Publications by authors named "Madalina Tuluc"

59 Publications

Impact of Lymph Node Yield in Patients Undergoing Total Laryngectomy and Neck Dissection.

Ann Otol Rhinol Laryngol 2020 Oct 14:3489420964824. Epub 2020 Oct 14.

Thomas Jefferson University Hospitals, Philadelphia, Pennsylvania, USA.

Objectives: To determine the impact of lymph node yield (LNY) in patients undergoing neck dissection at the time of total laryngectomy (TL). To determine the impact of radiation therapy (RT) on LNY.

Methods: Retrospective review of LNY and clinical outcomes in 232 patients undergoing primary or salvage total laryngectomy (TL) with ND.

Results: Preoperative RT significantly decreased mean LNY from 31.7 to 23.9 nodes ( < .001). In primary TL patients, age ( < .001) and positive margins ( = .044) were associated with decreased OS. In salvage TL patients, only positive margins was associated with poorer OS ( = .009). No LNY cutoff provided significant OS or DFS benefit.

Conclusions: Radiotherapy significantly reduces LNY in patients undergoing TL and ND. Within a single institution cohort, positive margins, but not LNY, is associated with survival in both primary and salvage TL patients. 4.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1177/0003489420964824DOI Listing
October 2020

Discordant Responses Between Primary Head and Neck Tumors and Nodal Metastases Treated With Neoadjuvant Nivolumab: Correlation of Radiographic and Pathologic Treatment Effect.

Front Oncol 2020 2;10:566315. Epub 2020 Dec 2.

Department of Otolaryngology - Head and Neck Surgery, Thomas Jefferson University, Philadelphia, PA, United States.

PD-1 blockade represents a promising treatment in patients with head and neck squamous cell carcinoma (HNSCC). We analyzed results of a neoadjuvant randomized window-of-opportunity trial of nivolumab plus/minus tadalafil to investigate whether immunotherapy-mediated treatment effects vary by site of involvement (primary tumor, lymph nodes) and determine how radiographic tumor shrinkage correlates with pathologic treatment effect.

Patients And Methods: Forty-four patients enrolled in trial NCT03238365 were treated with nivolumab 240 mg intravenously on days 1 and 15 with or without oral tadalafil, as determined by random assignment, followed by surgery on day 31. Radiographic volumetric response (RVR) was defined as percent change in tumor volume from pretreatment to posttreatment CT scan. Responders were defined as those with a 10% reduction in the volume of the primary tumor or lymph nodes (LN). Pathologic treatment effect (PTE) was defined as the area showing fibrosis or lymphohistiocytic inflammation divided by total tumor area.

Results: Sixteen of 32 patients (50%) with pathologic evidence of LN involvement exhibited discordant PTE between primary sites and LN. In four patients with widely discordant adjacent LN, increased PTE was associated with increased infiltration of tumor CD8 T cells and CD163 macrophages, whereas stromal regulatory T cells were associated with low nodal PTE. RVR correlated with PTE at both primary tumor (slope = 0.55, < 0.001) and in LN (slope = 0.62, < 0.05). 89% (16/18) of radiographic non-responders with T1-T3 primary sites had no (n = 7) or minimal PTE (n = 9), whereas 15/17 (88%) of radiographic responders had moderate (n = 12) or complete (n = 3) PTE.

Conclusion: Nivolumab often induces discordant treatment effects between primary tumor sites and metastatic lymph nodes within subjects. This treatment discordance was also demonstrated in adjacent lymph nodes, which may correlate with local immune cell makeup. Finally, although these data were generated by a relatively small population size, our data support the use of early radiographic response to assess immunotherapy treatment effect in HNSCC.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fonc.2020.566315DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7738605PMC
December 2020

Patient with uncontrolled diabetes with a nonpainful, exophytic, purulent mandibular mass.

Oral Surg Oral Med Oral Pathol Oral Radiol 2020 Nov 5. Epub 2020 Nov 5.

Associate Professor, Thomas Jefferson University, Department of Pathology, Philadelphia, PA, USA.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.oooo.2020.11.001DOI Listing
November 2020

Pathologist Opinions about EPIC Beaker AP: a Multi-Institutional Survey of Early Adopters.

J Med Syst 2020 May 6;44(6):111. Epub 2020 May 6.

Department of Pathology, Oregon Health & Science University, Portland, OR, United States.

EPIC Systems Corporation provides a widely used electronic medical record. Beaker Anatomic Pathology is a newly developed laboratory information system (LIS) that has been implemented at a small number of academic pathology departments. Pathologist opinions of EPIC Beaker AP have not been well described in the literature. A 37-question survey was administered to pathologists and pathology trainees to assess overall satisfaction and efficiency of report generation using Beaker AP. Data about experience in pathology, signout responsibilities, Beaker AP usage, and the legacy LIS was also collected. Seventy-four pathologists (51 faculty, 23 residents) responded to the survey (overall response rate 29.7%). Overall pathologist satisfaction with Beaker AP showed high inter-institutional variability; institutions with legacy LISs with a graphical interface had a generally neutral to negative assessment of Beaker AP. The majority of respondents disagreed with the statement "Beaker AP is easy to use and designed for my needs". Pathologists felt that Beaker AP was useful for reviewing clinical information and billing; areas of weakness included searching for prior cases and grossing efficiency. Overall, pathologists had a neutral opinion of whether generating and signing out a complete report was faster in Beaker AP, with marked inter-institutional variation. This variability was likely due to a combination of the efficacy of the legacy LIS, familiarity with Beaker AP at the time of the survey, and institution-specific optimization efforts.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s10916-020-01574-xDOI Listing
May 2020

A Pilot Study of Radiation Therapy in Combination With Pembrolizumab in Patients With Metastatic Renal Cell Cancer.

Am J Clin Oncol 2020 02;43(2):82-86

Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA.

Objectives: There is no study published regarding the benefit of radiation therapy (RT) in combination with immune checkpoint inhibitors (ICIs) for the treatment of metastatic renal cell cancer (mRCC). This report is part of an exploratory study aiming to determine the immunomodulatory activity of RT alone or in combination with pembrolizumab in solid tumors.

Materials And Methods: mRCC patients were treated with a combination of RT (8 Gy×1 or 4 Gy×5) followed by pembrolizumab with or without lead-in dose of pembrolizumab. Treatment response was measured based on the modified Response Evaluation Criteria in Solid Tumors criteria. Adverse events were monitored and graded. Pre-RT and post-RT tumor biopsies were obtained to evaluate programmed death-ligand 1 expression. Immune markers from peripheral blood before, during, and after treatment were analyzed using flow cytometry.

