Arjun Pennathur - Academia.edu (original) (raw)

Papers by Arjun Pennathur

Interactive Cardiovascular and Thoracic Surgery, Oct 1, 2017

Journal of Thoracic Disease, Dec 1, 2018

Background: It is important to identify patients with esophageal squamous cell carcinoma (ESCC) i... more Background: It is important to identify patients with esophageal squamous cell carcinoma (ESCC) in T1b stage that are the least likely to metastasize on the lymph nodes, to undergo endoscopic resection, especially for the patients unfit for esophagectomy. The relationship between endoscopic morphology and frequency of nodal metastasis has never been well studied. The aims of the study were to investigate the predictive value of endoscopic morphology for lymphatic metastasis, and to develop a risk stratification model in submucosal (T1b) ESCC. Methods: Pathologic variables of patients with T1b ESCC who underwent esophagectomy from 2006 through 2016 were collected and divided into training sets (patients between 2006 and 2011) and validation sets (patients between 2012 and 2016). The endoscopic morphology of the tumor was determined by analyzing endoscopic reports according to the Paris classification. The correlation between the clinicopathological factors and nodal metastasis was examined. A prediction model was developed to estimate the risk of metastasis using these predictors. Results: A total of 175 patients were included in this study. A tumor with an endoscopic shape of flat type (0-II type as Paris classification was defined) was significantly related to lower risk of lymphatic metastasis with the frequency of 15.5% (OR: 3.049, 95% CI: 1.363-6.819, P=0.005). The combination of endoscopic morphology with other pathologic characteristics including lymphovascular invasion, length of tumor, depth of tumor invasion into submucosa, and tumor differentiation improved the predictive value of the nodal metastasis. The risk stratification model was developed with a C-index of 0.726 (95% CI: 0.702-0.751), which identified a low risk subgroup with a lymph node rate of 7.2%. Conclusions: Our results suggest that when a tumor is in flat shape (0-II type) it is related to a less lymphatic metastasis, and the combination of the endoscopic morphology with the other four pathologic variables can yield a more robust approach to predict the risk of lymphatic metastasis in submucosal ESCC.

Chest

PURPOSE: Anatomic segmentectomy has emerged as an effective alternative to lobectomy for patients... more PURPOSE: Anatomic segmentectomy has emerged as an effective alternative to lobectomy for patients with small (# 2 cm) clinical stage I non-small cell lung cancers. Little is known about the efficacy of anatomic segmentectomy in the setting of N1 disease, which is traditionally treated with lobectomy. The purpose of the study is to determine the outcomes of anatomic segmentectomy vs. lobectomy in patients with pathological N1 disease. METHODS: Patients undergoing anatomic segmentectomy (n=21) and lobectomy (n=72) for histologically-proven N1 non-small cell lung cell lung cancer were identified from a prospectively maintained single-institution database. Primary outcomes included mortality, length of hospital stay, readmission rates as well as recurrence-free and overall survival. Comparisons were performed with Student's t-test and X 2 test. Recurrence-free and overall survival were analyzed by the Kaplan-Meier method. RESULTS: Age, gender and preoperative co-morbidities including hypertension, coronary artery disease, COPD, diabetes mellitus, reflux disease and prior cancers were similar between groups. Patients undergoing lobectomy had significantly larger tumors compared to patients undergoing segmentectomy (3.8cm vs. 2.6cm, respectively, p=.034) with a higher number of nodes sampled (19.4 vs. 9.0, p<.01). Overall peri-operative mortality (1.4% vs. 0%, p=.59), length of stay (8.1 days vs. 9.6 days, p=.68), re-admission within 30 days (11% vs. 19%, p=.69) were similar between lobectomy and segmentectomy, respectively. Locoregional (15 vs. 19%, p=.22) and distant metastasis (17 vs. 14%, p=.79) were also not significantly different. Recurrence-free survival was longer in lobectomy patients; however, this was not statistically significant (97.6 months vs. 65.7 months, p=.364). Overall survival was significantly greater for lobectomy compared with segmentectomy (median 89.8 months vs. 49.0 months, p=0.001). CONCLUSIONS: Anatomic segmentectomy was associated with similar peri-operative outcomes and recurrence risk compared to lobectomy in the setting of pathological N1 disease. Lobectomy was associated with improved overall survival. CLINICAL IMPLICATIONS: Lobectomy does not appear to be associated with reduced recurrence risk, but is associated with greater overall survival in patients with N1 non-small cell lung cancers. Therefore, lobectomy should remain standard of care when N1 disease is present. However, given similar recurrence risks, anatomic segmentectomy may by feasible in patients who cannot undergo lobectomy.

