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Computational portraits of the tumoral microenvironment in human breast cancer

Wu, Dongling; Hacking, Sean M; Chavarria, Hector; Abdelwahed, Mohammed; Nasim, Mansoor
Breast cancer is the most diagnosed cancer in humans. In recent years, myxoid and proportionated stroma have been described as clinically significant in many cancer subtypes. Here computational portraits of tumor-associated stromata were created from a machine learning (ML) classifier using QuPath to evaluate proportionated stromal area (PSA), myxoid stromal ratio (MSR), and immune stroma proportion (ISP) from whole slide images (WSI). The ML classifier was validated in independent training (n = 40) and validation (n = 109) cohorts finding MSR, PSA, and ISP to be associated with tumor stage, lymph node status, Nottingham grade, stromal differentiation (SD), tumor size, estrogen receptor (ER), progesterone receptor (PR), and receptor tyrosine-protein kinase erbB-2 (HER-2). Overall, MSR correlated better with the clinicopathologic profile than PSA and ISP. High MSR was found to be associated with high tumor stage, low ISP, and high Nottingham histologic score. As a computational biomarker, high MSR was more likely to be associated with luminal B like, Her-2 enriched, and triple-negative biomarker status when compared to luminal A like. The supervised ML superpixel approach demonstrated here can be performed by a trained pathologist to provide a faster and more uniformed approach to the analysis to the tumoral microenvironment (TME). The TME may be relevant for clinical decision-making, determining chemotherapeutic efficacy, and guiding a more overall precision-based breast cancer care.
PMID: 35821350
ISSN: 1432-2307
CID: 5516032

Contemporary surgical management of skull base chordomas-Anatomical reflections on a single center experience retrospective case series

Spiessberger, Alexander; Dogra, Siddhant; Golub, Danielle; Grueter, Basil; Nasim, Mansoor; Schneider, Steven; Moriggl, Bernhard; Dehdashti, Amir R; Schulder, Michael
Chordoma, a rare, locally aggressive tumor can affect the central skull base, usually centered at the midline. Complete surgical resection remains mainstay of therapy in case of primary as well as recurrent tumors. Owing to their secluded location, surgical resection of skull base chordomas remains a challenge, even though the recent advancement of endoscopic endonasal approaches has had a significant positive impact on the management of these patients. Endoscopic endonasal approaches have been shown to significantly reduce surgical morbidity when compared to traditional open approaches; however, the classical endoscopic transclival midline approach fails to sufficiently expose parts of many skull base chordomas. More recent refinements of the technique, such as the interdural pituitary transposition and posterior clinoidectomy, the transpterygoid plate approach and the transcondylar far medial approach enable the surgeon the increase the resection rate in these patients. This retrospective case series focuses on anatomical aspects in the surgical management of patients with skull base chordomas. We outline the surgical anatomy of contemporary endoscopic approaches to the skull base based intraoperative illustrations as well as pre- and postoperative 3D reconstructed CT and MR images if our patients. This article should help the clinical choose the most appropriate approach and be aware of relevant anatomy as well as potential shortcomings of a given approach.
PMID: 35088437
ISSN: 1098-2353
CID: 5264002

Nature and Significance of Stromal Differentiation, PD-L1, and VISTA in GIST

Hacking, Sean; Wu, Dongling; Lee, Lili; Vitkovski, Taisia; Nasim, Mansoor
The role of stromal differentiation (SD), program death-ligand 1 (PD-L1), and v-domain Ig suppressor of T cell activation (VISTA) in gastrointestinal stromal tumor (GIST) is largely unknown. Looking forward, the assessment of SD and immune check point inhibition will become more ubiquitous in surgical pathology. Immature, myxoid stroma has been found to be a poor prognostic signature in many cancer subtypes (colon, breast, cervix, esophagus, stomach); although little is known regarding its significance in GIST. For immune check-point inhibition, studies have demonstrated expression to be associated with patient outcomes in numerous cancer subtypes. The present body of work aims to evaluate SD, PD-L1 and VISTA; both in terms of its nature and significance in a clinical setting. Here we found PD-L1 expression in immune cells (IC) and immature SD to be associated with worse cancer free survival, while positive VISTA expression was found to be associated with improved outcomes. High-grade, immature SD had the highest propensity for death/recurrence and was the only variable found to have prognostic significance on multivariate analysis. Our findings support the evaluation of SD, PD-L1 and VISTA in GIST, with clinical practice implications for pathologists. Ultimately, we hope our findings lead to improved prognostication, further optimization of therapeutics, and improved outcomes in a true clinical environment. For GIST, PD-L1 and VISTA could be both clinically relevant and targetable, while SD may be the answer to clinical heterogeneity.
PMID: 34929600
ISSN: 1618-0631
CID: 5263982