Results: Twelve mRCC patients who progressed on prior antiangiogenic therapy were enrolled. Half had 2 lines of prior therapy. Two patients (16.7%) had partial responses and were on study for 12.4 and 14.5 months. Three patients had stable disease for a period ranging from 4.2 to 10.4 months, whereas 7 patients had progressive disease. Median progression-free survival was 8.6 months and median overall survival was 32.3 months. Three patients had grade ≥3 events (hyperglycemia, thrombocytopenia, transaminitis). Biopsied tissue programmed death-ligand 1 expression and tumor-infiltrating lymphocytes were numerically higher in responders comparing to nonresponders (Modified Proportion Score 45% vs. 30.45%; tumor-infiltrating lymphocytes odds ratio 4.92).

Conclusion: Combining RT with pembrolizumab in pretreated mRCC is well-tolerated and appears to have comparable efficacy with single-agent nivolumab.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/COC.0000000000000636DOI Listing
February 2020

Microscopic tumor invasion of contralateral mucosa in cancer involving unilateral septum.

Head Neck 2019 10 1;41(10):3535-3541. Epub 2019 Aug 1.

Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University Hospital, Philadelphia, Pennsylvania.

Background: Preservation of contralateral mucosa with microscopic tumor invasion in unilateral septal involvement increases the recurrence risk. The purpose of this study was to analyze the risk of invasion of contralateral mucosa in unilateral septal involvement of cancer and to risk stratify patients.

Methods: Retrospective chart review of patients with histologically proven malignancy with unilateral septal involvement and absence of gross septal tumor involvement on the contralateral side were included.

Results: Among 40 patients, majority (55%) belonged to sixth and seventh decade. The most common type was squamous cell carcinoma (63%). Approximately one-fourth (23%) showed microscopic contralateral invasion. Females (OR 12; 95% CI 2.01-71.35) and patients with septal bone invasion (OR 28.5; CI 3.35-242.0) had a higher risk of developing contralateral mucosal invasion.

Conclusion: Complete resection of contralateral mucosa is preferred in areas along the bony septum. When complete resection is not performed, intraoperative frozen section is strongly recommended.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/hed.25870DOI Listing
October 2019

Cigarette Smoke Induces Metabolic Reprogramming of the Tumor Stroma in Head and Neck Squamous Cell Carcinoma.

Mol Cancer Res 2019 09 25;17(9):1893-1909. Epub 2019 Jun 25.

Department of Medical Oncology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania.

Head and neck squamous cell carcinoma (HNSCC) is comprised of metabolically linked distinct compartments. Cancer-associated fibroblasts (CAF) and nonproliferative carcinoma cells display a glycolytic metabolism, while proliferative carcinoma cells rely on mitochondrial oxidative metabolism fueled by the catabolites provided by the adjacent CAFs. Metabolic coupling between these reprogrammed compartments contributes to HNSCC aggressiveness. In this study, we examined the effects of cigarette smoke-exposed CAFs on metabolic coupling and tumor aggressiveness of HNSCC. Cigarette smoke (CS) extract was generated by dissolving cigarette smoke in growth media. Fibroblasts were cultured in CS or control media. HNSCC cells were cocultured and coinjected with CS or control fibroblasts. We found that CS induced oxidative stress, glycolytic flux and MCT4 expression, and senescence in fibroblasts. MCT4 upregulation was critical for fibroblast viability under CS conditions. The effects of CS on fibroblasts were abrogated by antioxidant treatment. Coculture of carcinoma cells with CS fibroblasts induced metabolic coupling with upregulation of the marker of glycolysis MCT4 in fibroblasts and markers of mitochondrial metabolism MCT1 and TOMM20 in carcinoma cells. CS fibroblasts increased CCL2 expression and macrophage migration. Coculture with CS fibroblasts also increased two features of carcinoma cell aggressiveness: resistance to cell death and enhanced cell migration. Coinjection of carcinoma cells with CS fibroblasts generated larger tumors with reduced apoptosis than control coinjections, and upregulation of MCT4 by CS exposure was a driver of these effects. We demonstrate that a tumor microenvironment exposed to CS is sufficient to modulate metabolism and cancer aggressiveness in HNSCC. IMPLICATIONS: CS shifts cancer stroma toward glycolysis and induces head and neck cancer aggressiveness with a mitochondrial profile linked by catabolite transporters and oxidative stress. VISUAL OVERVIEW: http://mcr.aacrjournals.org/content/molcanres/17/9/1893/F1.large.jpg.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/1541-7786.MCR-18-1191DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6726526PMC
September 2019

Early squamous cell carcinoma of the oral tongue with histologically benign lymph nodes: A model predicting local control and vetting of the eighth edition of the American Joint Committee on Cancer pathologic T stage.

Cancer 2019 09 7;125(18):3198-3207. Epub 2019 Jun 7.

Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania.

Background: The eighth edition of the American Joint Committee on Cancer staging manual (AJCC8) added depth of invasion to the definition of pathologic T stage (pT). In the current study, the authors assess pT stage migration and the prognostic performance of the updated pT stage and compare it with other clinicopathologic variables in patients with early squamous cell carcinoma of the oral tongue (OTSCC; tumors measuring ≤4 cm) with histologically benign lymph nodes (pN0).

Methods: A multi-institutional cohort of patients with early OTSCC was restaged as per AJCC8. Primary endpoints were local recurrence (LR) and locoregional recurrence (LRR). Influential variables were identified and an LR/LRR prediction model was developed.

Results: There were a total of 494 patients, with 49 LR and 73 LRR. AJCC8 pT criteria resulted in upstaging of 37.9% of patients (187 of 494 patients), including 34.5% (64 of 185 patients) from pT2 to pT3, without improving the prognostication for LR or LRR. Both LR and LRR were found to be similar for patients with AJCC8 pT2 and pT3 disease. On multivariate analysis, LR was only found to be associated with distance to the closest margin (hazard ratio, 0.36; 95% CI, 0.20-0.64 [P = .0007]) and perineural invasion (hazard ratio, 1.92; 95% CI, 1.10-0.64 [P = .046]). Based on these 2 predictors, a final proportional hazards regression model (which may be used similar to a nomogram) was developed. The proposed model appeared to be superior to AJCC pT stage for estimating the probability of LR and LRR for individual patients with early OTSCC.

Conclusions: AJCC8 pT criteria resulted in pT upstaging of patients with pN0 disease without improved LR or LRR prognostication. The proposed model based on distance to the closest margin and perineural invasion, status outperformed pT as a predictor of LR and LRR in patients with early OTSCC.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/cncr.32199DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7723468PMC
September 2019

Pigmented Melanotic Schwannoma of the Neck: Report of 2 Cases and Review of the Literature.

Ear Nose Throat J 2019 Feb 13;98(2):102-106. Epub 2019 Feb 13.

