Pathology Commons^™

Reduced Er-Mitochondria Connectivity Promotes Neuroblastoma Multidrug Resistance., Jorida Çoku, David M. Booth, Jan Skoda, Madison C Pedrotty, Jennifer Vogel, Kangning Liu, Annette Vu, Erica L Carpenter, Jamie C Ye, Michelle A Chen, Peter Dunbar, Elizabeth Scadden, Taekyung D Yun, Eiko Nakamaru-Ogiso, Estela Area-Gomez, Yimei Li, Kelly C Goldsmith, C Patrick Reynolds, György Hajnóczky, Michael D Hogarty

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

Most cancer deaths result from progression of therapy resistant disease, yet our understanding of this phenotype is limited. Cancer therapies generate stress signals that act upon mitochondria to initiate apoptosis. Mitochondria isolated from neuroblastoma cells were exposed to tBid or Bim, death effectors activated by therapeutic stress. Multidrug-resistant tumor cells obtained from children at relapse had markedly attenuated Bak and Bax oligomerization and cytochrome c release (surrogates for apoptotic commitment) in comparison with patient-matched tumor cells obtained at diagnosis. Electron microscopy identified reduced ER-mitochondria-associated membranes (MAMs; ER-mitochondria contacts, ERMCs) in therapy-resistant cells, and genetically or biochemically reducing MAMs in therapy-sensitive …

Characterisation Of Drug-Resistant Mycobacterium Tuberculosis Mutations And Transmission In Pakistan, Gary Napier, Anwar Sheed Khan, Abdul Jabbar, Muhammad Tahir Khan, Sajid Ali, Muhammad Qasim, Noor Mohammad, Rumina Hasan, Zahra Hasan, Susana Campino

Department of Pathology and Laboratory Medicine

Tuberculosis, caused by Mycobacterium tuberculosis, is a high-burden disease in Pakistan, with multi-drug (MDR) and extensive-drug (XDR) resistance, complicating infection control. Whole genome sequencing (WGS) of M. tuberculosis is being used to infer lineages (strain-types), drug resistance mutations, and transmission patterns-all informing infection control and clinical decision making. Here we analyse WGS data on 535 M. tuberculosis isolates sourced across Pakistan between years 2003 and 2020, to understand the circulating strain-types and mutations related to 12 anti-TB drugs, as well as identify transmission clusters. Most isolates belonged to lineage 3 (n = 397; 74.2%) strain-types, and were MDR (n = …

Paratesticular Solitary Fibrous Tumour Mimicking Cellular Angiofibroma: An Unusual Morphology And Rare Site, Madiha Bilal Qureshi, Muhammad Usman, Qurratulain Chundriger, Nasir Uddin

Department of Pathology and Laboratory Medicine

Solitary fibrous tumour (SFT) is a ubiquitous benign mesenchymal tumour of fibroblastic origin, which occurs most often in middle-aged adults. It usually presents as lung mass originating from pleura, but extrapleural occurrence is also common. Tumour is characterised by hypo- and hyper-cellular areas of spindle-shaped cells, arranged in haphazard manner with dispersed staghorn-shaped vessels. Surgical excision is the curative treatment. SFTs of the primary testicular or paratesticular region are extremely rare, but they exhibit histologic findings similar to SFTs originating at other body sites. Here, we report the case of a paratesticular SFT in a 37-year male, who presented with …

A Streptococcus Pneumoniae Lineage Usually Associated With Pneumococcal Conjugate Vaccine (Pcv) Serotypes Is The Most Common Cause Of Serotype 35b Invasive Disease In South Africa, Following Routine Use Of Pcv, Kedibone M. Ndlangisa, Mignon Du Plessis, Stephani Lo, Linda De Gouveia, Chrispin Chaguza, Martin Antonio, Brenda Kwambana-Adams, Jennifer Cornick, Dean B. Everett, Sadia Shakoor

Department of Pathology and Laboratory Medicine

Pneumococcal serotype 35B is an important non-conjugate vaccine (non-PCV) serotype. Its continued emergence, post-PCV7 in the USA, was associated with expansion of a pre-existing 35B clone (clonal complex [CC] 558) along with post-PCV13 emergence of a non-35B clone previously associated with PCV serotypes (CC156). This study describes lineages circulating among 35B isolates in South Africa before and after PCV introduction. We also compared 35B isolates belonging to a predominant 35B lineage in South Africa (GPSC5), with isolates belonging to the same lineage in other parts of the world. Serotype 35B isolates that caused invasive pneumococcal disease in South Africa in …

