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Patient-derived xenografts (PDX) model human intra- and intertumoral heterogeneity in the context of the intact tissue of immunocompromised mice. Histologic imaging via hematoxylin and eosin (H&E) staining is routinely performed on PDX samples, which could be harnessed for computational analysis. Prior studies of large clinical H&E image repositories have shown that deep learning analysis can identify intercellular and morphologic signals correlated with disease phenotype and therapeutic response. In this study, we developed an extensive, pan-cancer repository of >1,000 PDX and paired parental tumor H&E images. These images, curated from the PDX Development and Trial Centers Research Network Consortium, had a range of associated genomic and transcriptomic data, clinical metadata, pathologic assessments of cell composition, and, in several cases, detailed pathologic annotations of neoplastic, stromal, and necrotic regions. The amenability of these images to deep learning was highlighted through three applications: (i) development of a classifier for neoplastic, stromal, and necrotic regions; (ii) development of a predictor of xenograft-transplant lymphoproliferative disorder; and (iii) application of a published predictor of microsatellite instability. Together, this PDX Development and Trial Centers Research Network image repository provides a valuable resource for controlled digital pathology analysis, both for the evaluation of technical issues and for the development of computational image-based methods that make clinical predictions based on PDX treatment studies. Significance: A pan-cancer repository of >1,000 patient-derived xenograft hematoxylin and eosin-stained images will facilitate cancer biology investigations through histopathologic analysis and contributes important model system data that expand existing human histology repositories.
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Aprendizado Profundo , Neoplasias , Humanos , Animais , Camundongos , Neoplasias/genética , Neoplasias/patologia , Neoplasias/diagnóstico por imagem , Genômica/métodos , Xenoenxertos , Ensaios Antitumorais Modelo de Xenoenxerto , Transtornos Linfoproliferativos/genética , Transtornos Linfoproliferativos/patologia , Processamento de Imagem Assistida por Computador/métodosRESUMO
Resistance to inactive state-selective RASG12C inhibitors frequently entails accumulation of RASGTP, rendering effective inhibition of active RAS potentially desirable. Here, we evaluated the anti-tumor activity of the RAS(ON) multi-selective tri-complex inhibitor RMC-7977 and dissected mechanisms of response and tolerance in KRASG12C-mutant NSCLC. Broad-spectrum, reversible RASGTP inhibition with or without concurrent covalent targeting of active RASG12C yielded superior and differentiated antitumor activity across diverse co-mutational KRASG12C-mutant NSCLC mouse models of primary or acquired RASG12C(ON) or (OFF) inhibitor resistance. Interrogation of time-resolved single cell transcriptional responses established an in vivo atlas of multi-modal acute and chronic RAS pathway inhibition in the NSCLC ecosystem and uncovered a regenerative mucinous transcriptional program that supports long-term tumor cell persistence. In patients with advanced KRASG12C-mutant NSCLC, the presence of mucinous histological features portended poor response to sotorasib or adagrasib. Our results have potential implications for personalized medicine and the development of rational RAS inhibitor-anchored therapeutic strategies.
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Targeted therapy is effective in many tumor types including lung cancer, the leading cause of cancer mortality. Paradigm defining examples are targeted therapies directed against non-small cell lung cancer (NSCLC) subtypes with oncogenic alterations in EGFR, ALK and KRAS. The success of targeted therapy is limited by drug-tolerant persister cells (DTPs) which withstand and adapt to treatment and comprise the residual disease state that is typical during treatment with clinical targeted therapies. Here, we integrate studies in patient-derived and immunocompetent lung cancer models and clinical specimens obtained from patients on targeted therapy to uncover a focal adhesion kinase (FAK)-YAP signaling axis that promotes residual disease during oncogenic EGFR-, ALK-, and KRAS-targeted therapies. FAK-YAP signaling inhibition combined with the primary targeted therapy suppressed residual drug-tolerant cells and enhanced tumor responses. This study unveils a FAK-YAP signaling module that promotes residual disease in lung cancer and mechanism-based therapeutic strategies to improve tumor response.