1 Department of Otolaryngology-Head and Neck Surgery, Thomas Jefferson University, Philadelphia, PA, USA.

Background:: Melanotic schwannoma is a rare tumor with indeterminate biologic behavior and varying treatment recommendations.

Methods:: We report 2 cases of pigmented melanotic schwannoma of the head and neck and perform literature review. The pathologic and immunohistochemical characteristics of melanotic schwannoma are reviewed.

Results:: Two cases of melanotic schwannoma are presented. Both cases underwent surgical resection with one patient receiving adjuvant radiation therapy.

Conclusions:: Melanotic schwannoma is a rare nerve sheath tumor that is frequently mistaken for malignant melanoma. We describe 2 cases of pigmented melanotic schwannoma of the head and neck with different presentations and review the histopathological and immunohistochemical features.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1177/0145561319826542DOI Listing
February 2019

INI1/SMARCB1-Deficient Carcinoma (Rhabdoid Tumor) of the Lacrimal Gland.

Ophthalmic Plast Reconstr Surg 2019 Mar/Apr;35(2):e41-e43

Wills Eye Hospital, Philadelphia, Pennsylvania, U.S.A.

Integrase interactor 1 (INI1) is a tumor suppressor gene that is ubiquitously expressed in all nucleated cells. The loss of INI1 protein activity was first demonstrated in aggressive pediatric tumors, including atypical teratoid/rhabdoid (AT/RT) tumor of the central nervous system and malignant rhabdoid tumor of the kidney. Subsequently, INI1 deficiency was discovered in other pediatric and some adult neoplasms. The spectrum of INI1-negative tumors includes a wide variety of neoplasms that occur over a wide age range, are variably aggressive, and have a variable rhabdoid component on histopathologic evaluation. In this report, the authors describe a 27-year-old gravid woman with INI1-deficient carcinoma of the lacrimal gland, previously not described in this location.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/IOP.0000000000001311DOI Listing
December 2019

Loss of CD169 Subcapsular Macrophages during Metastatic Spread of Head and Neck Squamous Cell Carcinoma.

Otolaryngol Head Neck Surg 2019 07 12;161(1):67-73. Epub 2019 Feb 12.

1 Department of Otolaryngology-Head and Neck Surgery, Thomas Jefferson University, Philadelphia, Pennsylvania, USA.

Objective: The purpose of this study is to assess CD169 expression in metastatic and nearby tumor-free lymph nodes of patients with head and neck squamous cell carcinoma (SCC).

Study Design: Retrospective analysis based on immunohistochemistry.

Setting: Tertiary care center.

Subjects And Methods: The abundance of CD169 cells in the subcapsular sinuses (SCSs) of lymph nodes was assessed immunohistochemically in paraffin-embedded tissue samples derived from 22 patients with oral cavity and oropharyngeal SCC.

Results: SCSs of lymph nodes harboring metastatic SCC contained significantly fewer CD169 macrophages (106.5 ± 113.6 cells/mm) compared to nearby tumor-free lymph nodes (321.3 ± 173.4 cells/mm, < .001). This observation extended to 21 of the 22 cases investigated. In addition, 6 patients who later developed recurrent disease contained lower numbers of CD169 cells (268.6 ± 169.5 cells/mm) in nearby tumor-free lymph nodes compared to 341.0 ± 176.1 cells/mm in those who remained disease free ( = .399). Human papillomavirus (HPV)-positive patients (n = 4) had a 6-fold lower number of CD169 cells in metastatic nodes (61.2 ± 85.5 cells/mm) compared to nearby tumor-free lymph nodes (369.5 ± 175.5 cells/mm, = .028). In comparison, HPV-negative patients had only a 3-fold reduction (116.6 ± 118.5 cells/mm vs 310.6 ± 176.2 cells/mm, < .001).

Conclusion: Metastatic spread of SCC to regional lymph nodes is associated with lower abundance of CD169 macrophages in the SCSs of draining lymph nodes. These results set the stage for an in-depth investigation into the mechanism(s) by which metastatic SCC controls CD169 macrophage abundance and its significance as it relates to prognosis and treatment response.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1177/0194599819829741DOI Listing
July 2019

Primary Cutaneous Angiosarcoma of the Eyelid: A Diagnostic and Therapeutic Challenge.

Ocul Oncol Pathol 2018 Jun 12;4(4):230-235. Epub 2018 Jan 12.

Department of Ophthalmic Pathology, Thomas Jefferson University, Philadelphia, PA, USA.

Primary cutaneous angiosarcoma is a rare vasoformative malignant neoplasm that can present a diagnostic and therapeutic challenge. We describe a 76-year-old Caucasian man with right upper eyelid swelling and nodularity, initially suspected clinically to represent either ocular adnexal lymphoma or basal cell carcinoma. Incisional biopsy and wide resection of the mass with frozen section control of margins were interpreted as compatible with hobnail (Dabska-retiform) hemangioendothelioma. Foci of atypia were noted in the tumor, raising speculation of evolution into a more aggressive neoplasm, such as conventional angiosarcoma. The patient subsequently underwent two additional wide resections with frozen section control of margins in an attempt to obtain complete excision of residual tumor, which demonstrated histopathologic features favoring angiosarcoma. The histologic material from the original and subsequent resections was sent in consultation to several soft tissue pathology experts and the final diagnosis of low-grade cutaneous angiosarcoma was established. Despite repeated surgical interventions, there was continued persistence of the tumor in the deep orbital tissues. Various management options, including adjuvant radiotherapy/chemotherapy with and without orbital exenteration, were discussed. The patient decided against further surgical intervention and is currently undergoing adjuvant radiotherapy/chemotherapy. This case illustrates the diagnostic and management difficulties of ocular adnexal angiosarcoma.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1159/000485427DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6322085PMC
June 2018

Metformin Clinical Trial in HPV+ and HPV- Head and Neck Squamous Cell Carcinoma: Impact on Cancer Cell Apoptosis and Immune Infiltrate.

Front Oncol 2018 11;8:436. Epub 2018 Oct 11.

Department of Medical Oncology, Thomas Jefferson University Philadelphia, Philadelphia, PA, United States.