A Novel Superpixel Approach to the Tumoral Microenvironment in Colorectal Cancer

Hacking, Sean M; Wu, Dongling; Alexis, Claudine; Nasim, Mansoor
Colorectal cancer (CRC) is the most common malignancy of the gastrointestinal tract. The stroma and the tumoral microenvironment (TME) represent ecosystem-like biological networks and are new frontiers in CRC. The present study demonstrates the use of a novel machine learning-based superpixel approach for whole slide images to unravel this biology. Findings of significance include the association of low proportionated stromal area, high immature stromal percentage, and high myxoid stromal ratio (MSR) with worse prognostic outcomes in CRC. Overall, stromal computational markers outperformed all others at predicting clinical outcomes. MSR may be able to prognosticate patients independent of pathological stage, representing an optimal way to effectively prognosticate CRC patients which circumvents the need for more extensive molecular and/or computational profiling. The superpixel approaches to the TME demonstrated here can be performed by a trained pathologist and recorded during synoptic cancer reporting with appropriate quality assurance. Future clinical trials will have the ultimate say in determining whether we can better tailor the need for adjuvant therapy in patients with CRC.
PMID: 35223135
ISSN: 2229-5089
CID: 5264012

Primary extradural tumors of the spinal column: A comprehensive treatment guide for the spine surgeon based on the 5th Edition of the World Health Organization bone and soft-tissue tumor classification

Arvind, Varun; Nevzati, Edin; Ghaly, Maged; Nasim, Mansoor; Farshad, Mazda; Guggenberger, Roman; Sciubba, Daniel; Spiessberger, Alexander
BACKGROUND:version of the soft tissue and bone tumor classification. Based on this novel classification system, we reviewed the current knowledge on all tumor entities with spinal manifestations, their biologic behavior, and most importantly the appropriate treatment options as well as surgical approaches. METHODS:Edition). PubMed and Google Scholar were searched for the published cases of spinal tumor manifestations for each entity, and the following characteristics were extracted: Growth pattern, ability to metastasize, peak age, incidence, treatment, type of surgical resection indicated, recurrence rate, risk factors, 5-year survival rate, key molecular or genetic alterations, and possible associated tumor syndromes. Surgical treatment strategies as well as nonsurgical treatment recommendations are presented based on the biologic behavior of each lesion. RESULTS:Out of 163 primary tumor entities of bone and soft tissue, 92 lesions have been reported along the spinal axis. Of these 92 entities, 54 have the potential to metastasize. The peak age ranges from conatal lesions to 72 years. For each tumor entity, we present recommended surgical treatment strategies based on the ability to locally destruct tissue, to grow, recur after resection, undergo malignant transformation as well as survival rates. In addition, potential systemic treatment recommendations for each tumor entity are outlined. CONCLUSION/CONCLUSIONS:Edition of the WHO bone and soft tumor classification, we identified 92 out of 163 tumor entities, which potentially can have spinal manifestations. Exact preoperative tissue diagnosis and interdisciplinary case discussions are crucial. Surgical resection is indicated in a significant subset of patients and has to be tailored to the specific biologic behavior of the targeted tumor entity based on the considerations outlined in detail in this article.
PMID: 35068816
ISSN: 0974-8237
CID: 5263992

Superpixel image segmentation of VISTA expression in colorectal cancer and its relationship to the tumoral microenvironment

