Publications by authors named "Kamaljeet Singh"

56 Publications

Immunohistochemical HER2 score correlates with response to neoadjuvant chemotherapy in HER2-positive primary breast cancer.

Breast Cancer Res Treat 2021 Feb 17. Epub 2021 Feb 17.

Department of Pathology and Laboratory Medicine, Rhode Island Hospital and Lifespan Medical Center, Warren Alpert Medical School of Brown University, 593 Eddy St, APC 12, Providence, RI, 02903, USA.

Purpose: The accuracy of biomarker assessment in breast cancer (BC) is paramount for therapy decisions and informs prognosis. We investigated neoadjuvant chemotherapy (NAC) response in HER2-positive BC with respect to immunohistochemistry (IHC) and in situ hybridization (ISH) results. We aimed to determine the role of HER2 protein expression in predicting NAC response and long-term outcome in two HER2-positive groups: IHC 3 + versus IHC 2 + ISH amplified groups.

Methods: This retrospective study included 192 consecutive HER2 + primary BCs diagnosed from 2007 to 2019 treated with NAC and HER2-targeted agent (NACH). There were 158 HER2 3 + and 34 HER2 2 + ISH + cases. Clinicopathological parameters and long-term outcomes were analyzed.

Results: The Pathological Complete Response (pCR) rate was 85.7% (72/84) in ER-/HER2 + BCs and was lower in ER + /HER2 + BCs (42.6%, 46/108). The pCR was 55.1% (86/156) in the HER2 3 + group and was only 17.6% in HER2 2 + ISH + group (p < 0.001). Patients who achieved pCR in HER2 2 + ISH + group did not show a significantly higher HER2/CEP17 ratio or HER2 copy number. The overall survival (OS) and progression-free survival (PFS) were significantly higher in pCR compared to non-pCR cases (p = 0.011 and p = 0.015, respectively).

Conclusions: There is significant heterogeneity in response to the NACH regimens in HER2 + cases. Our findings indicate that HER2 IHC score and ER expression determine NACH response in HER2 + BC. We recommend considering HER2 protein expression and ISH value to better select patients and assess the response for HER2-targeted therapy.
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http://dx.doi.org/10.1007/s10549-021-06124-8DOI Listing
February 2021

Neoadjuvant durvalumab plus weekly nab-paclitaxel and dose-dense doxorubicin/cyclophosphamide in triple-negative breast cancer.

NPJ Breast Cancer 2021 Feb 8;7(1). Epub 2021 Feb 8.

Section of Medical Oncology, Yale School of Medicine, New Haven, CT, USA.

The goal of this Phase I/II trial is to assess the safety and efficacy of administering durvalumab concurrent with weekly nab-paclitaxel and dose-dense doxorubicin/cyclophosphamide (ddAC) neoadjuvant therapy for stages I-III triple-negative breast cancer. The primary endpoint is pathologic complete response (pCR:ypT0/is, ypN0). The response was correlated with PDL1 expression and stromal tumor-infiltrating lymphocytes (sTILs). Two dose levels of durvalumab (3 and 10 mg/kg) were assessed. PD-L1 was assessed using the SP263 antibody; ≥1% immune and tumor cell staining was considered positive; sTILs were calculated as the area occupied by mononuclear inflammatory cells over the total intratumoral stromal area. 59 patients were evaluable for toxicity and 55 for efficacy in the Phase II study (10 mg/kg dose). No dose-limiting toxicities were observed in Phase I. In Phase II, pCR rate was 44% (95% CI: 30-57%); 18 patients (31%) experienced grade 3/4 treatment-related adverse events (AE), most frequently neutropenia (n = 4) and anemia (n = 4). Immune-related grade 3/4 AEs included Guillain-Barre syndrome (n = 1), colitis (n = 2), and hyperglycemia (n = 2). Of the 50 evaluable patients for PD-L1, 31 (62%) were PD-L1 positive. pCR rates were 55% (95% CI: 0.38-0.71) and 32% (95% CI: 0.12-0.56) in the PD-L1 positive and negative groups (p = 0.15), respectively. sTIL counts were available on 52 patients and were significantly higher in the pCR group (p = 0.0167). Concomitant administration of durvalumab with sequential weekly nab-paclitaxel and ddAC neoadjuvant chemotherapy resulted in a pCR rate of 44%; pCR rates were higher in sTIL-high cancers.
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http://dx.doi.org/10.1038/s41523-021-00219-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7870853PMC
February 2021

Androgen-induced Hyperplastic Prostatic Glands in the Uterine Cervix.

Int J Gynecol Pathol 2020 Dec 14. Epub 2020 Dec 14.

Alpert Medical School of Brown University, Women & Infants Hospital, Providence, Rhode Island (M.R.Q., R.R.R., K.S.).

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http://dx.doi.org/10.1097/PGP.0000000000000753DOI Listing
December 2020

Descriptive study comparing outcomes of classic and nonclassic lobular carcinoma in situ (florid and pleomorphic) initially diagnosed on core needle biopsy.