Science Translational Medicine, 2021

Persistent T cell receptor stimulation drives neuropilin-1 on intratumoral regulatory T cells, wh... more Persistent T cell receptor stimulation drives neuropilin-1 on intratumoral regulatory T cells, which is associated with poor clinical outcome.

The Journal of Thoracic and Cardiovascular Surgery, 2021

OBJECTIVE Lobectomy is a standard treatment for stage I non-small cell lung cancer, but a signifi... more OBJECTIVE Lobectomy is a standard treatment for stage I non-small cell lung cancer, but a significant proportion of patients are considered at high risk for complications, including mortality, after lobectomy and might not be candidates. Identifying who is at risk is important and in evolution. The objective of The American Association for Thoracic Surgery Clinical Practice Standards Committee expert panel was to review important considerations and factors in assessing who is at high risk among patients considered for lobectomy. METHODS The American Association for Thoracic Surgery Clinical Practice Standards Committee assembled an expert panel that developed an expert consensus document after systematic review of the literature. The expert panel generated a priori a list of important risk factors in the determination of high risk for lobectomy. A survey was administered, and the expert panel was asked to grade the relative importance of each risk factor. Recommendations were developed using discussion and a modified Delphi method. RESULTS The expert panel survey identified the most important factors in the determination of high risk, which included the need for supplemental oxygen because of severe underlying lung disease, low diffusion capacity, the presence of frailty, and the overall assessment of daily activity and functional status. The panel determined that factors, such as age (as a sole factor), were less important in risk assessment. CONCLUSIONS Defining who is at high risk for lobectomy for stage I non-small cell lung cancer is challenging, but remains critical. There was impressive strong consensus on identification of important factors and their hierarchical ranking of perceived risk. The panel identified several key factors that can be incorporated in risk assessment. The factors are evolving and as the population ages, factors such as neurocognitive function and frailty become more important. A minimally invasive approach becomes even more critical in this older population to mitigate risk. The determination of risk is a clinical decision and judgement, which should also take into consideration patient perspectives, values, preferences, and quality of life.

Oncogene, 2020

Inactivation of Pten gene through deletions and mutations leading to excessive pro-growth signali... more Inactivation of Pten gene through deletions and mutations leading to excessive pro-growth signaling pathway activations frequently occurs in cancers. Here, we report a Pten derived pro-cancer growth gene fusion Pten-NOLC1 originated from a chr10 genome rearrangement and identified through a transcriptome sequencing analysis of human cancers. Pten-NOLC1 fusion is present in primary human cancer samples and cancer cell lines from different organs. The product of Pten-NOLC1 is a nuclear protein that interacts and activates promoters of EGFR, c-MET, and their signaling molecules. Pten-NOLC1 promotes cancer proliferation, growth, invasion, and metastasis, and reduces the survival of animals xenografted with Pten-NOLC1-expressing cancer cells. Genomic disruption of Pten-NOLC1 induces cancer cell death, while genomic integration of this fusion gene into the liver coupled with somatic Pten deletion produces spontaneous liver cancers in mice. Our studies indicate that Pten-NOLC1 gene fusion is a driver for human cancers.

The Annals of Thoracic Surgery, 2019

Background. Recent literature has demonstrated the potential of "liquid biopsy" and detection of ... more Background. Recent literature has demonstrated the potential of "liquid biopsy" and detection of circulating tumor (ct)DNA as a cancer biomarker. However, to date there is a lack of data specific to esophageal adenocarcinoma (EAC). This study was conducted to determine how detection and quantification of ctDNA changes with disease burden in patients with EAC and evaluate its potential as a biomarker in this population. Methods. Blood samples were obtained from patients with stage I to IV EAC. Longitudinal blood samples were collected from a subset of patients. Imaging studies and pathology reports were reviewed to determine disease course. Tumor samples were sequenced to identify mutations. Mutations in plasma DNA were detected using custom, barcoded, patient-specific sequencing libraries. Mutations in plasma were quantified, and associations with disease stage and response to therapy were explored.

