Video-assisted thoracic surgery and robotic-assisted first-rib excision and thoracic outlet syndrome decompression.

Multiple surgical approaches have been used in the management of thoracic outlet syndrome. These approaches have traditionally been "open" approaches and have been associated with the inherent morbidities of an open approach, including a risk of injury to the neurovascular structures due to traction and trauma while resecting the first rib. In addition, there has been concern that recurrence of symptoms may be related to incomplete resection of the rib with conventional open techniques. With the advent of minimally invasive thoracic surgery, surgeons began to explore first-rib resection via a thoracoscopic approach. Unfortunately, the existing video-assisted thoracic surgery technology and equipment was not well suited to working in the apex of the chest. With the introduction and subsequent progress in robotic surgery and instrumentation, this dissection can be performed with all the advantages of robotics, but also with minimal traction and trauma to the neurovascular structures, and incorporates almost complete resection of the rib with minimal residual stump. Robotics has developed as a reliable, safe, and less invasive approach to first-rib resection, yielding excellent results while limiting the morbidity of the procedure.

Prevalence and risk factors for dysphagia in older adults after thyroid and parathyroid surgery.

BACKGROUND: We aimed to determine the prevalence and risk factors for dysphagia in adults 65 years and older before and after thyroidectomy or parathyroidectomy. METHODS: We performed a longitudinal prospective cohort study of older adults undergoing initial thyroidectomy or parathyroidectomy. We administered the Dysphagia Handicap Index questionnaire preoperatively and 1, 3, and 6 months postoperatively. We compared preoperative and postoperative total and domain-specific scores using paired t tests and identified risk factors for worse postoperative scores using multivariable logistic regression. RESULTS: Of the 175 patients evaluated, the mean age was 71.1 years (range = 65-94), 73.7% were female, 40.6% underwent thyroidectomy, 57% underwent bilateral procedures, and 21.1% had malignant diagnoses. Preoperative swallowing dysfunction was reported by 77.7%, with the prevalence 22.4% greater in frail than robust patients (P = .013). Compared to preoperative scores, 43.4% and 49.1% had worse scores at 3 and 6 months postoperatively. Mean functional domain scores increased by 62.3% at 3 months postoperatively (P = .007). Preoperative swallowing dysfunction was associated with a 3.07-fold increased likelihood of worse functional scores at 3 months. Whereas frailty was associated with preoperative dysphagia, there was no association between worse postoperative score and age, sex, race, frailty, body mass index, smoking status, gastroesophageal reflux disease, comorbidity index, malignancy, surgical extent, or type of surgery. CONCLUSION: Adults 65 years and older commonly report swallowing impairment preoperatively, which is associated with a 3.07-fold increased likelihood of worsened dysphagia after thyroid and parathyroid surgery that may persist up to 6 months postoperatively.

COVID-19 infection and large intestinal perforation: A case series.

INTRODUCTION: COVID-19 is a viral illness characterized primarily by respiratory symptoms. However, patients with COVID-19 infection may also present with gastrointestinal symptoms. Subsequent complications can be associated with high morbidity and mortality. METHODS: This is a retrospective observational study of three COVID-19 positive patients who developed large intestinal perforations and an analysis of their clinical characteristics, diagnosis, surgical treatment and outcomes. Three patients aged 45, 51 and 82 years old presented to our institution between November 2021 and March 2022 and were diagnosed with COVID-19 pneumonia requiring admission to the intensive care unit (ICU). All three patients received steroids and underwent surgery during their admission. None of our patients had prior history of bowel perforation or risks factors justifying their presentation. PRESENTATION OF CASES: Our first patient was found to have an ascending colon perforation and underwent right colon resection and end ileostomy. Our second patient was found to have a cecal perforation and underwent ileocecectomy with end ileostomy and mucus fistula creation. Our third patient was found to have a large cecal perforation and underwent right hemicolectomy and was left in discontinuity during the index operation. DISCUSSION: GI perforation is a less common but serious extra-pulmonary complication of COVID-19. The cases in the present study involve ascending colon perforations in the setting of active COVID-19 infection that occurred within two to five weeks after initial COVID-19 diagnosis. Given viral replication in GI cells, the local inflammatory effect of viral infection in the GI may play a role in bowel perforation. Providers should additionally be aware of the risk of perforation with steroids and immunomodulators. Immunosuppressive effects of these therapies may mask the classical signs of abdominal sepsis and lead to possible missed diagnoses. CONCLUSION: Gastrointestinal perforation is a rare but serious complication of COVID-19 infection. A high degree of clinical suspicion is necessary for timely diagnosis and management.

