10.4 (8.4)] dB, P =0.016) compared with other regions. Exfoliation glaucoma was more common in Eastern Africa (30/170=17.7%, P <0.001) compared with other regions. CONCLUSION: The initial presentation of glaucoma varies meaningfully across SSA. A comprehensive strategy with regional customization based on local differences is needed to reduce glaucoma blindness in SSA.


Subject(s)
Glaucoma, Open-Angle , Glaucoma , Aged , Blindness/diagnosis , Blindness/epidemiology , Blindness/etiology , Cross-Sectional Studies , Glaucoma/complications , Glaucoma/diagnosis , Glaucoma, Open-Angle/complications , Glaucoma, Open-Angle/diagnosis , Humans , Intraocular Pressure , Middle Aged
14.
PLoS Pathog ; 18(6): e1010507, 2022 06.
Article in English | MEDLINE | ID: mdl-35714165

ABSTRACT

The HIV/SIV envelope glycoprotein (Env) cytoplasmic domain contains a highly conserved Tyr-based trafficking signal that mediates both clathrin-dependent endocytosis and polarized sorting. Despite extensive analysis, the role of these functions in viral infection and pathogenesis is unclear. An SIV molecular clone (SIVmac239) in which this signal is inactivated by deletion of Gly-720 and Tyr-721 (SIVmac239ΔGY), replicates acutely to high levels in pigtail macaques (PTM) but is rapidly controlled. However, we previously reported that rhesus macaques and PTM can progress to AIDS following SIVmac239ΔGY infection in association with novel amino acid changes in the Env cytoplasmic domain. These included an R722G flanking the ΔGY deletion and a nine nucleotide deletion encoding amino acids 734-736 (ΔQTH) that overlaps the rev and tat open reading frames. We show that molecular clones containing these mutations reconstitute signals for both endocytosis and polarized sorting. In one PTM, a novel genotype was selected that generated a new signal for polarized sorting but not endocytosis. This genotype, together with the ΔGY mutation, was conserved in association with high viral loads for several months when introduced into naïve PTMs. For the first time, our findings reveal strong selection pressure for Env endocytosis and particularly for polarized sorting during pathogenic SIV infection in vivo.


Subject(s)
Simian Acquired Immunodeficiency Syndrome , Simian Immunodeficiency Virus , Animals , Endocytosis , Gene Products, env/genetics , Macaca mulatta/metabolism , Macaca nemestrina , Simian Acquired Immunodeficiency Syndrome/genetics , Simian Acquired Immunodeficiency Syndrome/pathology , Simian Immunodeficiency Virus/genetics , Simian Immunodeficiency Virus/metabolism
15.
J Natl Compr Canc Netw ; 20(13)2022 01 06.
Article in English | MEDLINE | ID: mdl-34991065

ABSTRACT

The NCCN Best Practices Committee, which is composed of senior physician, nursing, and administrative leaders from NCCN Member Institutions, evaluated the status of cancer center operations after 1 year of operating during the COVID-19 pandemic. Two major initiatives stood out: the increase in the utilization of network sites, and the gains made in telemedicine operations and reimbursement. Experts from NCCN Member Institutions participated in a webinar series in June 2021 to share their experiences, knowledge, and thoughts on these topics and discuss the impact on the future of cancer care.


Subject(s)
COVID-19 , Neoplasms , Physicians , Humans , COVID-19/epidemiology , Pandemics/prevention & control , Neoplasms/epidemiology , Neoplasms/therapy
16.
J Pathol Clin Res ; 8(1): 88-98, 2022 01.
Article in English | MEDLINE | ID: mdl-34618413

ABSTRACT

The tumor microenvironment (TME), including immune cells, cancer-associated fibroblasts, endothelial cells, adjacent normal cells, and others, plays a crucial role in influencing tumor behavior and progression. Here, we characterized the TME in 83 primary renal tumors and matched metastatic or recurrence tissue samples (n = 15) from papillary renal cell carcinoma (pRCC) types 1 (n = 20) and 2 (n = 49), collecting duct carcinomas (CDC; n = 14), and high-grade urothelial carcinomas (HGUC; n = 5). We investigated 10 different markers of immune infiltration, vasculature, cell proliferation, and epithelial-to-mesenchymal transition by using machine learning image analysis in conjunction with immunohistochemistry. Marker expression was compared by Mann-Whitney and Kruskal-Wallis tests and correlations across markers using Spearman's rank correlation coefficient. Multivariable Poisson regression analysis was used to compare marker expression between histological types, while accounting for variation in tissue size. Several immune markers showed different rates of expression across histological types of renal carcinoma. Using pRCC1 as reference, the incidence rate ratio (IRR) of CD3+ T cells (IRR [95% confidence interval, CI] = 2.48 [1.53-4.01]) and CD20+ B cells (IRR [95% CI] = 4.38 [1.22-5.58]) was statistically significantly higher in CDC. In contrast, CD68+ macrophages predominated in pRCC1 (IRR [95% CI] = 2.35 [1.42-3.9]). Spatial analysis revealed CD3+ T-cell and CD20+ B-cell expressions in CDC to be higher at the proximal (p < 0.0001) and distal (p < 0.0001) tumor periphery than within the central tumor core. In contrast, expression of CD68+ macrophages in pRCC2 was higher in the tumor center compared to the proximal (p = 0.0451) tumor periphery and pRCC1 showed a distance-dependent reduction, from the central tumor, in CD68+ macrophages with the lowest expression of CD68 marker at the distal tumor periphery (p = 0.004). This study provides novel insights into the TME of rare kidney cancer types, which are often understudied. Our findings of differences in marker expression and localization by histological subtype could have implications for tumor progression and response to immunotherapies or other targeted therapies.