Metformin, an oral anti-hyperglycemic drug which inhibits mitochondrial complex I and oxidative phosphorylation has been reported to correlate with improved outcomes in head and neck squamous cell carcinoma (HNSCC) and other cancers. This effect is postulated to occur through disruption of tumor-driven metabolic and immune dysregulation in the tumor microenvironment (TME). We report new findings on the impact of metformin on the tumor and immune elements of the TME from a clinical trial of metformin in HNSCC. Human papilloma virus-(HPV-) tobacco+ mucosal HNSCC samples ( = 12) were compared to HPV+ oropharyngeal squamous cell carcinoma (OPSCC) samples ( = 17) from patients enrolled in a clinical trial. Apoptosis in tumor samples pre- and post-treatment with metformin was compared by deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay. Metastatic lymph nodes with extra-capsular extension (ECE) in metformin-treated patients ( = 7) were compared to archival lymph node samples with ECE ( = 11) for differences in immune markers quantified by digital image analysis using co-localization and nuclear algorithms (PD-L1, FoxP3, CD163, CD8). HPV-, tobacco + HNSCC (mean Δ 13.7/high power field) specimens had a significantly higher increase in apoptosis compared to HPV+ OPSCC specimens (mean Δ 5.7/high power field) ( < 0.001). Analysis of the stroma at the invasive front in ECE nodal specimens from both HPV-HNSCC and HPV+ OPSCC metformin treated specimens showed increased CD8+ effector T cell infiltrate (mean 22.8%) compared to archival specimens (mean 10.7%) ( = 0.006). Similarly, metformin treated specimens showed an increased FoxP3+ regulatory T cell infiltrate (mean 9%) compared to non-treated archival specimens (mean 5%) ( = 0.019). This study presents novel data demonstrating that metformin differentially impacts HNSCC subtypes with greater apoptosis in HPV-HNSCC compared to HPV+ OPSCC. Moreover, we present the first human evidence that metformin may also trigger increased CD8+ Teff and FoxP3+ Tregs in the TME, suggesting an immunomodulatory effect in HNSCC. Further research is necessary to assess the effect of metformin on the TME of HNSCC.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fonc.2018.00436DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6193523PMC
October 2018

Monocarboxylate Transporter 4 (MCT4) Knockout Mice Have Attenuated 4NQO Induced Carcinogenesis; A Role for MCT4 in Driving Oral Squamous Cell Cancer.

Front Oncol 2018 28;8:324. Epub 2018 Aug 28.

Department of Pathology, Anatomy and Cell Biology, Sydney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, United States.

Head and neck squamous cell carcinoma (HNSCC) is the 6th most common human cancer and affects approximately 50,000 new patients every year in the US. The major risk factors for HNSCC are tobacco and alcohol consumption as well as oncogenic HPV infections. Despite advances in therapy, the overall survival rate for all-comers is only 50%. Understanding the biology of HNSCC is crucial to identifying new biomarkers, implementing early diagnostic approaches and developing novel therapies. As in several other cancers, HNSCC expresses elevated levels of MCT4, a member of the SLC16 family of monocarboxylate transporters. MCT4 is a H-linked lactate transporter which functions to facilitate lactate efflux from highly glycolytic cells. High MCT4 levels in HNSCC have been associated with poor prognosis, but the role of MCT4 in the development and progression of this cancer is still poorly understood. In this study, we used 4-nitroquinoline-1-oxide (4NQO) to induce oral cancer in MCT4 and wild type littermates, recapitulating the disease progression in humans. Histological analysis of mouse tongues after 23 weeks of 4NQO treatment showed that MCT4 mice developed significantly fewer and less extended invasive lesions than wild type. In mice, as in human samples, MCT4 was not expressed in normal oral mucosa but was detected in the transformed epithelium. In the 4NQO treated mice we detected MCT4 in foci of the basal layer undergoing transformation, and progressively in areas of carcinoma and invasive carcinomas. Moreover, we found MCT4 positive macrophages within the tumor and in the stroma surrounding the lesions in both human samples of HNSCC and in the 4NQO treated animals. The results of our studies showed that MCT4 could be used as an early diagnostic biomarker of HNSCC. Our finding with the MCT4 mice suggest MCT4 is a driver of progression to oral squamous cell cancer and MCT4 inhibitors could have clinical benefits for preventing invasive HNSCC.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fonc.2018.00324DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6120975PMC
August 2018

Measuring Depth of Invasion in Early Squamous Cell Carcinoma of the Oral Tongue: Positive Deep Margin, Extratumoral Perineural Invasion, and Other Challenges.

Head Neck Pathol 2019 Jun 26;13(2):154-161. Epub 2018 Apr 26.

Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, PA, USA.

The 8th edition of American Joint Committee on Cancer (AJCC 8th) staging manual incorporated depth of invasion (DOI) into pT stage of oral cavity cancer. The aim of this study was to characterize several histological findings that may complicate measurement of DOI in early conventional squamous cell carcinomas (SCC) of the oral tongue: (1) lack of or minimal residual carcinoma following biopsy; (2) positive deep margin; (3) extratumoral perineural invasion (PNI); and (4) lymphatic or vascular invasion. Conventional SCC of the oral tongue (n = 407) with the largest dimension of ≤ 4 cm and with a negative elective cervical lymph node dissection (pN0) were reviewed. A clear plastic ruler was used to measure DOI by dropping a "plumb line" to the deepest point of the invasive tumor from the level of the basement membrane of the normal mucosa closest to the invasive tumor. Examples of identifying  reference point on the mucosal surface of oral tongue from which to measure the DOI are illustrated. In the experience of one contributing institution, the residual carcinoma was absent in 14.2% of glossectomies (34/239), while in 4.8% of cases (10/205) there was only minimal residual carcinoma. In 11.5% (21/183) of pT2 cases the deep margin was positive and thus DOI and pT may be underestimated. Of all cases with PNI, extratumoral PNI was identified in 23.1% (31/134) of cases, but represented the deepest point of invasion in only two cases. In one case, lymphatic invasion represented the deepest point of invasion and could have led to upstaging from pT1 to pT2. In conclusion, DOI measurement for SCC of the oral tongue may require re-examination of the diagnostic biopsy in up to 20% of cases due to the absence or only minimal residual carcinoma in glossectomy specimens. In 11.5% of apparently pT2 cases, DOI may be underestimated due to the positive deep margin. Rarely, extratumoral PNI or lymphatic invasion may be the deepest point of invasion. Overall, two issues (absent or minimal residual disease and positive deep margin) may confound DOI measurement in early SCCs of oral tongue.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s12105-018-0925-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6514023PMC
June 2019

TERT, HRAS, and EIF1AX Mutations in a Patient with Follicular Adenoma.

Thyroid 2018 06 18;28(6):815-817. Epub 2018 May 18.

1 Department of Otolaryngology-Head and Neck Surgery, Thomas Jefferson University , Philadelphia, Pennsylvania.

Background: Molecular markers are increasingly used as diagnostic tools in the management of thyroid nodules. There is a paucity of studies evaluating the prevalence of molecular markers in benign lesions.