Breast J 2020 12 13;26(12):2350-2356. Epub 2020 Oct 13.

Warren Alpert Medical School of Brown University, Women & Infants Hospital of Rhode Island, Providence, RI, USA.

The lobular carcinoma in situ (LCIS) subtypes include classic (CLCIS), pleomorphic (PLCIS), and florid LCIS (FLCIS). The CLCIS is considered a breast cancer risk factor, but clinical significance and natural history of other LCIS subtypes are unclear. The outcome data on PLCIS and FLCIS is limited. The aim of current study is to compare excision and follow-up findings of CLCIS and nonclassic LCIS (NCLCIS). The breast needle biopsies (NBs) with LCIS during 01/2007-12/2017 were identified. The imaging, clinical findings, and outcome were compared between CLCIS and NCLCIS. A total of 36 NBs from 32 patients with NCLCIS (14 PLCIS & 22 FLCIS) and 73 NBs from 68 patients with CLCIS were identified. The NCLCIS patients were older (57 vs 52 years; P = .02) and presented more often with calcifications (78% vs 44%; P = .01). Seven (19%) PLCIS were initially diagnosed as ductal carcinoma in situ (DCIS). The microscopic invasion was frequent with NCLCIS (25%). No invasion was identified in NBs with CLCIS. A separate concurrent NBs with a carcinoma (29% vs 6%; P = .018) or ductal atypia (12% vs 3%; P = .1) was more frequent with CLCIS. The upgrade rate (invasion or DCIS) was higher with NCLCIS (25% vs 4%). Four NCLCIS developed ipsilateral recurrences: 2 NCLCIS, 1 IDC, and 1 ILC (50; 10-96 months). No breast event was reported in 24 pure CLCIS (60; 8-144 months). Invasive carcinoma with NCLCIS, unlike CLCIS, is always lobular type. Recurrences following NCLCIS are ipsilateral lobular tumors. NCLCIS subtypes are nonobligate precursors to invasive lobular carcinoma.
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http://dx.doi.org/10.1111/tbj.14085DOI Listing
December 2020

Epithelium Involving Bilateral Axillary Lymph Nodes: Metastasis, Misplaced, or Mullerian!

Int J Surg Pathol 2020 Sep 13:1066896920958121. Epub 2020 Sep 13.

Yale University, New Haven, CT, USA.

During breast cancer staging, histological evaluation of axillary sentinel lymph nodes (SLN) is usually straightforward. However, the exact characterization of a small epithelial deposit in an SLN can be challenging, especially during the frozen section examination. We report the first case of endosalpingiosis involving bilateral axillary lymph nodes. We review published literature on axillary endosalpingiosis and discuss the differential diagnosis of small epithelial deposits in an axillary SLN. Pathologists should consider benign epithelial rests and displaced epithelium as differential diagnoses for the microscopic epithelial nodal deposit, especially during the frozen section examination.
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http://dx.doi.org/10.1177/1066896920958121DOI Listing
September 2020

LIMK2 promotes the metastatic progression of triple-negative breast cancer by activating SRPK1.

Oncogenesis 2020 Aug 28;9(8):77. Epub 2020 Aug 28.

Department of Biochemistry and Molecular Genetics and UAB O'Neal Comprehensive Cancer Center, The University of Alabama at Birmingham, Birmingham, AL, 35294, USA.

Triple-negative breast cancer (TNBC) is a highly metastatic breast cancer subtype and due to the lack of hormone receptors and HER2 expression, TNBC has limited therapeutic options with chemotherapy being the primary choice for systemic therapy. LIM Domain Kinase 2 (LIMK2) is a serine/threonine kinase that plays an important role in the regulation of actin filament dynamics. Here, we show that LIM domain kinase 2 (LIMK2) is overexpressed in TNBC, and short-hairpin RNA (shRNA)-mediated LIMK2 knockdown or its pharmacological inhibition blocks metastatic attributes of TNBC cells. To determine the mechanism by which LIMK2 promotes TNBC metastatic progression, we performed stable isotope labeling by amino acids in cell culture (SILAC) based unbiased large-scale phosphoproteomics analysis. This analysis identified 258 proteins whose phosphorylation was significantly reduced due to LIMK2 inhibition. Among these proteins, we identified SRSF protein kinase 1 (SRPK1), which encodes for a serine/arginine protein kinase specific for the SR (serine/arginine-rich domain) family of splicing factors. We show that LIMK2 inhibition blocked SRPK1 phosphorylation and consequentially its activity. Furthermore, similar to LIMK2, genetic inhibition of SRPK1 by shRNAs or its pharmacological inhibition blocked the metastatic attributes of TNBC cells. Moreover, the pharmacological inhibition of LIMK2 blocked metastatic progression in mice without affecting primary tumor growth. In sum, these results identified LIMK2 as a facilitator of distal TNBC metastasis and a potential target for preventing TNBC metastatic progression.
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http://dx.doi.org/10.1038/s41389-020-00263-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7455732PMC
August 2020

A Novel "Google Classroom"-Based Pathology Education Tool for Trainees During the COVID-19 Pandemic: Impactful Learning While Social Distancing.