Chloroquine-Susceptible And -Resistant Plasmodium Falciparum Strains Survive High Chloroquine Concentrations By Becoming Dormant But Are Eliminated By Prolonged Exposure, Johan Ursing, Rasmus Johns, Berit Aydin-Schmidt, Carla Calçada, Poul-Erik Kofoed, Najia Karim Ghanchi, Maria Isabel Veiga, Lars Rombo

Department of Pathology and Laboratory Medicine

Background: Plasmodium falciparum strains that are resistant to standard-dose chloroquine can be treated by higher chloroquine concentrations maintained for a longer time in vivo.
Objectives: To determine the relative importance of chloroquine concentrations versus exposure time for elimination of chloroquine-susceptible and -resistant P. falciparum in vitro.
Methods: Chloroquine-susceptible (3D7) and -resistant (FCR3) strains were exposed in vitro to 1, 2, 4, 8, 16 or 32 times their respective 90% inhibitory chloroquine concentrations for 3, 5, 7 or 14 days and then followed until recrudescence, or not, by 42 days after the end of exposure.
Results: Exposure to chloroquine appeared to …

Development And Validation Of Standard And Real Patient Gallstone Library Using Fourier Transform Infra-Red Spectroscopy, Lena Jafri, Muhammad Abbas Abid, Humera Asif, Syed Bilal Hashmi, Hafsa Majid, Farooq Ghani, Sibtain Ahmed, Imran Siddiqui, Aysha Habib

Department of Pathology and Laboratory Medicine

Background: Analysis of the constituents of gallstones using various spectroscopic techniques assists in identification of the pathogenesis of gallstones. In the current study, using Fourier Transform Infra-Red (FTIR) Spectroscopy, a Gallstone Standard Library (GSL) and a Gallstone Real Patients' Library (GRPL) were developed and validated for gallstone composition analysis.
Methods: The study was conducted at the Department of Pathology & Laboratory Medicine, Aga Khan University, Pakistan. Pure standards (cholesterol, calcium carbonate, bilirubin and bile salts) and gallstone specimens were analyzed using FTIR Nicolet iS-5 Spectrometer from Thermo Fisher Scientific, USA. Thermo Scientific™ QCheck™ algorithm, embedded within the OMNIC™ software, was …

Rare Occurrence Of Pseudomyxoma Peritonei (Pmp) Syndrome Arising From A Malignant Transformed Ovarian Primary Mature Cystic Teratoma Treated By Cytoreductive Surgery And Hipec: A Case Report, Francesca Ponzini, Luke Kowal, Mariam Ghafoor, Allison F Goldberg, Joanna Chan, Ryan Lamm, Shawnna Cannaday, Scott D. Richard, Avinoam Nevler, Harish Lavu, Wilbur Bowne, Norman G Rosenblum

Department of Surgery Faculty Papers

Background: Pseudomyxoma peritonei (PMP) syndrome is a disease process that typically occurs from ruptured appendiceal mucocele neoplasms. PMP syndrome arising from malignant transformation of an ovarian primary mature cystic teratoma (MCT) is a pathogenesis rarely encountered.

Case presentation: Herein, we report a 28-year-old patient evaluated and treated for a right ovarian mass and large volume symptomatic abdominopelvic mucinous ascites. Molecular profiling and genetic analysis revealed mutations in ATM, GNAS, and KRAS proteins while IHC demonstrated gastrointestinal-specific staining for CK20, CDX2, CK7, and SATB2. Peritoneal cytology showed paucicellular mucin. Diffuse peritoneal adenomucinosis (DPAM) variant of PMP arising from a ruptured ovarian …

Design And Development Of Software With A Graphical User Interface To Display And Convert Multiple Microscopic Histology Images, Sayed Ahmadreza Razian, Majid Jadidi, Alexey Kamenskiy

UNO Student Research and Creative Activity Fair

Histological images are widely used to assess the microscopic anatomy of biological tissues. Recent advancements in image analysis allow the identification of structural features on histological sections that can help advance medical device development, brain and cancer research, drug discovery, vascular mechanobiology, and many other fields. Histological slide scanners create images in SVS and TIFF formats that were designed to archive image blocks and high-resolution textual information. Because these formats were primarily intended for storage, they are often not compatible with conventional image analysis software and require conversion before they can be used in research. We have developed a user-friendly …

Immortal Plain Gut Sutures: A Case Report, Hannah J. Anderson, Kathryn Lynn, Raziyeh Mahmoudzadeh, Tatyana Milman, Manish Jain, Sunir J Garg

Wills Eye Hospital Papers

Purpose: We report the case of a 79-year-old male who presented with irritation and foreign body sensation due to the subconjunctival plain gut sutures that did not dissolve three years after undergoing pars plana vitrectomy (PPV) for macular hole repair.