Patient Findings: A 68-year-old woman with hypothyroidism presented with a right thyroid nodule, which was atypia of undetermined significance on cytology. The fine-needle aspirate of the nodule was examined with next-generation sequencing and found to harbor a C228T mutation in the TERT gene, a Q61R mutation in the HRAS gene, and an A113_splice mutation in the EIF1AX gene. Right thyroid lobectomy was performed, with final pathology showing follicular adenoma. All three mutations detected in the original fine-needle aspirate specimen were detected in the final surgical specimen as well.

Conclusions: A rare case of TERT, HRAS, and EIF1AX mutations is reported in a patient with follicular adenoma. TERT promoter mutations may be an early genetic event in the molecular pathogenesis of follicular thyroid carcinoma.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1089/thy.2017.0504DOI Listing
June 2018

Pilot study demonstrating metabolic and anti-proliferative effects of in vivo anti-oxidant supplementation with N-Acetylcysteine in Breast Cancer.

Semin Oncol 2017 06 10;44(3):226-232. Epub 2017 Oct 10.

Department of Medical Oncology, Thomas Jefferson University, Philadelphia, PA. Electronic address:

Background: High oxidative stress as defined by hydroxyl and peroxyl activity is often found in the stroma of human breast cancers. Oxidative stress induces stromal catabolism, which promotes cancer aggressiveness. Stromal cells exposed to oxidative stress release catabolites such as lactate, which are up-taken by cancer cells to support mitochondrial oxidative phosphorylation. The transfer of catabolites between stromal and cancer cells leads to metabolic heterogeneity between these cells and increased cancer cell proliferation and reduced apoptosis in preclinical models. N-Acetylcysteine (NAC) is an antioxidant that reduces oxidative stress and reverses stromal catabolism and stromal-carcinoma cell metabolic heterogeneity, resulting in reduced proliferation and increased apoptosis of cancer cells in experimental models of breast cancer. The purpose of this clinical trial was to determine if NAC could reduce markers of stromal-cancer metabolic heterogeneity and markers of cancer cell aggressiveness in human breast cancer.

Methods: Subjects with newly diagnosed stage 0 and I breast cancer who were not going to receive neoadjuvant therapy prior to surgical resection were treated with NAC before definitive surgery to assess intra-tumoral metabolic markers. NAC was administered once a week intravenously at a dose of 150 mg/kg and 600 mg twice daily orally on the days not receiving intravenous NAC. Histochemistry for the stromal metabolic markers monocarboxylate transporter 4 (MCT4) and caveolin-1 (CAV1) and the Ki67 proliferation assay and TUNEL apoptosis assay in carcinoma cells were performed in pre- and post-NAC specimens.

Results: The range of days on NAC was 14-27 and the mean was 19 days. Post-treatment biopsies showed significant decrease in stromal MCT4 and reduced Ki67 in carcinoma cells. NAC did not significantly change stromal CAV1 and carcinoma TUNEL staining. NAC was well tolerated.

Conclusions: NAC as a single agent reduces MCT4 stromal expression, which is a marker of glycolysis in breast cancer with reduced carcinoma cell proliferation. This study suggests that modulating metabolism in the tumor microenvironment has the potential to impact breast cancer proliferation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1053/j.seminoncol.2017.10.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5737796PMC
June 2017

Metformin Effects on Metabolic Coupling and Tumor Growth in Oral Cavity Squamous Cell Carcinoma Coinjection Xenografts.

Otolaryngol Head Neck Surg 2018 05 12;158(5):867-877. Epub 2017 Dec 12.

1 Department of Otolaryngology-Head and Neck Surgery, Thomas Jefferson University, Philadelphia, Pennsylvania, USA.

Objective Many aggressive head and neck cancers contain 2 metabolically coupled tumor compartments: a glycolytic stromal compartment with low caveolin-1 (CAV1) and high monocarboxylate transporter 4 (MCT4) expression and a highly proliferative carcinoma cell compartment with high MCT1. Metabolites are shuttled by MCTs from stroma to carcinoma to fuel tumor growth. We studied the effect of carcinoma-fibroblast coinjection and metformin administration on a mouse model of head and neck squamous cell carcinoma. Study Design Xenograft head and neck squamous cell carcinoma model. Setting Basic science laboratory. Subjects and Methods Oral cavity carcinoma cells were injected alone or as coinjection with human fibroblasts into nude mice to generate xenograft tumors. Tumors were excised and stained with immunohistochemistry for markers of metabolic coupling and apoptosis, including MCT1, MCT4, CAV1, and TUNEL assay (terminal deoxynucleotidyl transferase nick end labeling). Strength of staining was assessed by a pathologist or computer-assisted pathology software. Metformin was administered orally to mice to test effects on immunohistochemical markers in xenografts. Results Coinjection tumors were 2.8-fold larger ( P = .048) and had 1.4-fold stronger MCT1 staining ( P = .016) than tumors from homotypic carcinoma cell injection. Metformin decreased the size of coinjection xenograft tumors by 45% ( P = .025). Metformin reduced MCT1 staining by 28% ( P = .05) and increased carcinoma cell apoptosis 1.8-fold as marked by TUNEL assay ( P = .005). Metformin did not have a significant effect on tumor size when CAV1 knockdown fibroblasts were used in coinjection. Conclusion Coinjection with fibroblasts increases tumor growth and metabolic coupling in oral cavity cancer xenografts. Fibroblast CAV1 expression is required for metformin to disrupt metabolic coupling and decrease xenograft size.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1177/0194599817746934DOI Listing
May 2018

Improving margin revision: Characterization of tumor bed margins in early oral tongue cancer.

Oral Oncol 2017 12 1;75:184-188. Epub 2017 Nov 1.

Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, PA, USA. Electronic address:

Objectives: To improve margin revision, this study characterizes the number, fragmentation, and orientation of tumor bed margins (TBM) in patients with pT1-2 pN0 squamous cell carcinoma (SCC) of the oral tongue.

Materials And Methods: Pathology reports (n=346) were reviewed. TBM parameters were indexed. In Group 1 patients all margins were obtained from the glossectomy specimen and there were no TBM. In Revision Group/Group 2 (n=103), tumor bed was sampled to revise suboptimal margins identified by examination of the glossectomy specimen. In Group 3 (n=124), TBM were obtained before examination of the glossectomy specimen.

Results And Conclusions: Fewer TBMs were obtained per patient in Group 2 compared to Group 3 (57/103, 55% of patients with <3 vs. 117/124, 94%, ≥3 TBMs, respectively). The new margin surface was more frequently indicated in Group 2 compared to Group 3 (59/103, 57%, vs. 19/124, 15%, p<.001). If glossectomy specimen margins are accepted as the reference standard, then the TBM was 15% sensitive in Group 2 (95% confidence interval [CI], 7-29) and 32% sensitive in Group 3 (95% CI, 15-55). TBM fragmentation (23/103, 22% vs. 42/124, 34%) and frozen vs. permanent discrepancies (8/103, 3% vs. 3/124, 2%) were similar between Groups 2 and 3. The new margin surface was not indicated in 6 of 11 cases with discrepant frozen vs. permanent pathology findings, precluding judgment on final margin status. To facilitate the assessment of final margins, TBM should be represented by one tissue fragment with a marked new margin surface.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.oraloncology.2017.10.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5774620PMC
December 2017

EIF1AX Mutation in a Patient with Hürthle Cell Carcinoma.