Arch Pathol Lab Med 2020 12;144(12):1445b-1447

Department of Pathology, Montefiore Medical Center and the Albert Einstein College of Medicine, Bronx, New York.

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http://dx.doi.org/10.5858/arpa.2020-0476-LEDOI Listing
December 2020

Commentary: Tools for standardization of skills transfer.

Authors:
Kamaljeet Singh

Indian J Ophthalmol 2020 08;68(8):1577-1578

Regional Institute of Ophthalmology, Prayagraj, Uttar Pradesh, India.

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http://dx.doi.org/10.4103/ijo.IJO_358_20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7640843PMC
August 2020

Commentary: Management of dislocated and subluxated intraocular lens.

Authors:
Kamaljeet Singh

Indian J Ophthalmol 2020 06;68(6):1150

Regional Institute of Ophthalmology, Moti Lal Nehru Medical College, Allahabad, Uttar Pradesh, India.

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http://dx.doi.org/10.4103/ijo.IJO_2071_19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7508128PMC
June 2020

Prospective multi-institutional evaluation of pathologist assessment of PD-L1 assays for patient selection in triple negative breast cancer.

Mod Pathol 2020 09 16;33(9):1746-1752. Epub 2020 Apr 16.

Yale School of Medicine, New Haven, CT, USA.

The US Food and Drug Administration (FDA) approved the PD-L1 immunohistochemical assay, SP142, as a companion test to determine eligibility for atezolizumab therapy in patients with advanced triple negative breast cancer (TNBC) but data in lung cancer studies suggest the assay suffers from poor reproducibility. We sought to evaluate reproducibility and concordance in PD-L1 scoring across multiple pathologists. Full TNBC sections were stained with SP142 and SP263 assays and interpreted for percentage (%) immune cell (IC) staining by 19 pathologists from 14 academic institutions. Proportion of PD-L1 positive cases (defined as ≥1% IC) was determined for each assay as well as concordance across observers. We utilized a new method we call Observers Needed to Evaluate Subjective Tests (ONEST) to determine the minimum number of evaluators needed to estimate concordance between large numbers of readers, as occurs in the real-world setting. PD-L1 was interpreted as positive with the SP142 assay in an average 58% of cases compared with 78% with SP263 (p < 0.0001). IC positive continuous scores ranged from 1 to 95% (mean = 20%) and 1 to 90% (mean = 10%) for SP263 and SP142, respectively. With SP142, 26 cases (38%) showed complete two category (<1% vs. ≥1%) concordance; with SP263, 38 cases (50%) showed complete agreement. The intraclass correlation coefficient (ICC) for two category scoring of SP263 and SP142 was 0.513 and 0.560. ONEST plots showed decreasing overall percent agreement (OPA) as observer number increased, reaching a low plateau of 0.46 at ten observers for SP263 and 0.41 at eight observers for SP142. IC scoring with both assays showed poor reproducibility across multiple pathologists with ONEST analysis suggesting more than half of pathologists will disagree about IC scores. This could lead to many patients either receiving atezolizumab when they are unlikely to benefit, or not receiving atezolizumab when they may benefit.
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http://dx.doi.org/10.1038/s41379-020-0544-xDOI Listing
September 2020

Stromal ColXα1 expression correlates with tumor-infiltrating lymphocytes and predicts adjuvant therapy outcome in ER-positive/HER2-positive breast cancer.

BMC Cancer 2019 Nov 1;19(1):1036. Epub 2019 Nov 1.

Department of Pathology and Laboratory Medicine, Rhode Island Hospital and Lifespan Medical Center, Warren Alpert Medical School of Brown University, 593 Eddy St, APC 12, Providence, RI, 02903, USA.

Background: The breast cancer microenvironment contributes to tumor progression and response to chemotherapy. Previously, we reported that increased stromal Type X collagen α1 (ColXα1) and low TILs correlated with poor pathologic response to neoadjuvant therapy in estrogen receptor and HER2-positive (ER+/HER2+) breast cancer. Here, we investigate the relationship of ColXα1 and long-term outcome of ER+/HER2+ breast cancer patients in an adjuvant setting.

Methods: A total of 164 cases with at least 5-year follow-up were included. Immunohistochemistry for ColXα1 was performed on whole tumor sections. Associations between ColXα1expression, clinical pathological features, and outcomes were analyzed.