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Carcinoma Pulmonar de Células não Pequenas , Resistencia a Medicamentos Antineoplásicos , Neoplasias Pulmonares , Transdução de Sinais , Fatores de Transcrição , Proteínas de Sinalização YAP , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Transdução de Sinais/efeitos dos fármacos , Fatores de Transcrição/metabolismo , Fatores de Transcrição/genética , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/patologia , Proteínas de Sinalização YAP/metabolismo , Linhagem Celular Tumoral , Animais , Resistencia a Medicamentos Antineoplásicos/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/genética , Neoplasia Residual , Camundongos , Quinase 1 de Adesão Focal/metabolismo , Quinase 1 de Adesão Focal/genética , Receptores ErbB/metabolismo , Receptores ErbB/genética , Quinase do Linfoma Anaplásico/metabolismo , Quinase do Linfoma Anaplásico/genética , Quinase do Linfoma Anaplásico/antagonistas & inibidores , Proteínas Proto-Oncogênicas p21(ras)/genética , Proteínas Proto-Oncogênicas p21(ras)/metabolismo , Proteína-Tirosina Quinases de Adesão Focal/metabolismo , Antineoplásicos/uso terapêutico , Antineoplásicos/farmacologia , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Although patient-derived xenografts (PDX) are commonly used for preclinical modeling in cancer research, a standard approach to in vivo tumor growth analysis and assessment of antitumor activity is lacking, complicating the comparison of different studies and determination of whether a PDX experiment has produced evidence needed to consider a new therapy promising. We present consensus recommendations for assessment of PDX growth and antitumor activity, providing public access to a suite of tools for in vivo growth analyses. We expect that harmonizing PDX study design and analysis and assessing a suite of analytical tools will enhance information exchange and facilitate identification of promising novel therapies and biomarkers for guiding cancer therapy.
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Neoplasias , Ensaios Antitumorais Modelo de Xenoenxerto , Humanos , Animais , Neoplasias/patologia , Neoplasias/tratamento farmacológico , National Cancer Institute (U.S.) , Estados Unidos , Camundongos , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , ConsensoRESUMO
OBJECTIVE: To investigate overall survival and length of stay (LOS) associated with differing management for high output (>1 L over 24 hours) leaks (HOCL) after cancer-related esophagectomy. BACKGROUND: Although infrequent, chyle leak after esophagectomy is an event that can lead to significant perioperative sequelae. Low-volume leaks appear to respond to nonoperative measures, whereas HOCLs often require invasive therapeutic interventions. METHODS: From a prospective single-institution database, we retrospectively reviewed patients treated from 2001 to 2021 who underwent esophagectomy for esophageal cancer. Within that cohort, we focused on a subgroup of patients who manifested a HOCL postoperatively. Clinicopathologic and operative characteristics were collected, including hospital LOS and survival data. RESULTS: A total of 53/2299 patients manifested a HOCL. These were mostly males (77%), with a mean age of 62 years. Of this group, 15 patients received nonoperative management, 15 patients received prompt (<72 hours from diagnosis) interventional management, and 23 received late interventional management. Patients in the late intervention group had longer LOSs compared with early intervention (slope = 9.849, 95% CI: 3.431-16.267). Late intervention (hazard ratio: 4.772, CI: 1.384-16.460) and nonoperative management (hazard ratio: 4.731, CI: 1.294-17.305) were associated with increased mortality compared with early intervention. Patients with early intervention for HOCL had an overall survival similar to patients without chyle leaks in survival analysis. CONCLUSIONS: Patients with HOCL should receive early intervention to possibly reverse the prognostic implications of this potentially detrimental complication.