Endocr Pathol 2018 Mar;29(1):27-29

Department of Otolaryngology-Head and Neck Surgery, Thomas Jefferson University, 925 Chestnut Street 6th Floor, Philadelphia, PA, 19107, USA.

The EIF1AX gene is a novel cancer gene that has been reported in the tumorigenesis of papillary thyroid carcinoma, follicular variant papillary thyroid carcinoma, and anaplastic thyroid carcinoma. A 71-year-old woman presented with a right thyroid mass, which was follicular neoplasm on cytology. The fine needle aspirate of the nodule was examined by next-generation sequencing and found to harbor EIF1AX and TP53 mutations. Right thyroid lobectomy was performed with final pathology showing Hürthle cell carcinoma with capsular and vascular invasion. We report an EIF1AX mutation in a patient found to have Hürthle cell carcinoma.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s12022-017-9501-8DOI Listing
March 2018

Macrophage type 2 differentiation in a patient with laryngeal squamous cell carcinoma and metastatic prostate adenocarcinoma to the cervical lymph nodes.

J Immunother Cancer 2017 07 18;5(1):60. Epub 2017 Jul 18.

Department of Otolaryngology-Head and Neck Surgery, Thomas Jefferson University, 925 Chestnut Street, 6th Floor, Philadelphia, PA, 19107, USA.

Background: The tumor microenvironment often polarizes infiltrating macrophages towards a type 2, or M2 phenotype, that is characterized by expression of various cysteine-rich, scavenger receptors, including CD163. The primary function of M2 macrophages is to facilitate wound healing. As such, they are capable of providing metabolic support to a growing tumor, neovascularization, as well as protection from cytotoxic T cells. The tumor microenvironment contains a milieu of secreted factors and vesicles, which in certain circumstances can gain access to lymphatic vessels that drain to local lymph nodes.

Case Presentation: We report a 59-year-old male with recurrent T4 squamous cell carcinoma (SCC) of the larynx with synchronous prostate adenocarcinoma confined to the prostate and regional pelvic lymph nodes, without metastatic disease. The patient underwent salvage total laryngectomy and bilateral neck dissection with final pathology revealing a recurrent moderately differentiated SCC involving the larynx as well as prostate cancer in draining level 4 cervical lymph nodes bilaterally. CD163 staining was performed on the primary tumor, a negative draining lymph node, and a level four lymph node with a focus of metastatic prostate cancer and compared to benign controls. The negative draining lymph node demonstrated a large CD163 population of cells as did the interface of the focus of prostate cancer and surrounding lymph node. CD163 levels were markedly increased in this patient compared to benign lymph node controls. The macrophage differentiation at the primary tumor in the larynx was strongly CD163 positive supporting an immune permissive environment for tumor growth and metastasis.

Conclusion: We describe a unique case of solitary metastatic prostate cancer to cervical lymph nodes in the setting of a laryngeal cancer. These observations suggest that SCC-derived factors drive a tumor-supportive environment in draining lymph nodes dominated by an overwhelming number of CD163+, M2 macrophages. Lymph nodes that are 'primed' by SCC differentiation to M2 phenotype may be at higher risk of harboring metastases.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s40425-017-0264-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5514504PMC
July 2017

Tumor Metabolism in the Microenvironment of Nodal Metastasis in Oral Squamous Cell Carcinoma.

Otolaryngol Head Neck Surg 2017 11 13;157(5):798-807. Epub 2017 Jun 13.

4 Department of Medical Oncology, Thomas Jefferson University, Philadelphia, Pennsylvania, USA.

Objective In many cancers, including head and neck squamous cell carcinoma (HNSCC), different regions within a tumor have different metabolic phenotypes. Transfer of metabolites between compartments promotes tumor growth and aggressive behavior. Metabolic compartmentalization in HNSCC nodal metastases has not been studied, nor has its impact on extracapsular extension or clinical outcomes been determined. Study Design Retrospective analysis based on immunohistochemistry staining. Setting Tertiary care center. Subjects and Methods Primary tumors and nodal metastases from 34 surgically treated oral cavity HNSCC patients with extracapsular extension (ECE) were stained for monocarboyxlate transporter (MCT) 4, MCT1, translocase of outer mitochondrial membrane 20, and Ki-67. Strength of staining was assessed using a computer-assisted pathology algorithm. Immunohistochemistry (IHC) scores along with clinical factors were used to predict disease-free survival (DFS). Results Patterns of IHC staining showed metabolic compartmentalization both at the primary tumor sites and in nodal metastases. MCT4 staining in the perinodal stroma was significantly higher in specimens with ECE greater than 1 mm (macro-ECE, P = .01). Patients with high perinodal MCT4 staining were compared with those with low perinodal MCT4 staining. On multivariate analysis, only high perinodal MCT4 staining had a significant impact on DFS ( P = .02); patients with high perinodal MCT4 had worse survival. DFS was not significantly worsened by advancing T stage, N stage, ECE extent, or perineural invasion. Conclusion Oral HNSCC displays compartmentalized tumor metabolism at both primary and metastases. Greater cancer-associated stromal conversion around ECE, denoted by high stromal MCT4, may be a biomarker for aggressive disease and worsened DFS.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1177/0194599817709224DOI Listing
November 2017

Desmoglein 2 modulates extracellular vesicle release from squamous cell carcinoma keratinocytes.

FASEB J 2017 08 24;31(8):3412-3424. Epub 2017 Apr 24.