Results: ColXα1 expression was directly proportional to the amount of tumor associated stroma (p = 0.024) and inversely proportional to TILs. Increased ColXα1 was significantly associated with shorter disease free survival and overall survival by univariate analysis. In multivariate analysis, OS was lower in ColXα1 expressing (HR = 2.1; 95% CI = 1.2-3.9) tumors of older patients (> = 58 years) (HR = 5.3; 95% CI = 1.7-17) with higher stage (HR = 2.6; 95% CI = 1.3-5.2). Similarly, DFS was lower in ColXα1 expressing (HR = 1.8; 95% CI = 1.6-5.7) tumors of older patients (HR = 3.2; 95% CI = 1.3-7.8) with higher stage (HR = 2.7; 95% CI = 1.6-5.7) and low TILs. In low PR+ tumors, higher ColXα1 expression was associated with poorer prognosis.

Conclusion: ColXα1 expression is associated with poor disease free survival and overall survival in ER+/HER2+ breast cancer. This study provides further support for the prognostic utility of ColXα1 as a breast cancer associated stromal factor that predicts response to chemotherapy.
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http://dx.doi.org/10.1186/s12885-019-6134-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6825361PMC
November 2019

Comparison of PAX8 Expression in Breast Carcinoma Using MRQ50 and BC12 Monoclonal Antibodies.

Appl Immunohistochem Mol Morphol 2020 08;28(7):558-561

Department of Pathology, Alpert Medical School of Brown University, Women and Infants Hospital of Rhode Island, Providence, RI.

PAX8 is a specific marker for kidney, ovarian, and thyroid tissue. Antibody-dependent cross-reactivity for PAX8 has been reported in mesothelial, pancreatic, and B-cell proliferations. We recently described antibody clone-dependent aberrant PAX8 expression in breast cancer. In this study we systematically analyze PAX8 expression in breast cancer on whole tissue sections, using MRQ50 and BC12 PAX8 monoclonal antibodies. Immunohistochemistry was performed on formalin-fixed paraffin-embedded whole tissue sections from 85 invasive mammary carcinomas. Immunostaining was evaluated at ×10 objective; extent (intervals of 10%, 0% to 100%) and intensity (weak, moderate, and strong) of nuclear staining was evaluated in the tumor, benign breast tissue, and lymphocytes. With MRQ50 variable PAX8 nuclear positivity was identified in tumor cells in 35/85 (41%) cases. Of 35 PAX8 cases, 23 (66%) showed only weak expression in 1% to 10% cells, 8 (23%) were weakly (5/8) or moderately (3/8) PAX8 in 11% to 50% cells, and 4 (11%) showed weak PAX8 positivity in >50% tumor cells. All 3 (3.5%) cases that showed moderate nuclear PAX8 staining with MRQ50 were histologic grade 3. No PAX8 expression was noted in benign lobules/ducts with either antibody. Breast carcinomas can show nuclear immunostaining with MRQ50 PAX8 antibody with up to 3.5% cases showing moderately intense expression. The BC12 PAX8 antibody does not cross-react with breast carcinoma and lymphocytes. During workup of metastatic carcinoma, weak to moderate PAX8 nuclear expression with MRQ50 clone should be interpreted with caution.
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http://dx.doi.org/10.1097/PAI.0000000000000796DOI Listing
August 2020

Correction: An elusive thermal [2 + 2] cycloaddition driven by visible light photocatalysis: tapping into strain to access C2-symmetric tricyclic rings.

Org Biomol Chem 2019 02;17(7):2028

107 Physical Science, Department of Chemistry, Oklahoma State University, Stillwater, OK 74078, USA.

Correction for 'An elusive thermal [2 + 2] cycloaddition driven by visible light photocatalysis: tapping into strain to access C2-symmetric tricyclic rings' by Kamaljeet Singh et al., Org. Biomol. Chem., 2018, DOI: 10.1039/c8ob01273c.
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http://dx.doi.org/10.1039/c8ob90145gDOI Listing
February 2019

Large Epithelial and Stromal Lesion of Breast: It's Not Always Phyllodes!

Int J Surg Pathol 2019 Jun 10;27(4):403-404. Epub 2018 Oct 10.

1 Women and Infants Hospital of Rhode Island, Providence, RI, USA.

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http://dx.doi.org/10.1177/1066896918805843DOI Listing
June 2019

ColXα1 is a stromal component that colocalizes with elastin in the breast tumor extracellular matrix.

J Pathol Clin Res 2019 01 1;5(1):40-52. Epub 2018 Nov 1.

Department of Pathology and Laboratory Medicine, Rhode Island Hospital and Lifespan Medical Center, Warren Alpert Medical School of Brown University, Providence, RI, USA.