Journal of Clinical Oncology, 2013

15 Background: Historically, the AJCC esophageal staging system separated patients into prognosti... more 15 Background: Historically, the AJCC esophageal staging system separated patients into prognostic groups based on tumor, node, and metastasis (TNM) classifications. In 2010, the 7th edition (AJCC 7) significantly modified esophageal squamous cell cancer (ESCC) staging by separating ESCC from adenocarcinoma, incorporating tumor grade and location for node negative cancers, and stratifying by the number of involved regional nodes for node positive cancers. Our study aim was to determine whether AJCC 7 stage groupings provide improved survival prognostication compared to 6th edition (AJCC 6). Methods: We abstracted pathology and survival for 150 consecutive ESCC patients who underwent esophagectomy (1994-2012); 44 patients received induction therapy. AJCC 6 and AJCC 7 stages were assigned and overall survival analyzed from esophagectomy to death or most recent alive contact and censored at 60 months. Discriminatory ability and homogeneity within subgroups was assessed with Kaplan-Meie...

Seminars in thoracic and cardiovascular surgery, 2012

Esophagectomy is an important curative treatment modality for esophageal cancer, but is a complex... more Esophagectomy is an important curative treatment modality for esophageal cancer, but is a complex operation with associated risks. A minimally invasive approach to esophagectomy may decrease the risks associated with resection. Recently, an important study was published in the Lancet by Biere and colleagues that reported the results of a randomized study, with the primary endpoint of postoperative pulmonary infection, comparing minimally invasive esophagectomy versus open esophagectomy for esophageal cancer. The findings from this trial confirm the data from previous, non-randomized studies and highlight the substantial early postoperative benefits of minimally invasive esophagectomy.

Seminars in thoracic and cardiovascular surgery, 2008

I n this issue of Seminars in Thoracic and Cardiovascular Surgery, we include a series of article... more I n this issue of Seminars in Thoracic and Cardiovascular Surgery, we include a series of articles which highlight new technologies and procedures in general thoracic surgery. These papers were presented as part of the New Technologies and Procedures Symposium at the 88th Annual Meeting of the American Association for Thoracic Surgery, May 10-14, 2008 in San Diego, CA. Thoracic surgery is rapidly evolving and it is critical that surgeons are apprised of new technological advances. Here, several new technologies are featured. Lung cancer is the most common cause of cancer-related mortality in the United States. It is important for the thoracic surgeon to stage patients accurately before initiation of therapy, to optimize results. While mediastinoscopy continues to be the standard, endobronchial ultrasound-guided biopsy of mediastinal lymph nodes is an important new modality for staging patients with lung cancer. Drs. Groth and Andrade from the University of Minnesota have presented the early results, strengths, and limitations of this technology. A significant proportion of patients who have early stage lung cancer are medically inoperable due to coexisting comorbidities. New modalities for the treatment of these medically inoperable patients include radiofrequency ablation and stereotactic radiosurgery. The results of these ablative technologies in the treatment of early stage lung neoplasm are summarized by Drs. Pennathur, Christie, and colleagues from our group at the University of Pittsburgh. Dr. McKenna has provided a concise review of endobronchial valve technology for the treatment of emphysema. While lung volume reduction surgery is a beneficial treatment in a selected group of emphysema patients, endobronchial valves may play a significant role in high-risk patients. There has been a dramatic increase in the incidence of adenocarcinoma of the esophagus over the last 3 decades. The reason for this increase is not entirely clear, however, Barrett's esophagus (BE) has been one of the main factors implicated in contributing to the rising incidence. Drs. Force and Miller from Emory University have provided a concise review of endoscopically delivered radiofrequency ablation

Surgery, 1993

Motilin induces phase III activity of the gastroesophageal tract. Erythromycin has a motilin-like... more Motilin induces phase III activity of the gastroesophageal tract. Erythromycin has a motilin-like effect on the stomach, but possible esophageal effects have not been evaluated and are the focus of our investigation. Esophageal manometry was performed in 11 healthy volunteers before and after intravenous infusion of 500 mg erythromycin. Values are expressed as means +/- SEM. Lower esophageal sphincter (LES) pressure increased from 21.1 +/- 2.6 mm Hg at baseline to 37.5 +/- 3.8 mm Hg after erythromycin infusion (p < 0.0001). Erythromycin did not affect LES length, esophageal body contraction amplitude, duration or velocity, or the upper esophageal sphincter. Serum motilin levels decreased from 96.4 +/- 10.9 pmol/L to 81.8 +/- 10.9 pmol/L (p < 0.01) after erythromycin administration. Erythromycin profoundly stimulates the normal human LES. This is a direct motilin agonist-like effect and is not mediated by release of endogenous motilin. Erythromycin has no important effect on th...