Observation: A 79-year-old male presented with foreign body sensation and irritation in his left eye. On slit lamp examination, the source of the foreign body sensation was two apparently intact plain gut sutures were visible under the conjunctiva, nasal and temporal to the cornea. These plain gut sutures were placed at the conclusion of PPV surgery three years prior to …

Final Counts Of Monoclonal Gammopathy Of Renal Significance (Mgrs) After Bone Marrow Biopsies (Bmb) And Follow-Up, Brandon Metcalf, James Zhiyan Huang, Wei Li, Hassan Kanaan, Ping Zhang

Conference Presentation Abstracts

Background: MGRS is a relatively new concept for patients with renal paraprotein deposition (RPD) (except monoclonal cast nephropathy) with no bone marrow confirmed diagnosis of malignancy or premalignancy (< 10% monoclonal plasma cells). This concept has been used as a reason for a nephrology consult for a bone marrow biopsy (BMB), therefore it is important to evaluate the outcome of MGRS tentatively diagnosed via renal biopsy and confirmed by BMB. This study’s purpose was to identify what percentage of various subtypes of MGRS tentatively diagnosed via renal biopsy can be confirmed as MGRS by BMB and followup. Design: In total, 124 renal biopsies with variants of RPD were identified at our center out of 3811 renal biopsies (3.3% of overall cases) over past 10 years. Biopsy cases with known Myeloma, B Cell Lymphoma or Monoclonal Cast Nephropathy were separated as a heavy burden group. The remaining biopsies with RPD were considered as tentative MGRS diagnoses. Their BMB and clinical indices were followed up to determine the percent that resulted in a confirmed MGRS diagnosis. Results: Among the 124 renal paraprotein deposition cases, 43 cases (34.7%) were categorized to the heavy burden group (Figure). The remaining 81 cases with other variants of RPD were further divided into four categories based on the follow-up. Myeloma or Lymphoma were found in 34 cases (27.4%). Twelve outside consultation cases (10%) did not show follow-up biopsies as we were unable to obtain record access. BMB’s diagnosed as nonmalignant (6 cases, 4.8%) or premalignant (29 cases, 23.4%) were confirmed to be MGRS for a total of 35 cases (28.2%). Among the different categories of tentative MGRS, Monoclonal Light/Heavy Chain Deposition Diseases (L/HCDD) had the highest positivity rate for myeloma on the subsequent BMB. Proliferative Glomerulonephritis with Monoclonal Immunoglobulin Deposition (PGNMID) had a high rate of nonmalignant or premalignant diagnosis by BMB. Monoclonal Amyloidosis had some nonmalignant and pre-malignant diagnoses after BMB although myeloma was associated with this renal entity. Conclusions: The data indicate that BMB is crucial for confirming a diagnosis of MGRS. The study also provides pathologists and clinicians with general expectations regarding the possible BMB outcome for the many variants of MGRS identified tentatively via renal biopsy.

A Soft Tissue Tumor With Eml4-Alk Fusion, Granular Cell Changes, Metastasis, And Response To Kinase Inhibitor Therapy In A Young Girl, Zhenhong Qu, Chris Hysell, Ping Zhang, Mark Micale

Conference Presentation Abstracts

Background: An increasing number of soft tissue neoplasms with fusion of well-defined driver genes are being discovered. We report such a case in a 3-year-old girl with a 2-year follow-up. Design: The patient first presented at age of 3.5 years with a painless right axillary/chest wall mass without constitutional symptoms. MRI demonstrated a 4.5 x 3.5 x 3.5 cm T2 hyper- and T1 hypointense mass. The mass was excised and showed a well-demarcated solid lesion with a homogeneous pale-white fleshy cut surface. No necrosis, myxoid or cystic change, hemorrhage, or calcification was noted. Microscopically, it was a variably hypercellular lesion …

A Soft Tissue Tumor With Eml4-Alk Fusion, Granular Cell Changes, Metastasis, And Response To Kinase Inhibitor Therapy In A Young Girl, Zhenhong Qu, Chris Hysell, Ping Zhang, Mark Micale