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Fístula Anastomótica , Neoplasias Esofágicas , Esofagectomia , Humanos , Masculino , Esofagectomia/efeitos adversos , Feminino , Pessoa de Meia-Idade , Neoplasias Esofágicas/cirurgia , Neoplasias Esofágicas/mortalidade , Estudos Retrospectivos , Idoso , Fístula Anastomótica/etiologia , Fístula Anastomótica/cirurgia , Quilo , Tempo de Internação , Taxa de Sobrevida , Resultado do Tratamento , Complicações Pós-Operatórias/mortalidadeRESUMO
Cancer cells exhibit heightened secretory states that drive tumor progression. Here, we identify a chromosome 3q amplicon that serves as a platform for secretory regulation in cancer. The 3q amplicon encodes multiple Golgi-resident proteins, including the scaffold Golgi integral membrane protein 4 (GOLIM4) and the ion channel ATPase Secretory Pathway Ca2+ Transporting 1 (ATP2C1). We show that GOLIM4 recruits ATP2C1 and Golgi phosphoprotein 3 (GOLPH3) to coordinate calcium-dependent cargo loading and Golgi membrane bending and vesicle scission. GOLIM4 depletion disrupts the protein complex, resulting in a secretory blockade that inhibits the progression of 3q-amplified malignancies. In addition to its role as a scaffold, GOLIM4 maintains intracellular manganese (Mn) homeostasis by binding excess Mn in the Golgi lumen, which initiates the routing of Mn-bound GOLIM4 to lysosomes for degradation. We show that Mn treatment inhibits the progression of multiple types of 3q-amplified malignancies by degrading GOLIM4, resulting in a secretory blockade that interrupts pro-survival autocrine loops and attenuates pro-metastatic processes in the tumor microenvironment. Potentially underlying the selective activity of Mn against 3q-amplified malignancies, ATP2C1 co-amplification increases Mn influx into the Golgi lumen, resulting in a more rapid degradation of GOLIM4. These findings show that functional cooperativity between co-amplified genes underlies heightened secretion and a targetable secretory addiction in 3q-amplified malignancies.
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The use of octreotide in managing intrathoracic chyle leak following esophagectomy has gained popularity in the adult population. While the benefits of octreotide have been confirmed in the pediatric population, there remains limited evidence to support its use in the adults post-esophagectomy. Thus, we performed a single-institution cohort study to characterize its efficacy. The study was performed using a prospective, single-center database, from which clinicopathologic characteristics were extracted of patients who had post-esophagectomy chyle leaks. Kaplan-Meier and multivariable Cox regression analyses were performed to investigate the effect of octreotide use on chest tube duration (CTD), hospital length of stay (LOS), and overall survival (OS). In our cohort, 74 patients met inclusion criteria, among whom 27 (36.5%) received octreotide. Kaplan-Meier revealed no significant effect of octreotide on CTD (P = 0.890), LOS (P = 0.740), or OS (P = 0.570). Multivariable Cox regression analyses further corroborated that octreotide had no effect on CTD (HR = 0.62, 95% confidence interval [CI]: 0.32-1.20, P = 0.155), LOS (HR = 0.64, CI: 0.34-1.21, P = 0.168), or OS (1.08, CI: 0.53-2.19, P = 0.833). Octreotide use in adult patients with chyle leak following esophagectomy lacks evidence of association with meaningful clinical outcomes. Level 1 evidence is needed prior to further consideration in this population.
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Quilotórax , Esofagectomia , Fármacos Gastrointestinais , Tempo de Internação , Octreotida , Complicações Pós-Operatórias , Humanos , Octreotida/uso terapêutico , Esofagectomia/efeitos adversos , Quilotórax/etiologia , Quilotórax/tratamento farmacológico , Masculino , Feminino , Pessoa de Meia-Idade , Tempo de Internação/estatística & dados numéricos , Idoso , Complicações Pós-Operatórias/etiologia , Complicações Pós-Operatórias/tratamento farmacológico , Fármacos Gastrointestinais/uso terapêutico , Estimativa de Kaplan-Meier , Estudos Prospectivos , Resultado do Tratamento , Tubos Torácicos , Modelos de Riscos Proporcionais , Adulto , Estudos RetrospectivosRESUMO