Subject(s)
Carcinoma, Renal Cell , Kidney Neoplasms , Biomarkers, Tumor/metabolism , Carcinoma, Renal Cell/pathology , Endothelial Cells/metabolism , Humans , Kidney Neoplasms/pathology , Tumor Microenvironment
17.
Nat Genet ; 53(9): 1348-1359, 2021 09.
Article in English | MEDLINE | ID: mdl-34493867

ABSTRACT

Lung cancer in never smokers (LCINS) is a common cause of cancer mortality but its genomic landscape is poorly characterized. Here high-coverage whole-genome sequencing of 232 LCINS showed 3 subtypes defined by copy number aberrations. The dominant subtype (piano), which is rare in lung cancer in smokers, features somatic UBA1 mutations, germline AR variants and stem cell-like properties, including low mutational burden, high intratumor heterogeneity, long telomeres, frequent KRAS mutations and slow growth, as suggested by the occurrence of cancer drivers' progenitor cells many years before tumor diagnosis. The other subtypes are characterized by specific amplifications and EGFR mutations (mezzo-forte) and whole-genome doubling (forte). No strong tobacco smoking signatures were detected, even in cases with exposure to secondhand tobacco smoke. Genes within the receptor tyrosine kinase-Ras pathway had distinct impacts on survival; five genomic alterations independently doubled mortality. These findings create avenues for personalized treatment in LCINS.


Subject(s)
DNA Copy Number Variations/genetics , Lung Neoplasms/genetics , Lung Neoplasms/pathology , Non-Smokers/statistics & numerical data , Adult , Aged , Aged, 80 and over , ErbB Receptors/genetics , Female , Genome/genetics , Genome-Wide Association Study , Humans , Male , Middle Aged , Neoplastic Stem Cells/pathology , Proto-Oncogene Proteins p21(ras)/genetics , Receptors, Androgen/genetics , Risk Factors , Smoking/genetics , Ubiquitin-Activating Enzymes/genetics , Whole Genome Sequencing , Young Adult
18.
Cancer Epidemiol Biomarkers Prev ; 30(7): 1397-1407, 2021 07.
Article in English | MEDLINE | ID: mdl-33952648

ABSTRACT

PURPOSE: Tumor-associated stroma is comprised of fibroblasts, tumor-infiltrating lymphocytes (TIL), macrophages, endothelial cells, and other cells that interactively influence tumor progression through inflammation and wound repair. Although gene-expression signatures reflecting wound repair predict breast cancer survival, it is unclear whether combined density of tumor-associated stromal cells, a morphologic proxy for inflammation and wound repair signatures on routine hematoxylin and eosin (H&E)-stained sections, is of prognostic relevance. METHODS: By applying machine learning to digitized H&E-stained sections for 2,084 breast cancer patients from China (n = 596; 24-55 years), Poland (n = 810; 31-75 years), and the United States (n = 678; 55-78 years), we characterized tumor-associated stromal cellular density (SCD) as the percentage of tumor-stroma that is occupied by nucleated cells. Hazard ratios (HR) and 95% confidence intervals (CI) for associations between SCD and clinical outcomes [recurrence (China) and mortality (Poland and the United States)] were estimated using Cox proportional hazard regression, adjusted for clinical variables. RESULTS: SCD was independently predictive of poor clinical outcomes in hormone receptor-positive (luminal) tumors from China [multivariable HR (95% CI)fourth(Q4) vs. first(Q1) quartile = 1.86 (1.06-3.26); P trend = 0.03], Poland [HR (95% CI)Q4 vs. Q1 = 1.80 (1.12-2.89); P trend = 0.01], and the United States [HR (95% CI)Q4 vs. Q1 = 2.42 (1.33-4.42); P trend = 0.002]. In general, SCD provided more prognostic information than most classic clinicopathologic factors, including grade, size, PR, HER2, IHC4, and TILs, predicting clinical outcomes irrespective of menopausal or lymph nodal status. SCD was not predictive of outcomes in hormone receptor-negative tumors. CONCLUSIONS: Our findings support the independent prognostic value of tumor-associated SCD among ethnically diverse luminal breast cancer patients. IMPACT: Assessment of tumor-associated SCD on standard H&E could help refine prognostic assessment and therapeutic decision making in luminal breast cancer.