Pearson's Thoracic and Esophageal Surgery, 2008

Recent Advances in Diseases of the Esophagus, 1993

Esophageal trauma remains a diagnostic and therapeutic challenge. This is reflected by reported m... more Esophageal trauma remains a diagnostic and therapeutic challenge. This is reflected by reported mortality rates of 15%–20% which have remained unchanged for several decades. Outcome is clearly influenced by several factors, such as the mechanism of injury, extent of associated injuries, age, anatomic location, and timing of operation [1]. Historically, early aggressive surgical intervention has been the mainstay of therapy. Conservative treatment is only appropriate for carefully selected cases of chronic contained perforations [2].

The Lancet Oncology, 2009

Multimodal treatment with surgical resection for stage IIIB non-small-cell lung cancer. By - Arju... more Multimodal treatment with surgical resection for stage IIIB non-small-cell lung cancer. By - Arjun Pennathur, James D Luketich.

Journal of Surgical Research, 2013

International Journal of Radiation Oncology*Biology*Physics, 2010

Purpose/Objective(s): Esophageal toxicity has been accepted reluctantly, as a necessary side effe... more Purpose/Objective(s): Esophageal toxicity has been accepted reluctantly, as a necessary side effect of the benefits of chemoradiotherapy for lung cancer. MnSOD-PL is a genetically engineered therapeutic DNA/liposome complex containing the human MnSOD transgene. Preclinical studies in mouse models have demonstrated that the expression of the human MnSOD transgene confers protection of normal tissues from ionizing irradiation damage. A phase I trial has been completed demonstrating MnSOD-PL may reduce esophagitis following chemoradiation in surgically unresectable Stage III non-small cell lung cancer.

Cancer Research, 2010

Introduction: The cyclin-dependent kinase 6 (CDK6) is a positive regulator of the cell cycle. It ... more Introduction: The cyclin-dependent kinase 6 (CDK6) is a positive regulator of the cell cycle. It binds to D-type cyclins and phosphorylates the pRb tumor suppressor proteins allowing progression through the G1-phase of the cell cycle. Amplification of the 7q21 chromosomal region has been reported in esophageal adenocarcinoma (EAC) and it has been proposed that CDK6 is the key gene targeted by this event. However, overexpression of CDK6 in vitro suppresses proliferation of breast cancer cells and causes nuclear accumulation of pRb2 tumor suppressor protein. Thus, it remains unclear whether amplification and overexpression of CDK6 is truly driving the 7q21 amplicon in EAC. Methods: For DNA copy number analysis we analyzed genomic DNA from 83 EAC tumors using Affymetrix 6.0 SNP arrays. Protein expression was analyzed in tissue microarrays comprised of 116 independent EAC samples and pre-EAC lesions (15 high grade dysplasia (HGD), 18 low grade dysplasia (LGD), and 283 cases of columnar ...

Cancer Research, 2012

Introduction: Esophageal cancer occurs with two distinct histologies_ squamous cell carcinoma (SC... more Introduction: Esophageal cancer occurs with two distinct histologies_ squamous cell carcinoma (SCC) and esophageal adenocarcinoma (EA). The incidence of EA has risen over the past few decades and is now the most common esophageal malignancy in the United States and Western Europe. The genome of esophageal adenocarcinoma is highly unstable due to the large number of amplification and deletion events. Presumably, such genomic events drive tumor formation and disease progression by altering the expression of genes within these regions. Several studies have reported large regions of genomic instability especially spanning chromosomal arms or in gene dense regions. Using a large patient cohort and high-resolution data for DNA copy number and expression, this study aims to identify potential driver genes and prognostic markers especially in whole chromosomal aberrations and gene dense regions. Materials & Methods: DNA copy number aberrations were explored in 116 esophageal adenocarcinomas...