BACKGROUND: Whereas current guidelines recommend staging laparoscopy for most patients with potentially resectable gastric cancer, such a recommendation for patients with adenocarcinoma of the gastroesophageal junction (AEG) is lacking. This study sought to identify baseline clinicopathologic characteristics associated with peritoneal metastasis (PM) among patients with Siewert II AEG. METHODS: Trimodality therapy-eligible patients with Siewert II AEG (2000-2015, single institution) were retrospectively identified. A composite PM outcome was defined as follows: (1) PM at staging laparoscopy; (2) PM diagnosed during neoadjuvant chemoradiation; or (3) PM ≤6 months postoperatively. Logistic regression was used to identify features associated with PM; bootstrapped analysis (Youden J) identified the distal tumor extension that best discriminated the composite outcome. RESULTS: Of 188 patients, a composite PM outcome was observed in 26 of 188 (13.8%); 12 of 26 had positive staging laparoscopy, 10 of 26 experienced PM during chemoradiation, and 4 of 26 had PM ≤6 months postoperatively. Tumor extension below the GEJ was greater in patients with PM (median, 4.0 cm [interquartile range, 3.0-5.0] vs 3.0 cm [interquartile range, 2.0-3.0]; P < .001). All patients with PM had cT3 to cT4 tumors. Among patients with cT3 to cT4 tumors (n = 168 of 188; 89.4%), distal tumor extent (odds ratio, 1.67/cm; 95% CI, 1.23-2.28; P = .001) was independently associated with increased odds of PM. Gastric tumor extension ≥4 cm remained independently associated with PM (OR, 5.14; 95% CI, 2.11-12.53; P < .001) after adjustment for signet ring cell status. CONCLUSIONS: Distal tumor extent beyond the GEJ is independently associated with increased odds of PM in patients with Siewert II AEG. Patients with extensive gastric involvement should therefore be considered for staging laparoscopy before trimodality therapy.
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Adenocarcinoma , Neoplasias Esofágicas , Neoplasias Peritoneais , Neoplasias Gástricas , Humanos , Estudos Retrospectivos , Neoplasias Peritoneais/terapia , Gastrectomia , Adenocarcinoma/cirurgia , Neoplasias Gástricas/cirurgia , Junção Esofagogástrica/cirurgia , Neoplasias Esofágicas/cirurgia , Estadiamento de NeoplasiasRESUMO
BACKGROUND AND OBJECTIVES: For patients with colorectal cancer (CRC), the lung is the most common extra-abdominal site of distant metastasis. However, practices for chest imaging after colorectal resection vary widely. We aimed to identify characteristics that may indicate a need for early follow-up imaging. METHODS: We retrospectively reviewed charts of patients who underwent CRC resection, collecting clinicopathologic details and oncologic outcomes. Patients were grouped by timing of pulmonary metastases (PM) development. Analyses were performed to investigate odds ratio (OR) of PM diagnosis within 3 months of CRC resection. RESULTS: Of 1600 patients with resected CRC, 233 (14.6%) developed PM, at a median of 15.4 months following CRC resection. Univariable analyses revealed age, receipt of systemic therapy, lymph node ratio (LNR), lymphovascular and perineural invasion, and KRAS mutation as risk factors for PM. Furthermore, multivariable regression showed neoadjuvant therapy (OR: 2.99, p < 0.001), adjuvant therapy (OR: 6.28, p < 0.001), LNR (OR: 28.91, p < 0.001), and KRAS alteration (OR: 5.19, p < 0.001) to predict PM within 3 months post-resection. CONCLUSIONS: We identified clinicopathologic characteristics that predict development of PM within 3 months after primary CRC resection. Early surveillance in such patients should be emphasized to ensure timely identification and treatment of PM.