Secondary hyperparathyroidism (CKD-MBD) treatment and the risk of dementia.

BACKGROUND: Elevated parathyroid hormone (PTH) levels have been reported as a potential risk factor for cognitive impairment. Compared with the general population, older adults with end-stage renal disease (ESRD) who are frequently affected by secondary hyperparathyroidism (SHPT) are at increased risk of developing dementia. The main objective of our study was to evaluate if the risk of dementia in older (age ≥66 years) ESRD patients differed if they were treated for SHPT. METHODS: Using the United States Renal Data System and Medicare claims, we identified 189 433 older adults without a diagnosis of dementia, who initiated dialysis between 2006 and 2016. SHPT treatment was defined as the use of vitamin D analogs, phosphate binders, calcimimetics or parathyroidectomy. We quantified the association between treated SHPT and incident dementia during dialysis using a multivariable Cox proportional hazards model with inverse probability weighting, considering SHPT treatment as a time-varying exposure. RESULTS: Of 189 433 older ESRD adults, 92% had a claims diagnosis code of SHPT and 123 388 (65%) were treated for SHPT. The rate of incident dementia was 6 cases per 100 person-years among SHPT treated patients compared with 11 cases per 100 person-years among untreated patients. Compared with untreated SHPT patients, the risk of dementia was 42% lower [adjusted hazard ratio (aHR) = 0.58, 95% confidence interval (CI): 0.56-0.59] among SHPT treated patients. The magnitude of the beneficial effect of SHPT treatment differed by sex (Pinteraction = .02) and race (Pinteraction ≤ .01), with females (aHR = 0.56, 95% CI: 0.54-0.58) and those of Asian (aHR = 0.51, 95% CI: 0.46-0.57) or Black race (aHR = 0.51, 95% CI: 0.48-0.53) having a greatest reduction in dementia risk. CONCLUSION: Receiving treatment for SHPT was associated with a lower risk of incident dementia among older patients with ESRD. This work provides additional support for the treatment of SHPT in older ESRD patients.

The impact of patient age on practice patterns and outcomes for primary hyperparathyroidism.