The tumor microenvironment regulates tissue development and homeostasis, and its dysregulation contributes to neoplastic progression. Increased expression of type X collagen α-1 (ColXα1) in tumor-associated stroma correlates with poor pathologic response to neoadjuvant chemotherapy in estrogen receptor (ER) and human epidermal growth factor receptor 2 (HER2)-positive breast cancers. Evaluation of ColXα1 expression patterns suggests a potential connection with elastin fibers. To investigate the possible interaction between ColXα1 and elastin, we evaluated the expression of ColXα1 in relation to elastin fibers in normal breast tissue, ductal carcinoma in situ, and invasive breast carcinomas at cellular and subcellular levels. Our findings demonstrate that ColXα1 colocalizes with elastin in invasive breast cancer-associated stroma by immunohistochemistry, immunofluorescence, and electron microscopy. In 212 invasive breast carcinomas, this complex was aberrantly and selectively expressed in tumor extracellular matrix in 79% of ER+/HER2-, 80% of ER+/HER2+, 76% of ER-/HER2+, and 58% of triple negative breast cancers. In contrast, ColXα1 was generally absent, while elastin was present perivascularly in normal breast tissue. ColXα1 and elastin were coexpressed in 58% of ductal carcinoma in situ (DCIS) in periductal areas. In mass-forming DCIS with desmoplastic stroma, the complex was intensely expressed in periductal areas as well as within the tumor-associated stroma in all cases. Our data suggest that the breast carcinoma neoplastic process may involve aberrant expression of ColXα1 and elastin in the tumor microenvironment emerging early at the DCIS stage. Enrichment of these complexes in tumor-associated stroma may represent a stromal signature indicative of intrinsic differences between breast cancers. These findings shed light on investigation into the role of aberrant collagen complex expression in tumorigenesis and tumor progression which may be leveraged in therapeutic and theranostic applications.
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http://dx.doi.org/10.1002/cjp2.115DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6317058PMC
January 2019

While women await surgery for type I endometrial cancer, depot medroxyprogesterone acetate reduces tumor glandular cellularity.

Am J Obstet Gynecol 2018 10 29;219(4):381.e1-381.e10. Epub 2018 Jul 29.

Program in Women's Oncology, Department of Obstetrics and Gynecology, Women and Infants Hospital of Rhode Island, Providence, RI; Department of Obstetrics and Gynecology, Women and Infants Hospital of Rhode Island, Providence, RI; Warren Alpert Medical School of Brown University, Providence, RI.

Background: Multiple population-level studies have demonstrated an adverse effect of long wait times to surgery on survival for women with endometrial cancer. Other retrospective and nonrandomized prospective studies have shown that preoperative administration of depot medroxyprogesterone acetate decreases tumor glandular cellularity, which may be a surrogate marker for clinically meaningful tumor response.

Objective: We sought to determine whether preoperative injection with depot medroxyprogesterone acetate decreases tumor glandular cellularity when compared to placebo injection in women awaiting hysterectomy for endometrial intraepithelial neoplasia or type I endometrial cancer, and to determine whether depot medroxyprogesterone acetate injection affects quality of life while waiting for surgery.

Study Design: This was a double-blind, randomized controlled trial of 400-mg depot medroxyprogesterone acetate injection or 0.9% saline injection at the preoperative visit. Patients with recent use of progesterone analogs were excluded. A sample size of 76 patients (38 per arm) was calculated to detect a 20% difference in decreased glandular cellularity between arms. Pathologic characteristics including the primary outcome, tumor glandular cellularity, from patients' diagnostic biopsies were reviewed by 2 dedicated gynecologic pathologists and compared to posttreatment hysterectomy specimens. On the night prior to surgery, patients completed the Functional Assessment of Cancer Therapy-Endometrial Survey (Version 4) to report quality of life while waiting for surgery. In comparing characteristics between the intervention and control groups, t tests were used for continuous variables, and χ or Fisher exact tests were used where appropriate for categorical data.

Results: From March 2015 through March 2016, 148 women were screened and 76 patients were enrolled. In all, 38 patients were randomized to and received depot medroxyprogesterone acetate injection and 38 were randomized to and received placebo injection. Demographics were similar between groups. Patients who received depot medroxyprogesterone acetate injection experienced a larger decrease in tumor glandular cellularity (mean change -64 [-31.8%] vs -14 [-5.5%] cells per quarter high-powered field in depot medroxyprogesterone acetate vs placebo groups, P = .002). This effect was most pronounced in women waiting ≥3 weeks for surgery. Several additional histologic and immunohistochemical markers of tumor differentiation and decreased cell proliferation were more pronounced in the depot medroxyprogesterone acetate group than in the placebo group. There were no significant differences in quality of life between groups on the Functional Assessment of Cancer Therapy-Endometrial Survey. Only 5.3% of patients who were approached declined to participate due to concerns regarding an intramuscular injection.

Conclusion: Administration of depot medroxyprogesterone acetate prior to surgery for type I endometrial cancers caused greater tumor effect than placebo injection. Injection of depot medroxyprogesterone acetate was acceptable to and well tolerated by patients. Depot medroxyprogesterone acetate may represent a meaningful bridge to surgery in women who can expect long wait times.
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http://dx.doi.org/10.1016/j.ajog.2018.07.024DOI Listing
October 2018

Invasive Lobular Carcinoma With Extracellular Mucin: Not All Mucinous Mammary Carcinomas Are Ductal!

Int J Surg Pathol 2019 Feb 23;27(1):55-58. Epub 2018 Jul 23.