Wu, Dongling; Hacking, Sean; Vitkovski, Taisia; Nasim, Mansoor
Colorectal cancer (CRC) is the third most common cause of cancer related death in the United States (Jasperson et al. in Gastroenterology 138:2044-2058, , 2010). Many studies have explored prognostic factors in CRC. Today, much focus has been placed on the tumor microenvironment, including different immune cells and the extracellular matrix (ECM). The present study aims to evaluate the role of V-domain immunoglobulin suppressor of T cell activation (VISTA). We utilized QuPath for whole slides image analysis, performing superpixel image segmentation (SIS) on a 226 patient-cohort. High VISTA expression correlated with better disease-free survival (DFS), high tumor infiltrative lymphocyte, microsatellite instability, BRAF mutational status as well as lower tumor stage. High VISTA expression was also associated with mature stromal differentiation (SD). When cohorts were separated based on SD and MMR, only patients with immature SD and microsatellite stability were found to correlate VISTA expression with DFS. Considering raised VISTA expression is associated with improved survival, TILs, mature SD, and MMR in CRC; careful, well-designed clinical trials should be pursued which incorporate the underlying tumoral microenvironment.
PMID: 34465822
ISSN: 2045-2322
CID: 5263962

GATA binding protein 3 (GATA3) as a marker for metaplastic spindle cell carcinoma of the breast

Jin, Cao; Hacking, Sean; Sajjan, Sujata; Kamanda, Sonia; Bhuiya, Tawfiqul; Nasim, Mansoor
Spindle cell lesions of the breast comprise a diverse set of tumors; harboring significant histological and immunohistochemical (IHC) overlap. Accurate diagnosis and classification of spindle cell lesions in the breast remains challenging, especially in core biopsies. In the current study, we evaluated a spectrum of spindle cell lesion of the breast with a panel of IHC antibodies in an effort to differentiate metaplastic spindle cell carcinoma from its benign and malignant mimickers. Our study included 92 patients who underwent breast core biopsies or breast resections at Northwell Health who were diagnosed with benign and malignant tumor/tumor-like spindle cell lesions. Tumors subtypes in this the study included: angiosarcoma, nodular fasciitis, fibromatosis, myofibroblastoma, phyllodes tumors (benign, borderline and malignant), primary sarcomas and metaplastic spindle cell carcinoma. Our biomarker panel included high molecular weight keratin (HMWK), CAM5.2, AE1/AE3, p63, CD34 and GATA3. GATA3 expression was significantly higher in metaplastic carcinomas (88.9 % vs 4.1 %, p < 0.001), when compared to other spindle cell lesions. The sensitivity and specificity for detecting metaplastic carcinomas reached 84.2 % and 97.3 %, respectively. Regarding cytokeratin panels, none of the three individual markers were as sensitive or specific for metaplastic breast carcinoma. GATA3 is the most specific and sensitive marker forfor the identification of metaplastic spindle cell carcinoma of the breast.
PMID: 33770555
ISSN: 1618-0631
CID: 5263932

Spondylectomy in the treatment of neoplastic spinal lesions - A retrospective outcome analysis of 582 patients using a patient-level meta-analysis

Spiessberger, Alexander; Dietz, Nicholas; Arvind, Varun; Nasim, Mansoor; Gruter, Basil; Nevzati, Edin; Hofer, Silvia; Cho, Samuel K
This study aims at identifying predictors of postoperative complications, lesion recurrence, and overall survival in patients undergoing en bloc spondylectomy (EBS) for spinal tumors. For this purpose a systematic review of the literature was conducted and patient-level data extracted. Linear-regression models were calculated to predict postoperative complications, lesion recurrence and overall survival based on age, tumor etiology, surgical approach, mode of resection (extra- vs. intralesional), tumor extension, and number of levels treated. A total of 582 patients were identified from the literature: 45% of females, median age 46 years (5-78); most common etiologies were: sarcoma (46%), metastases (31%), chordoma (11%); surgical approach was anterior (2.5%), combined (45%), and posterior (52.4%); 68.5% underwent EBS; average levels resected were 1.6 (1-6); average survival was 2.6 years; Complication rate was 17.7%. The following significant correlations were found: postoperative complications and resection mode (Odds ratio [OR] 1.35) as well as number of levels treated (OR 1.35); tumor recurrence and resection mode (OR 0.78); 5-year survival and age (OR 0.79), tumor grade (OR 0.65), tumor stage at diagnosis (OR 0.79), and resection mode (OR 1.68). EBS was shown to improve survival, decreases recurrence rates but also has a higher complication rate. Interestingly, the complication rate was not influenced by tumor extension or tumor etiology.
PMID: 34194155
ISSN: 0974-8237
CID: 5263952