BACKGROUND: Management of asymptomatic primary hyperparathyroidism (PHPT) in older patients (age >50) is controversial. The 4th International Workshop on the Management of Asymptomatic PHPT recommends surveillance for older patients who lack objective signs of disease, whereas The American Association of Endocrine Surgeons (AAES) guidelines recommend consideration of parathyroidectomy for patients of any age with subjective constitutional, neuropsychiatric, or cognitive symptoms. Therefore, the primary objective of this study was to evaluate the association between patient age and both practice patterns and outcomes in the management of patients with sporadic PHPT. METHODS: The Collaborative Endocrine Surgery Quality Improvement Program (CESQIP) database was queried for all adults (age ≥18) who underwent an index parathyroidectomy for sporadic primary hyperparathyroidism between 2014 and 2020. Associations between patient age (≤50 years vs. >50 years) and both practice patterns and outcomes were evaluated separately using adjusted multivariable logistic and multinomial regression models. RESULTS: Of 9,938 patients who underwent parathyroidectomy, 8,080 (81.3%) were >50 years old and 1,858 (18.7%) were ≤50. Of this cohort, 17% of older patients and 26% of younger patients presented with only subjective symptoms. Compared to younger patients, older patients were more likely to have an objective indication for parathyroidectomy (aOR = 1.8, 95%CI: 1.6-2.0, p < 0.001). They were also more likely to undergo ≥2 imaging studies pre-operatively (aOR = 1.2, 95%CI: 1.1-1.3, p = 0.003), to undergo bilateral neck exploration (aOR = 1.4, 95%CI: 1.3-1.6, p < 0.001), and to have multi-gland disease (aOR = 1.6, 95%CI: 1.4-1.8, p < 0.001). There was no difference between age groups and parathyroidectomy-related complications including hypocalcemia, vocal cord dysfunction, hematoma requiring evacuation, or reintubation, however, older patients were less likely to have any peri-operative morbidity (aOR = 0.7, 95%CI: 0.6-0.9, p = 0.011). CONCLUSIONS: Older patients were more likely to meet objective criteria prior to undergoing parathyroidectomy by CESQIP participating high-volume endocrine surgeons, however they were less likely to have peri-operative complications compared to younger patients. Given the growing evidence demonstrating improvement of both objective and subjective symptoms after parathyroidectomy for PHPT, additional studies are still needed to fully understand the benefit of surgical referral in older adults for less objective indications.

Increasing rates of parathyroidectomy to treat secondary hyperparathyroidism in dialysis patients with Medicare coverage.

BACKGROUND: Secondary hyperparathyroidism affects nearly all patients with renal failure on dialysis. Medical treatment of secondary hyperparathyroidism has considerably evolved over the past 2 decades, with parathyroidectomy reserved for severe cases. The primary objective of our study was to understand how trends in medical treatments affected parathyroidectomy rates in patients with secondary hyperparathyroidism on dialysis. METHODS: We used the United States Renal Data System to identify 379,835 adult patients (age ≥18) who were on maintenance dialysis in the United States between 2006 and 2016 with Medicare as the primary payor and ascertained treatment for secondary hyperparathyroidism. Adjusted rate ratios for rates of parathyroidectomy were calculated using multivariable-adjusted Poisson regression. RESULTS: Of 379,835 secondary hyperparathyroidism patients, 4,118 (1.1%) underwent parathyroidectomy, 39,835 (10.5%) received cinacalcet, 243,522 (64.1%) received phosphate binders, 17,571 (4.6%) received vitamin D analogs, and 86,899 (22.9%) received no treatment during the 10 years of follow-up. Over the entire study period, there was a 3.5-fold increase in the use of calcimimetics and a 3.4-fold increase in rates of parathyroidectomy. Compared to 2006 through 2009, utilization of parathyroidectomy increased 52% (adjusted rate ratio = 1.52, 95% confidence interval: 1.39-1.65) between 2010 and 2013 and by 106% (adjusted rate ratio = 2.06, 95% confidence interval: 1.90-2.24) between 2014 and 2016. The greatest increase in parathyroidectomy utilization occurred in younger patients (age 18-64 years), Black patients, female patients, those living in higher poverty neighborhoods, those listed for kidney transplant, and those who live in the Southern region of the United States. CONCLUSION: Despite the evolution of medical treatments and an increase in the use of calcimimetics to treat secondary hyperparathyroidism, parathyroidectomy rates have been steadily increasing among dialysis patients with Medicare coverage.

Impact of the 2015 American thyroid association guidelines on treatment in older adults with low-risk, differentiated thyroid cancer.