1 Brown University, Providence, RI, USA.

Mucinous component in mammary carcinoma indicates ductal phenotype. Although intracytoplasmic mucin and signet ring cell change are frequently described with lobular carcinomas, extracellular mucin is not associated with lobular phenotype. We report 4 cases of invasive lobular carcinoma with extracellular mucin (ILCEM) and review findings of previously published cases of this rare ILC variant. Variable amount of extracellular mucin and pseudoglandular architectural pattern may lead to diagnosis of ILCEM as ductal mucinous carcinoma. Pathologists should be aware of this rare variant of ILC that will help identify more cases of this entity and clarify relevance of extracellular mucin production in ILC.
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http://dx.doi.org/10.1177/1066896918788660DOI Listing
February 2019

Visible Light Mediated Generation of trans-Arylcyclohexenes and Their Utilization in the Synthesis of Cyclic Bridged Ethers.

J Am Chem Soc 2018 08 24;140(31):9934-9941. Epub 2018 Jul 24.

107 Physical Science, Department of Chemistry , Oklahoma State University , Stillwater , Oklahoma 74078 , United States.

While accessible via UV-irradiation of cis-cyclohexene, trans-cyclohexene has thus far been an investigation driven by curiosity, and due primarily to its short lifespan, has until recently not been employed for productive synthesis. Herein, we present straightforward conditions that provide access to a class of trans-arylcyclohexenes and demonstrate their utility in the formation of oxabicyclic ethers, which are otherwise inaccessible from the corresponding cis-cyclohexene. A key challenge to utilizing the incredible ca. 52 kcal/mol strain energy of trans-cyclohexene to drive synthesis was overcoming its short lifetime. Herein, we show that preorganization via hydrogen bonding between the substrate and the reaction partner prior to isomerization is a viable strategy to overcome the inherently short lifetime of trans-cyclohexene.
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http://dx.doi.org/10.1021/jacs.8b04642DOI Listing
August 2018

An elusive thermal [2 + 2] cycloaddition driven by visible light photocatalysis: tapping into strain to access C2-symmetric tricyclic rings.

Org Biomol Chem 2019 02;17(7):1854-1861

107 Physical Science, Department of Chemistry, Oklahoma State University, Stillwater, OK 74078, USA.

A mild and operationally simple methodology is reported for the synthesis of cyclobutane rings imbedded within a C2-symmetric tricyclic framework. The method uses visible light and an iridium-based photocatalyst to drive the oft-stated "forbidden" thermal [2 + 2] cycloaddition of cycloheptenes and analogs. Importantly, it generates cyclobutane with four new stereocenters with excellent stereoselectivity, and perfect regioselectivity. The reaction is propelled forward when the photocatalyst absorbs a visible light photon, which transfers this energy to the cycloheptene. Key to success is, upon excitation to the triplet via sensitization from the photocatalyst, the double bond isomerizes to give the transient, highly strained, trans-cycloheptene. The trans-cycloheptene undergoes a strain relieving thermal, intermolecular [π2s + π2a] cycloaddition with another cis-cycloheptene. X-ray analysis reveals that the major product is the head-to-head, C2-symmetric all trans-cyclobutane. Additionally, a dramatic display structural complexity enhancement is observed with the use of chiral cycloheptenols possessing one stereocenter, which results in the formation of cyclobutanes with six contiguous stereocenters with good to excellent diastereocontrol, and can be used to isolate single stereoisomers of stereochemically complex cyclobutanes in good yield.
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http://dx.doi.org/10.1039/c8ob01273cDOI Listing
February 2019

Aberrant Immunostaining of Breast Carcinoma by MRQ-50 PAX8 Antibody.

Appl Immunohistochem Mol Morphol 2020 04;28(4):e37-e38

Department of Pathology, Alpert Medical School of Brown University, Women and Infants Hospital of Rhode Island Providence, RI.

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http://dx.doi.org/10.1097/PAI.0000000000000682DOI Listing
April 2020

BRCA1 Mutations Associated With Increased Risk of Brain Metastases in Breast Cancer: A 1: 2 Matched-pair Analysis.

Am J Clin Oncol 2018 12;41(12):1252-1256

Departments of Radiation Oncology.

Background: Brain metastases (BM) occur in ∼5% of breast cancer patients. BRCA1-associated cancers are often basal-like and basal-like cancers are known to have a predilection for central nervous system metastases. We performed a matched-pair analysis of breast cancer patients with and without BRCA mutations and compared the frequency of BM in both groups.

Materials And Methods: From a database of 1935 patients treated for localized breast cancer at our institution from 2009 to 2014 we identified 20 patients with BRCA1 or BRCA2 mutations and manually matched 40 patients without BRCA mutations accounting for age, stage, estrogen receptor expression, and human epidermal growth factor receptor 2 (HER2) expression. Comparisons of freedom from brain metastasis, brain metastasis-free survival, and overall survival were made using the log rank test. Testing for a basal-type phenotype using the immunohistochemistry definition (ER/PR/HER2 and either CK 5/6 or EGFR) was performed for BRCA patients who developed BM and their matched controls.