Clinical Significance of Program Death Ligand-1 and Indoleamine-2,3-Dioxygenase Expression in Colorectal Carcinoma

Hacking, Sean; Vitkovski, Taisia; Jain, Swachi; Jin, Cao; Chavarria, Hector; Wu, Dongling; Nasim, Mansoor
Colorectal cancer is a heterogenous disease with striking biological diversity. Colorectal carcinoma (CRC) is one of the most common malignancies, accounting for over 9% of all cancers worldwide. To put it in perspective, 5% of people will develop CRC in their lifetime. Biomarkers specific to a particular cancer type can assist in the evaluation of survival probability and help clinicians assess treatment modalities, an example being programmed death ligand-1 (PD-L1). With regards to PD-L1, this is the first study to evaluate the SP-142 antibody clone in CRC. The Ventana PD-L1 (SP-142) assay for PD-L1 expression identifies patients who may benefit from treatment with atezolizumab. SP-142 was chosen as large stage 3 clinical trials are being undertaken with atezolizumab in CRC. Indoleamine 2,3-dioxygenase (IDO-1) was also chosen as there are several ongoing trials for Epacadostat, the best-in-class oral IDO-1 enzyme inhibitor, in many solid tumors. For solid tumors, IDO-1-based immune escape has the potential to inhibit monotherapeutic efficacy of PD-L1-based therapeutics. In this study, a total of 223 cases of CRC were retrospectively reviewed and clinicopathologic data were analyzed in relation to PD-L1 and IDO-1 protein expression. Moreover, tumor-infiltrating lymphocytes, mismatch repair deficiency, high mitotic index, and worse survival outcomes were found in cohorts with significant PD-L1 and IDO-1 expression. Both PD-L1 and IDO-1 are actionable biomarkers, with potential therapeutic implications in CRC. Our findings support the theoretical foundation for targeting PD-L1 and IDO-1 in CRC, which now needs verification in well-designed robust clinical trials.
PMID: 32842025
ISSN: 1533-4058
CID: 5263922

Nature and significance of stromal differentiation in carcinosarcoma (MMMT): unravelling the biology and shifting current paradigms

Hacking, Sean; Wu, Dongling; Nasim, Rafae; Chavarria, Hector; Nasim, Mansoor
Carcinosarcoma (CS) is a rare, aggressive malignancy of the Mullerian system often termed mixed malignant Mullerian tumor (MMMT). It is biphasic in nature, differentiating into epithelial and sarcomatous components. Tumor-node-metastasis (TNM) staging and mismatch repair (MMR) status is the basis for both prognostication and therapeutic decision making. However, stromal differentiation (SD) is a new frontier in the field of histopathology and many studies have demonstrated its prognostic significance. The present study is the first study to evaluate the role of SD in carcinosarcoma. Here we found immature SD to be a significant prognostic signature (p = 0.04). It outperformed age, nodal metastasis, and lymphovascular invasion for predicting cancer-free survival. Immature SD also corelated with both myometrial invasion (p = 0.01) and tumor stage (p = 0.02). Carcinosarcoma has been previously thought to have universally poor outcomes; however, mature SD was found to be protective in this cancer subtype. Our findings support the integration of SD into the synoptic reporting for carcinosarcoma; however, this will require pathologists to shoulder the adoption of SD into clinical practice.
PMID: 34017587
ISSN: 2036-3605
CID: 5263942