BACKGROUND: The impact of the 2015 ATA guidelines on treatment for differentiated thyroid cancer (DTC) in older adults is unclear. METHODS: 60,567 adults (age≥18) with low-risk DTC diagnosed between 2010 and 2018 were identified using SEER-21. Annual rates of total thyroidectomy (TT), hemithyroidectomy (HT), and active surveillance (AS) were analyzed using interrupted time series stratified by age: younger adults (18-64), older adults (65-79), and the super-elderly (≥80). RESULTS: After 2015, annual rates of TT decreased by 2.6% and 1.9% in younger and older adults (p < 0.001), but increased by 4.6% in the super-elderly (p = 0.0126). Annual rates of HT increased by 2.6% and 1.7% in younger and older adults (p < 0.001), but decreased by 3.8% in the super-elderly (p = 0.0029). Older adults and the super-elderly were more likely than younger adults to undergo HT (aOR = 1.1, 95% CI: 1.03-1.2, p = 0.002 and aOR = 1.5, 95% CI: 1.3-1.7, p < 0.001) and AS (aOR = 1.5, 95% CI: 1.4-1.7, p < 0.001 and aOR = 6.5, 95% CI: 5.4-7.7, p < 0.001) when compared to TT following 2015. CONCLUSIONS: Treatment of DTC continues to vary significantly among age groups.

Ambient particulate matter air pollution is associated with increased risk of papillary thyroid cancer.

BACKGROUND: The association between exposure to air pollution and papillary thyroid carcinoma is unknown. We sought to estimate the relationship between long-term exposure to the fine (diameter ≤ 2.5 µm) particulate matter component of air pollution and the risk of papillary thyroid cancer. METHODS: Adult (age ≥18) patients with newly diagnosed papillary thyroid carcinoma between January 1, 2013 and December 31, 2016 across a single health system were identified using electronic medical records. Data from 1,990 patients with papillary thyroid carcinoma were compared with 3,980 age- and sex-matched control subjects without any evidence of thyroid disease. Cumulative fine (diameter <2.5 µm) particulate matter exposure was estimated by incorporating patients' residential zip codes into a deep learning neural networks model, which uses both meteorological and satellite-based measurements. Conditional logistic regression was performed to assess for association between papillary thyroid carcinoma and increasing fine (diameter ≤2.5 µm) particulate matter concentrations over 1, 2, and 3 years of cumulative exposure preceding papillary thyroid carcinoma diagnosis. RESULTS: Increased odds of developing papillary thyroid carcinoma was associated with a 5 µg/m3 increase of fine (diameter ≤2.5 µm) particulate matter concentrations over 2 years (adjusted odds ratio = 1.18, 95% confidence interval: 1.00-1.40) and 3 years (adjusted odds ratio = 1.23, 95% confidence interval: 1.05-1.44) of exposure. This risk differed by smoking status (pinteraction = 0.04). Among current smokers (n = 623), the risk of developing papillary thyroid carcinoma was highest (adjusted odds ratio = 1.35, 95% confidence interval: 1.12-1.63). CONCLUSION: Increasing concentration of fine (diameter ≤2.5 µm) particulate matter in air pollution is significantly associated with the incidence of papillary thyroid carcinoma with 2 and 3 years of exposure. Our novel findings provide additional insight into the potential associations between risk factors and papillary thyroid carcinoma and warrant further investigation, specifically in areas with high levels of air pollution both nationally and internationally.

Prevalence and risk factors for tertiary hyperparathyroidism in kidney transplant recipients.