Results: We analyzed 60 patients: 20 BRCA and 40 were matched controls. Median follow-up was 37 and 49 months, respectively. Three years freedom from brain metastasis was 84% for BRCA patients and 97% for BRCA controls (P=0.049). Three years brain metastasis-free survival was 84% and 97% for the BRCA+ and controls, respectively (P=0.176). Mean time to brain failure was 11 months from diagnosis for the BRCA patients. All 3 BRCA1 patients who developed BM were of a basal-type triple negative phenotype.

Conclusions: Breast cancer patients with germline BRCA1 mutations appear to have a shorter interval to brain progression while accounting for confounding factors.
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http://dx.doi.org/10.1097/COC.0000000000000466DOI Listing
December 2018

Evaluating agreement, histological features, and relevance of separating pleomorphic and florid lobular carcinoma in situ subtypes.

Hum Pathol 2018 08 9;78:163-170. Epub 2018 May 9.

Women and Infants Hospital of Rhode Island, Department of Pathology, Providence, RI, United States.

Morphological variants of lobular carcinoma in situ (LCIS) include classical (CLCIS), pleomorphic (PLCIS) and florid type (FLCIS). Treatment guidelines suggest managing PLCIS and FLCIS like ductal carcinoma in situ (DCIS); therefore accurate identification of LCIS subtypes is critical. However, the significance of separating PLCIS from FLCIS is not clear. Also, interobserver agreement in identifying LCIS subtypes, using contemporary criteria, is not known. We aimed to evaluate interobserver agreement amongst breast pathologists in diagnosing LCIS subtypes and use the agreement data to justify LCIS classification for management purposes. Six breast pathologists independently reviewed 50 hematoxylin and eosin-stained slides comprised of a mix of LCIS subtypes. After reviewing published criteria, participants diagnosed PLCIS, CLCIS and apocrine change in a marked region of interest and FLCIS based on entire section. PLCIS was identified in 8 to 37 slides with overall moderate agreement (Fleiss' κ = 0.565) and pairwise κ (Cohen's) ranging from -.008 to 0.492. FLCIS was diagnosed in 15-26 slides with overall substantial agreement (Fleiss' κ = 0.687) and pairwise κ ranging from -.068 to 0.706. Both FLCIS and PLCIS coexisted in 45% of slides with consensus on non-classical LCIS. Comedo-type necrosis (odds ratio = 5.5) and apoptosis (odds ratio = 1.8) predicted FLCIS. We found moderate and substantial agreement in diagnosing PLCIS and FLCIS respectively. Objective histological features linked with aggressive behavior were more frequent with FLCIS. PLCIS and FLCIS patterns frequently coexist, contain similar molecular aberrations, and are managed similarly (like DCIS); therefore, combining FLCIS and PLCIS into one category (non-classical LCIS) should be considered.
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http://dx.doi.org/10.1016/j.humpath.2018.04.026DOI Listing
August 2018

Squamous differentiation in breast carcinoma following neo-adjuvant chemotherapy: Therapy effect vs tumor heterogeneity.

Breast J 2018 09 23;24(5):823-824. Epub 2018 Apr 23.

Department of Pathology, Women and Infants Hospital of Rhode Island, Alpert Medical School of Brown University, Providence, RI, USA.

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http://dx.doi.org/10.1111/tbj.13046DOI Listing
September 2018

Endometrial Pneumatosis.

Int J Surg Pathol 2018 10 13;26(7):627-628. Epub 2018 Mar 13.

1 Alpert Medical School of Brown University, Women and Infants Hospital of Rhode Island, Providence, RI, USA.

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http://dx.doi.org/10.1177/1066896918760193DOI Listing
October 2018

Squamous epithelialization of bilateral breast implant capsules complicated by implant extrusion.

Breast J 2018 07 8;24(4):654-655. Epub 2018 Jan 8.

Department of Pathology and Laboratory Medicine, Alpert Medical School of Brown University, Women & Infants Hospital of Rhode Island, Providence, RI, USA.

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http://dx.doi.org/10.1111/tbj.12988DOI Listing
July 2018

Relationship of histologic grade and histologic subtype with oncotype Dx recurrence score; retrospective review of 863 breast cancer oncotype Dx results.

Breast Cancer Res Treat 2018 Feb 11;168(1):29-34. Epub 2017 Dec 11.

Department of Pathology and Laboratory Medicine, Women & Infants Hospital, Alpert Medical School of Brown University, 101 Dudley Street, Providence, RI, 02903, USA.

Purpose: Oncotype Dx (ODx) is a multigene assay that is prognostic and predictive in estrogen receptor (ER) positive early breast cancer. ODx recurrence score (RS) is reported to be histologic grade dependent. Relationship of RS with breast cancer histologic subtypes is unknown. This study was designed to assess the relationship of histologic subtype with RS. Histologic grade dependence of RS was also investigated.