Subject(s)
Breast Neoplasms/mortality , Breast/pathology , Neoplasm Recurrence, Local/epidemiology , Adult , Aged , Breast/cytology , Breast Neoplasms/pathology , Breast Neoplasms/therapy , Cell Count , China/epidemiology , Disease-Free Survival , Endothelial Cells , Female , Fibroblasts , Humans , Lymphocytes, Tumor-Infiltrating , Middle Aged , Neoplasm Recurrence, Local/pathology , Poland/epidemiology , Prognosis , Risk Assessment/methods , United States/epidemiology , Young Adult
19.
JNCI Cancer Spectr ; 5(3)2021 06.
Article in English | MEDLINE | ID: mdl-33981950

ABSTRACT

Background: Benign breast disease (BBD) is a strong breast cancer risk factor, but identifying patients that might develop invasive breast cancer remains a challenge. Methods: By applying machine-learning to digitized hematoxylin and eosin-stained biopsies and computer-assisted thresholding to mammograms obtained circa BBD diagnosis, we generated quantitative tissue composition metrics and determined their association with future invasive breast cancer diagnosis. Archival breast biopsies and mammograms were obtained for women (18-86 years of age) in a case-control study, nested within a cohort of 15 395 BBD patients from Kaiser Permanente Northwest (1970-2012), followed through mid-2015. Patients who developed incident invasive breast cancer (ie, cases; n = 514) and those who did not (ie, controls; n = 514) were matched on BBD diagnosis age and plan membership duration. All statistical tests were 2-sided. Results: Increasing epithelial area on the BBD biopsy was associated with increasing breast cancer risk (odds ratio [OR]Q4 vs Q1 = 1.85, 95% confidence interval [CI] = 1.13 to 3.04; P trend = .02). Conversely, increasing stroma was associated with decreased risk in nonproliferative, but not proliferative, BBD (P heterogeneity = .002). Increasing epithelium-to-stroma proportion (ORQ4 vs Q1 = 2.06, 95% CI =1.28 to 3.33; P trend = .002) and percent mammographic density (MBD) (ORQ4 vs Q1 = 2.20, 95% CI = 1.20 to 4.03; P trend = .01) were independently and strongly predictive of increased breast cancer risk. In combination, women with high epithelium-to-stroma proportion and high MBD had substantially higher risk than those with low epithelium-to-stroma proportion and low MBD (OR = 2.27, 95% CI = 1.27 to 4.06; P trend = .005), particularly among women with nonproliferative (P trend = .01) vs proliferative (P trend = .33) BBD. Conclusion: Among BBD patients, increasing epithelium-to-stroma proportion on BBD biopsies and percent MBD at BBD diagnosis were independently and jointly associated with increasing breast cancer risk. These findings were particularly striking for women with nonproliferative disease (comprising approximately 70% of all BBD patients), for whom relevant predictive biomarkers are lacking.


Subject(s)
Breast Diseases/diagnostic imaging , Breast Diseases/pathology , Breast Neoplasms/etiology , Breast/diagnostic imaging , Breast/pathology , Diagnosis, Computer-Assisted , Supervised Machine Learning , Adult , Age Factors , Aged , Aged, 80 and over , Biopsy/methods , Breast Density , Case-Control Studies , Confidence Intervals , Female , Humans , Mammography/methods , Middle Aged , Odds Ratio , Risk Factors , Young Adult
20.
Molecules ; 26(7)2021 Mar 24.
Article in English | MEDLINE | ID: mdl-33804938

ABSTRACT

Phytophthora is a genus of microorganisms that cause devastating dieback and root-rot diseases in thousands of plant hosts worldwide. The economic impact of Phytophthora diseases on crops and native ecosystems is estimated to be billions of dollars per annum. These invasive pathogens are extremely difficult to control using existing chemical means, and the effectiveness of the few treatments available is being jeopardized by increasing rates of resistance. There is an urgent need to identify new chemical treatments that are effective against Phytophthora diseases. Natural products have long been regarded as "Nature's medicine chest", providing invaluable leads for developing front-line drugs and agrochemical agents. Here, we have screened a natural product-inspired library of 328 chemicals against two key Phytophthora species: Phytophthora cinnamomi and Phytophthora agathidicida. The library was initially screened for inhibition of zoospore germination. From these screens, we identified twenty-one hits that inhibited germination of one or both species. These hits were further tested in mycelial growth inhibition studies to determine their half-maximal inhibitory concentrations (IC50s). Four compounds had IC50 values of approximately 10 µM or less, and our best hit had IC50s of approximately 3 µM against both Phytophthora species tested. Overall, these hits may serve as promising leads for the development of new anti-Phytophthora agrochemicals.


Subject(s)
Antifungal Agents , Biological Products , Phytophthora/growth & development , Plant Diseases/microbiology , Small Molecule Libraries , Antifungal Agents/chemistry , Antifungal Agents/pharmacology , Biological Products/chemistry , Biological Products/pharmacology , Mycelium/growth & development
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