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Neoplasias Colorretais , Neoplasias Pulmonares , Humanos , Neoplasias Colorretais/patologia , Estudos Retrospectivos , Proteínas Proto-Oncogênicas p21(ras) , Terapia Combinada , Neoplasias Pulmonares/diagnóstico por imagem , Neoplasias Pulmonares/cirurgiaRESUMO
OBJECTIVE: Chemotherapy plus nivolumab is the standard of care neoadjuvant treatment for patients with resectable stage IB to IIIA non-small cell lung cancer. The influence of dual checkpoint blockade with chemotherapy on surgical outcomes remains unknown. We aimed to determine operative complexity and perioperative outcomes associated with neoadjuvant chemotherapy and nivolumab with or without ipilimumab. METHODS: A total of 44 patients with stage IB (≥4 cm) to IIIA non-small cell lung cancer were treated on sequential platform arms of the NEOSTAR trial. A total of 22 patients were treated with nivolumab + chemotherapy, and 22 patients were treated with ipilimumab + nivolumab + chemotherapy. The safety of surgical resection after neoadjuvant therapy was estimated using 30-day complication rates. Operative reports and surgeons' narratives were evaluated to determine procedural complexity and operative conduct. RESULTS: All 22 of 22 patients (100%) treated with nivolumab + chemotherapy underwent surgical resection: 20 R0 (90.9%), 17 (77.3%) lobectomies, 1 wedge resection, 2 segmentectomies, and 2 pneumonectomies. The majority, 21 of 22 (95%), were performed by thoracotomy. A total of 13 of 22 (59.1%) were rated as challenging resections. A total of 4 of 22 patients (18.2%) experienced grade 3 or greater Clavien-Dindo complication. A total of 20 of 22 patients (90.9%) treated with ipilimumab + nivolumab + chemotherapy underwent surgical resection: 19 R0 (95%), 18 (90%) lobectomies, 1 pneumonectomy, and 1 segmentectomy. A total of 16 of 20 (80%) resections were performed via thoracotomy, 3 of 20 (15%) via robotics, and 1 of 20 (5%) via thoracoscopy. A total of 9 of 20 (45%) resections were considered challenging. A total of 4 of 20 patients (20%) experienced grade 3 or greater Clavien-Dindo complication. CONCLUSIONS: Surgical resections are feasible and safe, with high rates of R0 after neoadjuvant chemotherapy and nivolumab with or without ipilimumab. Overall, approximately half of cases (22/42, 52.3%) were considered to be more challenging than a standard lobectomy.
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Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Humanos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/cirurgia , Nivolumabe , Ipilimumab/efeitos adversos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/cirurgia , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Estadiamento de Neoplasias , Terapia Neoadjuvante/efeitos adversos , Resultado do TratamentoRESUMO
BACKGROUND: Appropriately selected patients clearly benefit from resection of colorectal cancer (CRC) pulmonary metastases (PMs). However, there remains equipoise surrounding optimal chest surveillance strategies following pulmonary metastasectomy. We aimed to identify risk factors that may inform chest surveillance in this population. METHODS: Patients who underwent CRC pulmonary metastasectomy were identified from a single institution's prospectively maintained surgical database. Clinicopathologic and genomic characteristics were collected. Patients were stratified by diagnosis of subsequent PM within 6 months of the index lung resection. Multivariate modeling was used to evaluate risk factors. RESULTS: A total of 197 patients met the study's inclusion criteria, of whom 52.3% (n = 103) developed subsequent PM, at a median of 9.51 months following the index metastasectomy. Patients with KRAS alterations (odds ratio [OR], 3.073; 95% confidence interval [CI], 1.363-6.926; P = .007), TP53 alterations (OR, 3.109; 95% CI, 1.318-7.341; P = .010) were found to be at risk of PM diagnosis within 6 months of the index metastasectomy, while those with an APC alteration (OR, .218; 95% CI, 0.080-0.598; P = .003) were protected. Moreover, patients who received systemic therapy within 3 months of the initial PM diagnosis also were more likely to develop early lung recurrence (OR, 2.105; 95% CI, 0.971-4.563; P = .059). CONCLUSIONS: Patients with KRAS alterations, TP53 alterations, and no APC alterations developed early recurrence in the lung following pulmonary metastasectomy, as did those who received chemotherapy after their initial PM diagnosis. As such, these groups benefit from early lung imaging after metastasectomy, as chest surveillance protocols should be based on patient-centered clinicopathologic and genomic risk factors.