Methods: Results of consecutive ODx tests (1/2007-7/2016) from two institutions were reviewed. Histologic subtypes (in: Lakhani et al., WHO classification, IARC Press, Lyon, 2012), combined Nottingham histologic grade, age and tumor size were recorded from pathology reports. Univariate and multivariate analysis was performed to investigate the relationship between RS and ODx risk categories and histologic subtypes, grade, age and tumor size.

Results: RS was grade dependent. RS of grade 1 and grade 2 tumors were significantly lower than grade 3 tumors. There was no high-risk grade 1 tumor. In favorable histologic subtypes there was no high-risk tumor. Mean RS of grade 1 lobular tumors was significantly higher than grade 1 ductal tumors. Using newer ODx cut-offs, 5 grade 1 tumors were reclassified as high risk (RS > 25) and grade 3 lobular tumors showed significantly higher rate of reclassification as high-risk than grade 3 ductal tumors. In a multivariate analysis, only grade showed a significant positive correlation with RS. Adding dichotomous histologic subtyping (favorable vs. non-favorable) to grade further improved correlation with RS.

Conclusions: The Oncotype Dx result is impacted by histologic grade and histologic subtype. Tumors with favorable histologic subtypes and histologic grade 1 tumors do not have high-risk RS. High RS in a grade 1 tumor or in a tumor with favorable histology is unusual that warrants further investigation. Invasive lobular carcinomas rarely show high-risk RS. Histologic grade and histologic subtype should be considered while ordering ODx testing.
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http://dx.doi.org/10.1007/s10549-017-4619-4DOI Listing
February 2018

Review of manual small-incision cataract surgery.

Indian J Ophthalmol 2017 Dec;65(12):1281-1288

Department of Ophthalmology, Regional Institute of Ophthalmology, Government M.D. Eye Hospital, Allahabad, Uttar Pradesh, India.

Cataract surgery has undergone many changes with the size of incision progressively decreasing over time with an incision of 12.0 mm for intracapsular cataract extraction to 2.2-2.8 mm in phacoemulsification. However, phacoemulsification due to high cost and equipment maintenance cannot be employed widely in developing countries. Manual small-incision cataract surgery (MSICS) offers similar advantages with the merits of wider applicability, less time consuming, a shorter learning curve, and lower cost. MSICS can be performed in high-volume setups due to fast technique. Here, we review the various techniques, safety and efficacy of MSICS, and its progress and utility in developing and underdeveloped countries.
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http://dx.doi.org/10.4103/ijo.IJO_863_17DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5742955PMC
December 2017

Cystic Hypersecretory Hyperplasia of Breast.

Int J Surg Pathol 2018 Aug 3;26(5):432-433. Epub 2017 Dec 3.

1 Alpert Medical School of Brown University, Providence, RI, USA.

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http://dx.doi.org/10.1177/1066896917741979DOI Listing
August 2018

Extremely rare congenital tracheobronchial anomaly of bronchus suis: A hidden cause of pulmonary infection.

Lung India 2017 Nov-Dec;34(6):577-579

Department of Respiratory Medicine, BPSGMC(W), Sonepat, Haryana, India.

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http://dx.doi.org/10.4103/lungindia.lungindia_222_17DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5684825PMC
November 2017

Effect of health education on awareness about oral cancer and oral self-examination.

J Educ Health Promot 2017 5;6:27. Epub 2017 May 5.

Department of Community Medicine, School of Public Health, Post Graduate Institute of Medical Education and Research, Chandigarh, India.

Context: Oral cancer is preceded by visible changes in the oral mucosa. These lesions can be detected by oral self-examination, but awareness about oral cancer is still low in developing countries.

Aim: To evaluate the effect of health education on awareness about oral cancer and oral self-examination.

Settings And Design: Quasi-experimental trial was conducted in an urban resettlement colony of Chandigarh, India.

Materials And Methods: A brochure having information and pictorials on oral lesions was used for conducting health education sessions on a one-to-one basis in the household setting among 85 males in age group 15-59 years during 2013, and each participant was encouraged to perform an oral self-examination. Study participants were interviewed about their awareness on oral cancer and oral self-examination before- and after-health education using a pretested interview schedule.

Statistical Analysis: Awareness items were scored, and mean change in awareness score was computed. Paired -test was used for testing statistical significance.

Results: Thirty-three percent of the study participants were current smokers, 25% consumed alcohol, and 9.4% chewed tobacco. The awareness scores after health education increased significantly from 5.3 to 6.7 ( < 0.05), and 34% of the tobacco or alcohol users expressed their intention to quit these habits, and two persons actually quit tobacco chewing. Out of the 77 study participants who performed oral self-examination, nine were able to detect lesions, and one was found to have submucous fibrosis.

Conclusions: Health education intervention was able to initiate a favorable behavior change in the community. Hence, oral self-examination programs should be promoted.
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http://dx.doi.org/10.4103/jehp.jehp_82_15DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5441190PMC
May 2017