BACKGROUND: Tertiary hyperparathyroidism after kidney transplantation has been associated with graft dysfunction, cardiovascular morbidity, and osteopenia; however, its true prevalence is unclear. The objective of our study was to evaluate the prevalence of and risk factors for tertiary hyperparathyroidism. METHODS: A prospective cohort of 849 adult kidney transplantation recipients (December 2008-February 2020) was used to estimate the prevalence of hyperparathyroidism 1-year post-kidney transplant. Tertiary hyperparathyroidism was defined as hypercalcemia (≥10mg/dL) and hyperparathyroidism (parathyroid hormone≥70pg/mL) 1-year post-kidney transplantation. Modified Poisson regression models were used to evaluate risk factors associated with the development of both persistent hyperparathyroidism and tertiary hyperparathyroidism. RESULTS: Among kidney transplantation recipients, 524 (61.7%) had persistent hyperparathyroidism and 182 (21.5%) had tertiary hyperparathyroidism at 1-year post-kidney transplantation. Calcimimetic use before kidney transplantation was associated with 1.30-fold higher risk of persistent hyperparathyroidism (adjusted prevalence ratio = 1.30, 95% CI: 1.12-1.51) and 1.84-fold higher risk of tertiary hyperparathyroidism (adjusted prevalence ratio = 1.84, 95% CI: 1.25-2.72). Pre-kidney transplantation parathyroid hormone ≥300 pg/mL was associated with 1.49-fold higher risk of persistent hyperparathyroidism (adjusted prevalence ratio = 1.49, 95% CI = 1.19-1.85) and 2.21-fold higher risk of tertiary hyperparathyroidism (adjusted prevalence ratio = 2.21, 95% CI = 1.25-3.90). Pre-kidney transplantation tertiary hyperparathyroidism was associated with an increased risk of post-kidney transplantation tertiary hyperparathyroidism (adjusted prevalence ratio = 1.71, 95% CI = 1.29-2.27), but not persistent hyperparathyroidism. Furthermore, 73.0% of patients with persistent hyperparathyroidism and 61.5% with tertiary hyperparathyroidism did not receive any treatment at 1-year post-kidney transplantation. CONCLUSION: Persistent hyperparathyroidism affected 61.7% and tertiary hyperparathyroidism affected 21.5% of kidney transplantation recipients; however, the majority of patients were not treated. Pre-kidney transplantation parathyroid hormone levels ≥300pg/mL and the use of calcimimetics are associated with the development of tertiary hyperparathyroidism. These findings encourage the re-evaluation of recommended pre-kidney transplantation parathyroid hormone thresholds and reconsideration of pre-kidney transplantation secondary hyperparathyroidism treatments to avoid the adverse sequelae of tertiary hyperparathyroidism in kidney transplantation recipients.

Association Between Treatment of Secondary Hyperparathyroidism and Posttransplant Outcomes.

BACKGROUND: Secondary hyperparathyroidism (SHPT) affects nearly all patients on maintenance dialysis therapy. SHPT treatment options have considerably evolved over the past 2 decades but vary in degree of improvement in SHPT. Therefore, we hypothesize that the risks of adverse outcomes after kidney transplantation (KT) may differ by SHPT treatment. METHODS: Using the Scientific Registry of Transplant Recipients and Medicare claims data, we identified 5094 adults (age ≥18 y) treated with cinacalcet or parathyroidectomy for SHPT before receiving KT between 2007 and 2016. We quantified the association between SHPT treatment and delayed graft function and acute rejection using adjusted logistic models and tertiary hyperparathyroidism (THPT), graft failure, and death using adjusted Cox proportional hazards; we tested whether these associations differed by patient characteristics. RESULTS: Of 5094 KT recipients who were treated for SHPT while on dialysis, 228 (4.5%) underwent parathyroidectomy, and 4866 (95.5%) received cinacalcet. There was no association between treatment of SHPT and posttransplant delayed graft function, graft failure, or death. However, compared with patients treated with cinacalcet, those treated with parathyroidectomy had a lower risk of developing THPT (adjusted hazard ratio, 0.56; 95% confidence interval, 0.35-0.89) post-KT. Furthermore, this risk differed by dialysis vintage (Pinteraction = 0.039). Among patients on maintenance dialysis therapy for ≥3 y before KT (n = 3477, 68.3%), the risk of developing THPT was lower when treated with parathyroidectomy (adjusted hazard ratio, 0.43; 95% confidence interval, 0.24-0.79). CONCLUSIONS: Parathyroidectomy should be considered as treatment for SHPT, especially in KT candidates on maintenance dialysis for ≥3 y. Additionally, patients treated with cinacalcet for SHPT should undergo close surveillance for development of tertiary hyperparathyroidism post-KT.