Department of Dermatology and Cutaneous Biology, Thomas Jefferson University, Philadelphia, Pennsylvania, USA;

Extracellular vesicles (EVs) are nanoscale membrane-derived vesicles that serve as intercellular messengers carrying lipids, proteins, and genetic material. Substantial evidence has shown that cancer-derived EVs, secreted by tumor cells into the blood and other bodily fluids, play a critical role in modulating the tumor microenvironment and affecting the pathogenesis of cancer. Here we demonstrate for the first time that squamous cell carcinoma (SCC) EVs were enriched with the C-terminal fragment of desmoglein 2 (Dsg2), a desmosomal cadherin often overexpressed in malignancies. Overexpression of Dsg2 increased EV release and mitogenic content including epidermal growth factor receptor and c-Src. Inhibiting ectodomain shedding of Dsg2 with the matrix metalloproteinase inhibitor GM6001 resulted in accumulation of full-length Dsg2 in EVs and reduced EV release. When cocultured with Dsg2/green fluorescence protein-expressing SCC cells, green fluorescence protein signal was detected by fluorescence-activated cell sorting analysis in the CD90 fibroblasts. Furthermore, SCC EVs activated Erk1/2 and Akt signaling and enhanced fibroblast cell proliferation. Dsg2 was highly up-regulated in the head and neck SCCs, and EVs isolated from sera of patients with SCC were enriched in Dsg2 C-terminal fragment and epidermal growth factor receptor. This study defines a mechanism by which Dsg2 expression in cancer cells can modulate the tumor microenvironment, a step critical for tumor progression.-Overmiller, A. M., Pierluissi, J. A., Wermuth, P. J., Sauma, S., Martinez-Outschoorn, U., Tuluc, M., Luginbuhl, A., Curry, J., Harshyne, L. A., Wahl, J. K. III, South, A. P., Mahoney, M. G. Desmoglein 2 modulates extracellular vesicle release from squamous cell carcinoma keratinocytes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1096/fj.201601138RRDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5503718PMC
August 2017

MCT1 in Invasive Ductal Carcinoma: Monocarboxylate Metabolism and Aggressive Breast Cancer.

Front Cell Dev Biol 2017 3;5:27. Epub 2017 Apr 3.

Department of Medical Oncology, Sidney Kimmel Cancer Center, Thomas Jefferson UniversityPhiladelphia, PA, USA.

Monocarboxylate transporter 1 (MCT1) is an importer of monocarboxylates such as lactate and pyruvate and a marker of mitochondrial metabolism. MCT1 is highly expressed in a subgroup of cancer cells to allow for catabolite uptake from the tumor microenvironment to support mitochondrial metabolism. We studied the protein expression of MCT1 in a broad group of breast invasive ductal carcinoma specimens to determine its association with breast cancer subtypes and outcomes. MCT1 expression was evaluated by immunohistochemistry on tissue micro-arrays (TMA) obtained through our tumor bank. Two hundred and fifty-seven cases were analyzed: 180 cases were estrogen receptor and/or progesterone receptor positive (ER+ and/or PR+), 62 cases were human epidermal growth factor receptor 2 positive (HER2+), and 56 cases were triple negative breast cancers (TNBC). MCT1 expression was quantified by digital pathology with Aperio software. The intensity of the staining was measured on a continuous scale (0-black to 255-bright white) using a co-localization algorithm. Statistical analysis was performed using a linear mixed model. High MCT1 expression was more commonly found in TNBC compared to ER+ and/or PR+ and compared to HER-2+ ( < 0.001). Tumors with an component were less likely to stain strongly for MCT1 ( < 0.05). High nuclear grade was associated with higher MCT1 staining ( < 0.01). Higher T stage tumors were noted to have a higher expression of MCT1 ( < 0.05). High MCT1 staining in cancer cells was associated with shorter progression free survival, increased risk of recurrence, and larger size independent of TNBC status ( < 0.05). MCT1 expression, which is a marker of high catabolite uptake and mitochondrial metabolism, is associated with recurrence in breast invasive ductal carcinoma. MCT1 expression as quantified with digital image analysis may be useful as a prognostic biomarker and to design clinical trials using MCT1 inhibitors.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fcell.2017.00027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5376582PMC
April 2017

Metformin effects on head and neck squamous carcinoma microenvironment: Window of opportunity trial.

Laryngoscope 2017 08 10;127(8):1808-1815. Epub 2017 Feb 10.

Department of Medical Oncology, Philadelphia, Pennsylvania, U.S.A.

Objective: The tumor microenvironment frequently displays abnormal cellular metabolism, which contributes to aggressive behavior. Metformin inhibits mitochondrial oxidative phosphorylation, altering metabolism. Though the mechanism is unclear, epidemiologic studies show an association between metformin use and improved outcomes in head and neck squamous cell carcinoma (HNSCC). We sought to determine if metformin alters metabolism and apoptosis in HNSCC tumors.

Study Design: Window of opportunity trial of metformin between diagnostic biopsy and resection. Participants were patients with newly diagnosed HNSCC. Fifty patients were enrolled, and 39 completed a full-treatment course. Metformin was titrated to standard diabetic dose (2,000 mg/day) for a course of 9 or more days prior to surgery.

Methods: Immunohistochemistry (IHC) for the metabolic markers caveolin-1 (CAV1), B-galactosidase (GALB), and monocarboxylate transporter 4 (MCT4), as well as the Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) apoptosis assay and Ki-67 IHC, were performed in pre- and postmetformin specimens. Exploratory mass spectroscopy imaging (MSI) to assess lactate levels also was performed in three subjects.

Results: Metformin was well tolerated. The average treatment course was 13.6 days. Posttreatment specimens showed a significant increase in stromal CAV1 (P < 0.001) and GALB (P < 0.005), as well as tumor cell apoptosis by TUNEL assay (P < 0.001). There was no significant change in stromal MCT4 expression or proliferation measured by Ki67. Lactate levels in carcinoma cells were increased 2.4-fold postmetformin (P < 0.05), as measured by MSI.

Conclusion: Metformin increases markers of reduced catabolism and increases senescence in stromal cells as well as carcinoma cell apoptosis. This study demonstrates that metformin modulates metabolism in the HNSCC microenvironment.

Level Of Evidence: 4. Laryngoscope, 127:1808-1815, 2017.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/lary.26489DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5515672PMC
August 2017

TP53-inducible Glycolysis and Apoptosis Regulator (TIGAR) Metabolically Reprograms Carcinoma and Stromal Cells in Breast Cancer.

J Biol Chem 2016 Dec 1;291(51):26291-26303. Epub 2016 Nov 1.