Conference Presentation Abstracts

Background: An increasing number of soft tissue neoplasms with fusion of well-defined driver genes are being discovered. We report such a case in a 3-year-old girl with a 2-year follow-up. Design: The patient first presented at age of 3.5 years with a painless right axillary/chest wall mass without constitutional symptoms. MRI demonstrated a 4.5 x 3.5 x 3.5 cm T2 hyper- and T1 hypointense mass. The mass was excised and showed a well-demarcated solid lesion with a homogeneous pale-white fleshy cut surface. No necrosis, myxoid or cystic change, hemorrhage, or calcification was noted. Microscopically, it was a variably hypercellular lesion …

Clinical Validation Of A Multiplex Pcr-Based Detection Assay Using Saliva Or Nasopharyngeal Samples For Sars-Cov-2, Influenza A And B, Nikhil S. Sahajpal, Ashis K. Mondal, Sudha Ananth, Allan Njau, Kimya Jones, Pankaj Ahluwalia, Eesha Oza, Ted M. Ross, Vamsi Kota, Arvind Kothandaraman

Pathology, East Africa

The COVID-19 pandemic has resulted in significant diversion of human and material resources to COVID-19 diagnostics, to the extent that influenza viruses and co-infection in COVID-19 patients remains undocumented and pose serious public-health consequences. We optimized and validated a highly sensitive RT-PCR based multiplex-assay for the detection of SARS-CoV-2, influenza A and B viruses in a single-test. This study evaluated clinical specimens (n = 1411), 1019 saliva and 392 nasopharyngeal swab (NPS), tested using two-assays: FDA-EUA approved SARS-CoV-2 assay that targets N and ORF1ab gene, and the PKamp-RT-PCR based assay that targets SARS-CoV-2, influenza viruses A and B. Of the …

Molecular Epidemiology Of Mycobacterium Tuberculosis Complex Strains In Urban And Slum Settings Of Nairobi, Kenya, Glennah Kerubo, Perpetua Ndungu, Yassir Adam Shuaib, Evans Amukoye, Gunturu Revathi, Susanne Homolka, Samuel Kariuki, Matthias Merker, Stefan Niemann

Pathology, East Africa

Kenya is a country with a high tuberculosis (TB) burden. However, knowledge on the genetic diversity of Mycobacterium tuberculosis complex (MTBC) strains and their transmission dynamics is sparsely available. Hence, we used whole-genome sequencing (WGS) to depict the genetic diversity, molecular markers of drug resistance, and possible transmission clusters among MTBC strains in urban and slum settings of Nairobi. We analyzed 385 clinical MTBC isolates collected between 2010 and 2015 in combination with patients’ demographics. We showed that the MTBC population mainly comprises strains of four lineages (L1–L4). The two dominating lineages were L4 with 55.8% (n = 215) and …

Influenza Clinical Testing And Oseltamivir Treatment In Hospitalized Children With Acute Respiratory Illness, 2015-2016., Lubna Hamdan, Varvara Probst, Zaid Haddadin, Herdi Rahman, Andrew J. Spieker, Simon Vandekar, Laura S. Stewart, John V. Williams, Julie A. Boom, Flor Munoz, Janet A. Englund, Rangaraj Selvarangan, Mary A. Staat, Geoffrey A. Weinberg, Parvin H. Azimi, Eileen J. Klein, Monica Mcneal, Leila C. Sahni, Monica N. Singer, Peter G. Szilagyi, Christopher J. Harrison, Manish Patel, Angela P. Campbell, Natasha B. Halasa

Manuscripts, Articles, Book Chapters and Other Papers

BACKGROUND: Antiviral treatment is recommended for all hospitalized children with suspected or confirmed influenza, regardless of their risk profile. Few data exist on adherence to these recommendations, so we sought to determine factors associated with influenza testing and antiviral treatment in children.

METHODS: Hospitalized children(ARI) were enrolled through active surveillance at pediatric medical centers in seven cities between 11/1/2015 and 6/30/2016; clinical information was obtained from parent interview and chart review. We used generalized linear mixed-effects models to identify factors associated with influenza testing and antiviral treatment.