Understanding surgical decision-making in older adults with differentiated thyroid cancer: A discrete choice experiment.

BACKGROUND: Prior studies demonstrated that older adults tend to undergo less surgery for thyroid cancer. Our objective was to use a discrete choice experiment to identify factors influencing surgical decision-making for older adults with thyroid cancer. METHODS: Active and candidate members of the American Association of Endocrine Surgeons were invited to participate in a web-based survey. Multinomial logistic regression was utilized to assess patient and surgeon factors associated with treatment choices. RESULTS: Complete survey response rate was 25.7%. Most respondents were high-volume surgeons (88.5%) at academic centers (76.9%). Multinomial logistic regression demonstrated that patient age was the strongest predictor of management. Increasing age and comorbidities were associated with the choice for active surveillance (P = .000), not performing a lymphadenectomy in patients with nodal metastases (relative-risk ratio: 2.5, 95% CI: 1.4-4.2, P = .002 and relative-risk ratio: 1.6, 95% CI: 1.2-2.1, P = .004, respectively), and recommending hemithyroidectomy versus total thyroidectomy for a cancer >4 cm (relative-risk ratio: 4.4, 95% CI: 2.5-7.9, P = .000 and relative-risk ratio: 3.4, 95% CI: 2.3-5.1, P = .000, respectively). Surgeons with ≥10 years of experience (relative-risk ratio: 3.3, 95% CI: 1.1-10.3, P = .039) favored total thyroidectomy for a cancer <4 cm, and nonfellowship trained surgeons (relative-risk ratio: 7.3, 95% CI: 1.3-42.2, P = .027) opted for thyroidectomy without lymphadenectomy for lateral neck nodal metastases. CONCLUSION: This study highlights the variation in surgical management of older adults with thyroid cancer and demonstrates the influence of patient age, comorbidities, surgeon experience, and fellowship training on management of this population.

Is patient age associated with risk of malignancy in a ≥4 cm cytologically benign thyroid nodule?

BACKGROUND: Current data regarding the risk of malignancy in a large thyroid nodule with benign fine-needle aspiration biopsy(FNAB) is conflicting. We investigated the impact of patient age on the risk of malignancy in nodules≥4 cm with benign cytology. METHODS: We performed a single-institution retrospective review of patients who underwent surgery from 07/2008-08/2019 for a cytologically benign thyroid nodule ≥4 cm. The relationship between malignant histopathology and patient and ultrasound features was assessed with multivariable logistic regression. RESULTS: Of 474 nodules identified, 25(5.3%) were malignant on final pathology. In patients <55 years old, 21/273(7.7%) nodules were malignant, compared to 4/201(2.0%) in patients ≥55. Patient age ≥55 was independently associated with significantly lower risk of malignancy(OR:0.2,95%CI:0.1-0.7,p = 0.011). Increasing nodule size >4 cm and high-risk ultrasound features were not associated with risk of malignancy(OR:1.0,95%CI:0.7-1.4,p = 0.980, and OR:9.6,95%CI:0.9-107.8,p = 0.066, respectively). CONCLUSIONS: Patients <55 years old are 3.7-fold more likely to have a falsely benign FNA biopsy in a nodule≥4 cm.

Treatment Variation in Older Adults With Differentiated Thyroid Cancer.