From the Department of Medical Oncology,

A subgroup of breast cancers has several metabolic compartments. The mechanisms by which metabolic compartmentalization develop in tumors are poorly characterized. TP53 inducible glycolysis and apoptosis regulator (TIGAR) is a bisphosphatase that reduces glycolysis and is highly expressed in carcinoma cells in the majority of human breast cancers. Hence we set out to determine the effects of TIGAR expression on breast carcinoma and fibroblast glycolytic phenotype and tumor growth. The overexpression of this bisphosphatase in carcinoma cells induces expression of enzymes and transporters involved in the catabolism of lactate and glutamine. Carcinoma cells overexpressing TIGAR have higher oxygen consumption rates and ATP levels when exposed to glutamine, lactate, or the combination of glutamine and lactate. Coculture of TIGAR overexpressing carcinoma cells and fibroblasts compared with control cocultures induce more pronounced glycolytic differences between carcinoma and fibroblast cells. Carcinoma cells overexpressing TIGAR have reduced glucose uptake and lactate production. Conversely, fibroblasts in coculture with TIGAR overexpressing carcinoma cells induce HIF (hypoxia-inducible factor) activation with increased glucose uptake, increased 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase-3 (PFKFB3), and lactate dehydrogenase-A expression. We also studied the effect of this enzyme on tumor growth. TIGAR overexpression in carcinoma cells increases tumor growth in vivo with increased proliferation rates. However, a catalytically inactive variant of TIGAR did not induce tumor growth. Therefore, TIGAR expression in breast carcinoma cells promotes metabolic compartmentalization and tumor growth with a mitochondrial metabolic phenotype with lactate and glutamine catabolism. Targeting TIGAR warrants consideration as a potential therapy for breast cancer.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1074/jbc.M116.740209DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5159492PMC
December 2016

Molecular Profiling of Synchronous Colon Cancers and Anaplastic Thyroid Cancer in a Patient with Lynch Syndrome.

J Gastrointest Cancer 2018 Jun;49(2):203-206

Department of Medical Oncology, Thomas Jefferson University, Philadelphia, PA, USA.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s12029-016-9878-5DOI Listing
June 2018

Immune biomarkers of treatment failure for a patient on a phase I clinical trial of pembrolizumab plus radiotherapy.

J Hematol Oncol 2016 Sep 23;9(1):96. Epub 2016 Sep 23.

Department of Radiation Oncology, Bodine Center, Sidney Kimmel Medical College at Thomas Jefferson University, 111 South 11th Street, Philadelphia, PA, 19107, USA.

Background: Pembrolizumab is a monoclonal antibody that is designed against programmed cell death protein 1 (PD-1). Pembrolizumab and other immunocheckpoint-blocking monoclonal antibodies work by modulating a patient's own immune system to increase anti-tumor activity. While immunocheckpoint blockade has shown promising results, only 20-40 % of patients experience objective clinical benefit. Differences in individual tumor biology and the presence multiple immune checkpoints present a challenge for treatment. Because radiotherapy has immunomodulatory effects on the tumor microenvironment, it has the potential to synergize with immunotherapy and augment tumor response. NCT02318771 is a phase 1 clinical trial designed to investigate the immunomodulatory effects of radiation therapy in combination with pembrolizumab.

Case Presentation: The patient is a 64-year-old male with metastatic clear cell renal cell carcinoma, Fuhrman grade 4, pathologically staged as T3 N0. Metastatic disease was well controlled for several years with sunitinib. Following disease progression, he was switched to axitinib. When disease progression continued, the patient was enrolled in NCT02318771, a phase 1 clinical trial combining radiotherapy and pembrolizumab. The patient experienced unusually rapid disease progression during treatment, which was confirmed by repeated CT scans to rule out pseudoprogression. Tissue biopsies and peripheral blood draws were obtained before, during, and after treatment. Samples were analyzed to provide plausible rationale for rapid treatment failure.

Conclusions: Biomarker analysis demonstrated an absence of TILs, which may be a cause of treatment failure as pembrolizumab works through T cell-dependent mechanisms. Furthermore, the presence of other non-redundant immune checkpoints in the periphery and tumor microenvironment presents a treatment challenge. Additionally, the radiation dose and fractionation schedule may have played a role in treatment failure as these factors play a role in the effect radiotherapy on the tumor microenvironment as well as the potential for synergy with immunotherapy.

Trial Registration: An Exploratory Study to Investigate the Immunomodulatory Activity of Radiation Therapy (RT) in Combination With MK-3475 in Patients With Recurrent/Metastatic Head and Neck, Renal Cell Cancer, Melanoma and Lung Cancer, NCT02318771 .
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s13045-016-0328-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5034602PMC
September 2016

Thyroid Cancer Metabolism: A Review.

J Thyroid Disord Ther 2016 Feb 14;5(1). Epub 2016 Jan 14.

Department of Otolaryngology-Head and Neck Surgery, Thomas Jefferson University, Philadelphia, USA.

Metabolic dysregulation within the tumor microenvironment (TME) is critical to the process of tumorigenesis in various cancer types. Thyrocyte metabolism in papillary and anaplastic thyroid cancer, however, remains poorly characterized, and studies analyzing the role of multicompartment metabolism in thyrocyte oncogenesis are sparse. We present a review of the current knowledge on cellular metabolism in non-cancerous and cancerous thyroid tissues, focusing on the monocarboxylate transporters MCT1 and MCT4, and on a transporter of the outer mitochondrial membrane TOMM20. Understanding the metabolic phenotype of tumor cells and associated stromal cells in thyroid cancer can have profound implications on the use of biomarker staining in detecting subclinical cancer, imaging as it relates to expression of various transport proteins, and therapeutic interventions that manipulate this dysregulated tumor metabolism to halt tumorigenesis and eradicate the cancer. Future studies are required to confirm the prognostic significance of these biomarkers and their correlation with existing staging schemas such as the AGES, AMES, ATA and MACIS scoring systems.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.4172/2167-7948.1000200DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4874252PMC
February 2016

Prognostic Indications of Elevated MCT4 and CD147 across Cancer Types: A Meta-Analysis.

Biomed Res Int 2015 8;2015:242437. Epub 2015 Dec 8.

Department of Otolaryngology-Head and Neck Surgery, Thomas Jefferson University, Philadelphia, PA 19107, USA.

Background: Metabolism in the tumor microenvironment can play a critical role in tumorigenesis and tumor aggression. Metabolic coupling may occur between tumor compartments; this phenomenon can be prognostically significant and may be conserved across tumor types. Monocarboxylate transporters (MCTs) play an integral role in cellular metabolism via lactate transport and have been implicated in metabolic synergy in tumors. The transporters MCT1 and MCT4 are regulated via expression of their chaperone, CD147.

Methods: We conducted a meta-analysis of existing publications on the relationship between MCT1, MCT4, and CD147 expression and overall survival and disease-free survival in cancer, using hazard ratios derived via multivariate Cox regression analyses.

Results: Increased MCT4 expressions in the tumor microenvironment, cancer cells, or stromal cells were all associated with decreased overall survival and decreased disease-free survival (p < 0.001 for all analyses). Increased CD147 expression in cancer cells was associated with decreased overall survival and disease-free survival (p < 0.0001 for both analyses). Few studies were available on MCT1 expression; MCT1 expression was not clearly associated with overall or disease-free survival.

Conclusion: MCT4 and CD147 expression correlate with worse prognosis across many cancer types. These results warrant further investigation of these associations.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1155/2015/242437DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4686628PMC
October 2016