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Neoplasias Colorretais , Neoplasias Pulmonares , Metastasectomia , Humanos , Metastasectomia/efeitos adversos , Metastasectomia/métodos , Proteínas Proto-Oncogênicas p21(ras)/genética , Pneumonectomia/efeitos adversos , Pulmão/patologia , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/cirurgia , Neoplasias Pulmonares/secundário , Fatores de Risco , Neoplasias Colorretais/patologia , Prognóstico , Taxa de Sobrevida , Estudos RetrospectivosRESUMO
OBJECTIVE: We evaluated self-reported financial burden (FB) after lung cancer surgery and sought to assess patient perspectives, risk factors, and coping mechanisms within this population. METHODS: Patients with lung cancer resected at our institution between January 1, 2016, and December 31, 2021, were surveyed. Descriptive and multivariable analyses were performed to evaluate the association between clinical and financial characteristics with patient-reported major ("significant" or "catastrophic") FB. RESULTS: Of 1477 patients contacted, 31.3% (n = 463) completed the survey. Major FB was reported by 62 (13.4%) patients. multivariable analyses demonstrated increasing age (odds ratio [OR], 0.92; 95% CI, 0.88-0.96), credit score >740 (OR, 0.29; 95% CI, 0.14-0.60), and employer-based insurance (OR, 0.24; 95% CI, 0.07-0.80) were protective factors. In contrast, an out of pocket cost greater than expected (OR, 3.63; 95% CI, 1.67-7.88), decrease in work hours (OR, 4.42; 95% CI, 1.59-12.25), or cessation of work (OR, 5.13; 95% CI, 2.06-12.78), chronic obstructive pulmonary disease diagnosis (OR, 5.39, 95% CI, 1.87-15.50), and hospital readmission (OR, 4.87; 95% CI, 1.11-21.42) were risk factors for FB. To pay for care, some patients reported "often" or "always" decreasing food (n = 102 [23.4%]) or leisure spending (n = 179 [40.7%]). Additionally, use of savings (n = 246 [62.9%]), borrowing funds (n = 72 [16.6%]), and skipping clinic visits (n = 36 [8.3%]) at least once were also reported. Coping mechanisms occurred more often in patients with major FB compared with those without (P < .001). CONCLUSIONS: Patients with resected lung cancer may experience major FB related to treatment with several identifiable risk factors. Targeted interventions are needed to limit the adoption of detrimental coping mechanisms and potentially affect survivorship.
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Neoplasias Pulmonares , Humanos , Autorrelato , Neoplasias Pulmonares/cirurgia , Efeitos Psicossociais da Doença , Estresse Financeiro , Fatores de Risco , Adaptação PsicológicaRESUMO
OBJECTIVES: Disparities in cancer care are omnipresent and originate from a multilevel set of barriers. Our objectives were to describe the likelihood of undergoing surgery for early-stage non-small cell lung cancer at minority-serving hospitals (MSHs), and evaluate the association of race/ethnicity with resection based on MSH status. METHODS: A retrospective study using the National Cancer Database (2008-2016) was conducted including patients with clinical stage I non-small cell lung cancer. MSHs were defined as hospitals in the top decile of providing care to Hispanic or African American patients. The primary outcome evaluated was receipt of definitive surgery at MSHs vs non-MSHs. Outcomes related to race/ethnicity stratified by hospital type were also investigated. RESULTS: A total of 142,580 patients were identified from 1192 hospitals (120 MSHs and 1072 non-MSHs). Most patients (85% [n = 121,240]) were non-Hispanic White, followed by African American (9% [n = 12,772]), and Hispanic (3%, [n= 3749]). MSHs cared for 7.4% (n = 10,491) of the patients included. In adjusted analyses, patients treated at MSHs were resected less often than those at non-MSHs (odds ratio, 0.87; 95% CI, 0.76-1.00; P = .0495). African American patients were less likely to receive surgery in the overall analysis (P < .01), and at MSHs specifically (P < .01), compared with non-Hispanic White patients. Hispanic patients had similar rates of resection in the overall analysis (P = .11); however, at MSHs, they underwent surgery more often compared with non-Hispanic White patients (P = .02). Resected patients at MSHs had similar overall survival (median, 91.7 months; 95% CI, 86.6-96.8 months) compared with those resected at non-MSHs (median, 85.7 months; 95% CI, 84.5-86.8 months). CONCLUSIONS: Patients with early-stage non-small cell lung cancer underwent resection less often at MSHs compared with non-MSHs. Disparities related to underutilization of surgery for African American patients continue to persist, regardless of hospital type.