BACKGROUND: The growth of the aging population coupled with the increasing incidence of thyroid cancer warrants a better understanding of thyroid cancer in older adults. We aimed to investigate the variation of treatment patterns and determine if the extent of surgery is associated with disease-specific mortality in older adults with differentiated thyroid cancer (DTC). METHODS: We performed a population-based study using the Surveillance, Epidemiology, and End Results 18 program to examine patients diagnosed with DTC between 2004 and 2015. Patients were stratified by age: younger adults (aged 18-54 y), middle adults (aged 55-64 y), older adults (aged 65-79 y), and super elderly (aged ≥80 y). Disease-specific mortality was estimated using Kaplan-Meier curves and compared using the log-rank test. Multivariable Cox regression was used to assess associations between clinicopathologic characteristics and treatment patterns on disease-specific mortality. RESULTS: Of 117,098 patients with DTC, 72,368 were younger adults, 23,726 middle adults, 18,119 older adults, and 2885 were super elderly. In patients with DTC, compared with younger adults, fewer middle, older, and super elderly adults underwent any surgery (99.0%, 98.4%, 97.4%, and 89.1%, respectively; P < 0.001) or received radioactive iodine (RAI; 48.7%, 42.5%, 39.7%, and 30.7%, respectively; P < 0.001). Furthermore, middle, older, and super elderly adults had higher risk of mortality from DTC (hazard ratio [HR]: 4.0, 95% confidence interval [CI]: 3.2-4.8, P < 0.001; HR: 7.6, 95% CI: 6.3-9.1, P < 0.001; and HR: 17.2, 95% CI: 13.8-21.3, P < 0.001, respectively). On multivariable Cox regression while adjusting for clinicopathologic confounders, management was a significant prognostic factor (no surgery HR: 3.8, 95% CI: 3.1-4.6, P < 0.001; and RAI HR: 0.7, 95% CI: 0.6-0.8, P < 0.001). CONCLUSIONS: In patients with DTC, fewer older adults (≥65 y) underwent surgery or treatment with RAI, and this was associated with a worse disease-specific survival. Surgical decision-making in the older population is complex, and future prospective studies are needed to assess this age-related treatment variation.

Papillary thyroid carcinoma with bilateral axillary lymph node involvement: a case report outlining hypothesis for locoregional spread and therapeutic implications.

Axillary lymph node involvement (ALNI) in well differentiated papillary thyroid carcinoma (WDPTC) is a rare sequela of disease presentation. We report a case of PTC with extensive cervical lymph node involvement, local extension to the skin of the neck and bilateral ALNI without evidence of distant disease. We posit that ALNI represents local extension of disease rather than distant metastasis. Therefore, in the absence of distant spread, ALNI should result in surgical intervention. This optimizes removal of all bulky disease and increases effectiveness of radioactive iodine (RAI) therapy. Future research centered on genomics should focus on ascertaining the behavior and prognosis of such cases, especially when anatomic spread is discordant with biologic behavior.

Role of PTEN in basal cell derived lung carcinogenesis.

Lung adenocarcinoma (AdC) and lung squamous cell carcinoma (SCC) are the most common non-small cell lung cancer (NSCLC) subtypes, however, most genetic mouse models of lung cancer produce predominantly, if not exclusively, AdC. Whether this is secondary to targeting mutations to the distal airway cells or to the use of activating Kras mutations that drive AdC formation is unknown. We previously showed that targeting Kras(G12D) activation and transforming growth factor ß receptor type II (TGFßRII) deletion to airway basal cells via a keratin promoter induced formation of both lung AdC and SCC. In this study we assessed if targeting phosphatase and tensin homologue (PTEN) deletion to airway basal cells could initiate lung tumor formation or increase lung SCC formation. We found that PTEN deletion is capable of initiating both lung AdC and SCC formation when targeted to basal cells and although PTEN deletion is a weaker tumor initiator than Kras(G12D) with low tumor multiplicity and long latency, tumors initiated by PTEN deletion were larger and displayed more malignant conversion than Kras(G12D) initiated tumors. That PTEN deletion did not increase lung SCC formation compared to Kras(G12D) activation, suggests that the initiating genetic event does not dictate tumor histology when genetic alterations are targeted to a specific cell. These studies also confirm that basal cells of the conducting airway are capable of giving rise to multiple NSCLC tumor types.