RESULTS: Of the 2299 hospitalized children with ARI enrolled during one influenza season, …

Myeloperoxidase (Mpo) Immunostaining Can Identify Endothelial Injury Of Peritubular Capillaries And Glomeruli In Renal Antibody Mediated Rejection, Olabisi Afolayan-Oloye, Megan Moore, Wei Li, Hassan Kanaan, Ping Zhang

Conference Presentation Abstracts

Background: C4d positive staining in peritubular capillaries (PTC) of renal grafts has been used as a marker to support antibody mediated rejection (AMR), if there are morphologic changes of AMR and the renal recipient has positive donor specific antibody. But it is not clear if the C4d staining is related to any peritubular and glomerular injury during AMR. As injured endothelial cells can uptake the MPO into the endothelial cells, we used MPO immunostaining to highlight glomerular endothelial injury in crescentic glomerulonephritis previously. The goal of this study was to determine if there was an endothelial injury of PTC and …

Proteinuria In Thrombotic Microangiopathy (Tma) Can Be Associated With Adaptive Partial Podocytopathy With Focal Podocyte Hyperplasia, Megan Moore, Olabisi Afolayan-Oloye, Wei Li, Hassan Kanaan, Ping Zhang

Conference Presentation Abstracts

Background: TMA associated renal failure is easy to understand, but it has been difficult to explain the significant proteinuria in some cases of TMA. We recently confirmed that 100% of hyperplastic podocytes in collapsing glomerulopathy stained positively for CD133 (a stem cell/progenitor marker) as previously reported. The goal of this study was to determine if there was significant fusion of foot processes (FFP) and CD133-positive hyperplastic podocytes in TMA to correlate with the proteinuria. Design: The study included 12 negative controls (renal parenchyma away from renal cell carcinoma) and 25 TMA cases, either induced by drugs or due to other …

Myeloperoxidase (Mpo) Immunostaining Can Identify Endothelial Injury Of Peritubular Capillaries And Glomeruli In Renal Antibody Mediated Rejection, Olabisi Afolayan-Oloye, Megan Moore, We Li, Hassan Kanaan, Ping Zhang

Conference Presentation Abstracts

Background: C4d positive staining in peritubular capillaries (PTC) of renal grafts has been used as a marker to support antibody mediated rejection (AMR), if there are morphologic changes of AMR and the renal recipient has positive donor specific antibody. But it is not clear if the C4d staining is related to any peritubular and glomerular injury during AMR. As injured endothelial cells can uptake the MPO into the endothelial cells, we used MPO immunostaining to highlight glomerular endothelial injury in crescentic glomerulonephritis previously. The goal of this study was to determine if there was an endothelial injury of PTC and …

Proteinuria In Thrombotic Microangiopathy (Tma) Can Be Associated With Adaptive Partial Podocytopathy With Focal Podocyte Hyperplasia, Megan Moore, Olabisi Afaolayan-Oloye, Wei Li, Hassan Kanaan, Ping Zhang

Conference Presentation Abstracts

Background: TMA associated renal failure is easy to understand, but it has been difficult to explain the significant proteinuria in some cases of TMA. We recently confirmed that 100% of hyperplastic podocytes in collapsing glomerulopathy stained positively for CD133 (a stem cell/progenitor marker) as previously reported. The goal of this study was to determine if there was significant fusion of foot processes (FFP) and CD133-positive hyperplastic podocytes in TMA to correlate with the proteinuria. Design: The study included 12 negative controls (renal parenchyma away from renal cell carcinoma) and 25 TMA cases, either induced by drugs or due to other …

Variants Associated With Bedaquiline (Bdq) Resistance Identified In Rv0678 And Efflux Pump Genes In Mycobacterium Tuberculosis Isolates From Bdq Naïve Tb Patients In Pakistan, Dania Khalid Saeed, Sadia Shakoor, Safina Abdul Razzak, Zahra Hasan, Saba Faraz Sabzwari, Zahida Azizullah, Akber Kanji, Asghar Nasir, Samreen Shafiq, Najia Karim Ghanchi, Rumina Hasan

Department of Pathology and Laboratory Medicine

Background: Mutations in the Rv0678, pepQ and atpE genes of Mycobacterium tuberculosis (MTB) have been reported to be associated with reduced antimycobacterial susceptibility to bedaquiline (BDQ). Resistance conferring mutations in treatment naïve MTB strains is likely to have implications for BDQ based new drug regimen that aim to shorten treatment duration. We therefore investigated the genetic basis of resistance to BDQ in MTB clinical isolates from BDQ naïve TB patients from Pakistan. In addition, mutations in genes associated with efflux pumps were investigated as an alternate mechanism of resistance.
Methods: Based on convenience sampling, we studied 48 MTB clinical isolates …