Academic Background:

BS (Cell Biology), Cornell University, Ithaca, NY

MD, Brown University, Providence, Rhode Island

Resident, Department of Pathology and Laboratory Medicine, Hospital of the University of Pennsylvania, Philadelphia, PA

Cytopathology Fellow with Prabodh Gupta, Hospital of the University of Pennsylvania, Philadelphia, PA

Academic Interests:

Cytology is the field that uses the smallest possible biopsy for diagnosis, by identifying structural changes in cells and small tissue fragments. My basic research interest has been to try to define diagnostic structural changes in molecular terms (see Basic Science Research Interest below).

My clinical interest is fine needle aspiration (FNA) biopsy. FNAs are minimally invasive, safe, rapid, and relatively painless means of definitive diagnosis. Having performed over 2,500 FNAs in my career so far, a UMASS ultrasound-guided STAT FNA Clinic has been started whereby a Cytopathologist performs and immediately interprets the FNA.

I have also been interested in developing technical solutions to the problem of acquiring and processing microsized pieces of tissue for diagnosis. I invented the CellientTM Automated Cell Block System (covered with eight patents), licensed to Hologic Corporation in Marlborough, MA.  CellientTM automatically recovers small tissue fragments from a specimen container and delivers them to an indexable plane in paraffin for histologic sectioning in under one hour. CellientTM allows fine needle (22-25 guage) biopsies to be examined in essentially the same manner as much larger core biopsies, with essentially 100% recovery and no chance for cross contamination during processing. Two other patents relate to automated processing and embedding of larger biopsies.  An improved microbiopsy needle was patented and clinical trials are pending.  Automating rapid onsite assessment of adequacy of microbiopsies is an important goal for Cytology. 

As criteria become defined at a molecular level, and techniques for procuring and handling micro-sized biopsies are developed, most cancers can be diagnosed with minimally invasive, rapid, and safe cytologic techniques.

Basic Science Research Interests:

In spite of years of progress in cancer research, the diagnosis of cancer still generally requires a pathologist to examine a biopsy by light microscopy. Cytopathologists are experts at recognizing changes in cell structure that are diagnostic of various cancers. Surprisingly, cancer researchers still know very little about how or why cancer cells are structured differently from normal cells.  My long term goal is to bridge the molecular and cellular levels, to learn the biochemical basis and functional significance of diagnostic changes in the structure of cancer cells. My lab has developed the idea that there are predictable relationships between cellular-level structural changes diagnostic of cancer and the genes that are active. In some cases (predictably), cancer genes directly induce the changes diagnostic of the particular cancers associated with the genes.  We have identified 8 different cancer genes with such a relationship to diagnostic cell structural changes, involving chromatin and the nuclear envelope, characteristic of different types of cancers. We think that the structural changes oncogenes induce during their activation provide an essential insight into the functional changes that occur during carcinogenesis.

Nuclear envelope irregularity and changes in large-scale chromatin organization are important diagnostic alterations in many forms of cancer. We have been focused on a pair of tyrosine kinases—RET/PTC and TRK/PTC—that induce the nuclear envelope irregularity and chromatin dispersal diagnostic of papillary thyroid carcinoma. Very likely, but still unproven, these will function very similar to B-RAF V600E in inducing these cellular level diagnostic structural changes.  We have determined the phosphotyrosine docking site on these tyrosine kinases that mediates these changes. We showed that the nuclear lamina composition is very similar between papillary thyroid carcinomas and normal thyroid, and histone composition at a global level is not apparently altered for H3K4m, H3K9m, H3K9/14Ac, and H3K27m. Using micro-injection of RET/PTC into normal thyroid cells in culture, we showed that nuclear envelope irregularity develops during interphase, without an intervening post-mitotic nuclear envelope reassembly, because the nuclear envelope is distorted actively during interphase by forces exerted on it from the cytoskeleton and/or chromatin. Using cell lines we confirmed that there are active interphase deflections of the nuclear lamina in prostate cancer, and we found that depolymerization of actin or microtubules does not inhibit these dynamics, as if chromatin-based forces distorted the nuclear lamina.

The finding of dynamic changes led us to develope a technique for immobilizing living human tissue fragments with mussel-adhesive protein, and performing two-photon microscopy in time lapse.  This live tissue imaging system is amenable to gene editing and therefore offers the potential to model human disease dynamics in vitro.

The paradigm that cancer genes are linked predictably and directly to diagnostic cell structural changes should lead to improved diagnosis of cancer, insight into novel cell physiologies involving chromatin and the nuclear envelope, and a basis for a large-scale screen for novel anticancer drugs. Live cell imaging techniques seem likely to expose new sets of dynamic structural changes with a diagnostic utility surpassing that of classical static imaging.