IU Indianapolis ScholarWorks :: Browsing by Author "Denlinger, Chadrick E."

Browsing by Author "Denlinger, Chadrick E."

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Casual observation
(Elsevier, 2023-09) Zborek, Kirsten; Denlinger, Chadrick E.; Surgery, School of Medicine
Pulmonary carcinoid tumors are a rare form of lung cancer subdivided into typical and atypical variants. Long-term outcomes after surgical resection are excellent, with 5-year survival rates approaching 85% even among patients with N2 lymph node involvement. Surgical resection of carcinoids remains the standard of care. However, in patients with diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH), a condition characterized by the presence of innumerable small pulmonary carcinoids, observing small carcinoids may be acceptable.
Commentary: Quality vs. conformity
(Elsevier, 2021) Denlinger, Chadrick E.; Surgery, School of Medicine
Fifteen is just a number
(Elsevier, 2023-07) Denlinger, Chadrick E.; Surgery, School of Medicine
Lymph node dissection remains an essential part of any oncologic surgery. At a minimum, sentinel node sampling is required for some cancers. For many solid malignancies, including lung and esophageal cancer, the number of lymph nodes resected correlates with long-term outcomes. The debate remains regarding the relative contributions of the oncologic impact of a thorough lymph node sampling vs stage migration leading to the improved outcomes. An alternative explanation, still, is that a thorough lymph node sampling may just be a surrogate marker of comprehensive quality care, without having any direct impact on cancer-related outcomes.
Glass half full
(Elsevier, 2023) Denlinger, Chadrick E.; Surgery, School of Medicine
Neuropilin-2b facilitates resistance to tyrosine kinase inhibitors in non–small cell lung cancer
(Elsevier, 2021) Dimou, Anastasios; Nasarre, Cecile; Peterson, Yuri K.; Pagano, Rose; Gooz, Monika; Nasarre, Patrick; Drabkin, Harry A.; Armeson, Kent E.; Gibney, Barry C.; Gemmill, Robert M.; Denlinger, Chadrick E.; Surgery, School of Medicine
Objective: Innate and acquired resistance is the principle factor limiting the efficacy of tyrosine kinase inhibitors in lung cancer. We have observed a dramatic upregulation of the cell surface co-receptor neuropilin-2b in lung cancers clinically treated with tyrosine kinase inhibitors correlating with acquired resistance. We hypothesize that neuropilin-2b plays a functional role in acquired tyrosine kinase inhibitor resistance. Methods: Non-small cell lung cancer proliferation and survival were determined during chronic tyrosine kinase inhibitor exposure in the presence or absence of neuropilin-2b knock-down. Interactions of neuropilin-2a and neuropilin-2b isoforms with PTEN and GSK3β were assessed by immunoprecipitation. Neuropilin-2a and neuropilin-2b mutants deleted for their cytoplasmic domains were used to identify regions responsible for neuropilin-2b-GSK3β interaction. Because GSK3β is known to phosphorylate and degrade PTEN, phospho-PTEN and total PTEN levels were assessed after transfection of neuropilin-2a and neuropilin-2b wild-type and mutant constructs. Results: Non-small cell lung cancer cells chronically treated with gefitinib or osimertinib developed drug resistance and exhibited logarithmic growth in the presence of endothelial growth factor receptor tyrosine kinase inhibitors. However, neuropilin-2b knockdown cells remained sensitive to gefitinib. Likewise, neuropilin-2b knockdown suppressed and neuropilin-2a knockdown enhanced cellular migration. Acquired drug resistance and cell migration correlated with neuropilin-2b-dependent AKT activation with the intermediate step of GSK3β-dependent PTEN degradation. A specific binding site for GSK3β on the cytoplasmic domain of neuropilin-2b was identified with truncated protein constructs and computer modeling. Conclusions: Neuropilin-2b facilitates non-small cell lung cancer resistance to tyrosine kinase inhibitors, and this biological effect relates to AKT activation. Neuropilin-2b GSK3β interactions appear to be essential for PTEN degradation and AKT activation in lung cancer cells. Disruption of the neuropilin-2b GSK3β interaction may represent a novel treatment strategy to preserve sensitivity to tyrosine kinase inhibitors in non-small cell lung cancer.
One size does not fit all
(Elsevier, 2023-09) Denlinger, Chadrick E.; Surgery, School of Medicine
With broad strokes, major contributing oncogenic factors include the patient’s genetic composition, environmental exposures, and the host microbiome. Within specific cancer types, such as lung cancer, regional differences of genetics, environmental exposure, and the biome result in tumors with differential behaviors. Therefore, optimal lung cancer treatments in one part of the world may not be applicable elsewhere. For more than a decade, the Japanese have led the world’s pursuit of sublobar resections for early-stage lung cancers. Okada and colleagues showed in 2006 that the 5-year overall survival for patients with peripheral lung cancers ≤2 cm was nearly identical between patients treated with sublobar resections compared to lobectomy. Importantly, the survival in both groups was 89%, while the most patients had tumors at the at upper end of the ≤2 cm spectrum. This survival was notably better than what has been observed for similarly staged lung cancers in other regions of the world. Consistently, Japanese series have demonstrated better long-term survival for lung cancer patients in general and superior outcomes after sublobar resections compared with outcomes elsewhere. At the same time, Japanese lung cancer series typically are composed of greater proportions of women and nonsmokers than series in other regions of the world. These differences in demographics and outcomes suggest fundamental biological differences. As a result, treatments appropriate in Japan may or may not be applicable elsewhere. Recent results of a prospective, randomized, multiinstitutional North American study did support sublobar resections of small peripheral lung cancers.4 That study randomized 697 patients with ≤2 cm tumors over a 10-year period to lobectomy vs sublobar resection, resulting in similar outcomes with 5-year overall survival rates of 78.9% vs 80.3%, respectively. Most retrospective reviews and prospective clinical trials have used 2 cm as a cutoff for tumors acceptably treated with sublobar resection. In this issue of The Annals of Thoracic Surgery, Mimae and colleagues have pushed the envelope further by examining the outcomes of patients with tumors 2-4 cm among a patient cohort aged >70 years. They observed statistically similar outcomes in patients treated with sublobar resections compared to lobectomy and concluded that a sublobar resection should be considered the procedure of choice for octogenarians with tumors up to 4 cm. It may be important to consider that excellent outcomes can be achieved with sublobar resections among older patients if similar selection criteria are used. Its notable that in the entire cohort, a lobectomy was performed more than 3 times more frequently than sublobar resections, suggesting that a lobectomy was actually the preferred approach. Differences between the 2 surgical groups imply that surgeons may have selectively offered sublobar resections to patients with more indolent-appearing tumors. A greater proportion of patients in the sublobar group had tumors 2-3 cm rather than 3-4 cm. In addition, patients in the sublobar group had tumors with a greater ground glass component. The comparable long-term survival results support the authors’ intuition leading them to recommend sublobar resections for patients with more indolent features.
With a grain of salt
(ScienceDirect, 2022) Denlinger, Chadrick E.; Surgery, School of Medicine
Zeroing In on the Target
(Elsevier, 2022) Loria, Chelsea; Denlinger, Chadrick E.; Medicine, School of Medicine

Browsing by Author "Denlinger, Chadrick E."

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