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Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Humanos , Carcinoma Pulmonar de Células não Pequenas/cirurgia , Estudos Retrospectivos , Neoplasias Pulmonares/cirurgia , Hospitais , Disparidades em Assistência à Saúde , BrancosRESUMO
Background: Therapeutic decisions in non-small cell lung cancer (NSCLC) are stage-dependent, and, consequently, changes in an individual's stage carry potential for substantial alterations in management. Malignancy-related disturbances of the circulomic inflammatory environment may affect platelets quantitatively, ultimately leading to changes in tumor characteristics. Our objective was to identify circulomic characteristics associated with upstaging among chemotherapy-naïve patients with resected NSCLC and to assess the consequent impact on overall survival (OS). Methods: A retrospective review of a prospectively maintained thoracic surgery database was performed, identifying chemotherapy-naïve patients who underwent resection of clinical stage I-III NSCLC between 1998 and 2021. Clinicopathologic characteristics were gathered; circulomic variables comprised of platelet and lymphocyte count from the last blood draw prior to resection. Platelet-to-lymphocyte ratio (PLR) was calculated. A multivariate model evaluated variables that might affect upstaging. Kaplan-Meier analysis was performed to assess OS. Results: A total of 4,141 patients met inclusion criteria (median age: 67.0 years) among whom the sex distribution was fairly equal (2,189 female, 52.9%), and 1,016 (24.5%) individuals were upstaged. Patients with elevated PLR were found to have reduced risk of upstaging [odds ratio (OR): 0.757, 95% confidence interval (CI): 0.650-0.882]. Analyses revealed that median OS for patients who were upstaged was 80.0 months compared to 130.7 months among those who weren't upstaged (P<0.0001). Conclusions: PLR appears to predict upstaging in treatment-naïve patients with resected NSCLC. In addition to clinicopathologic characteristics, circulomic variables may provide insight relating to pathologic staging prior to resection. These findings may guide patient counseling regarding survival probability, as well as referral patterns for adjuvant therapy.
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Despite substantial advances in targeting mutant KRAS, tumor resistance to KRAS inhibitors (KRASi) remains a major barrier to progress. Here, we report proteostasis reprogramming as a key convergence point of multiple KRASi-resistance mechanisms. Inactivation of oncogenic KRAS down-regulated both the heat shock response and the inositol-requiring enzyme 1α (IRE1α) branch of the unfolded protein response, causing severe proteostasis disturbances. However, IRE1α was selectively reactivated in an ER stress-independent manner in acquired KRASi-resistant tumors, restoring proteostasis. Oncogenic KRAS promoted IRE1α protein stability through extracellular signal-regulated kinase (ERK)-dependent phosphorylation of IRE1α, leading to IRE1α disassociation from 3-hydroxy-3-methylglutaryl reductase degradation (HRD1) E3-ligase. In KRASi-resistant tumors, both reactivated ERK and hyperactivated AKT restored IRE1α phosphorylation and stability. Suppression of IRE1α overcame resistance to KRASi. This study reveals a druggable mechanism that leads to proteostasis reprogramming and facilitates KRASi resistance.
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Antineoplásicos , Resistencia a Medicamentos Antineoplásicos , Endorribonucleases , Inibidores Enzimáticos , MAP Quinases Reguladas por Sinal Extracelular , Fatores de Transcrição de Choque Térmico , Neoplasias , Proteostase , Proteínas Proto-Oncogênicas p21(ras) , Humanos , Neoplasias/tratamento farmacológico , Neoplasias/genética , Proteínas Serina-Treonina Quinases , Proteínas Proto-Oncogênicas p21(ras)/antagonistas & inibidores , Proteínas Proto-Oncogênicas p21(ras)/genética , Inibidores Enzimáticos/farmacologia , Antineoplásicos/farmacologia , Fatores de Transcrição de Choque Térmico/metabolismoRESUMO
Background: Malignant pleural mesothelioma (MPM) is associated with poor prognosis despite advances in multimodal therapeutic strategies. While patients with resectable disease may benefit from added survival with oncologic resection, patient selection for mesothelioma operations often relies on both objective and subjective evaluation metrics. We sought to evaluate factors associated with improved overall survival (OS) in patients with mesothelioma who underwent macroscopic complete resection (MCR). Methods: Patients with MPM who received neoadjuvant therapy and underwent MCR were identified in a prospectively maintained departmental database. Clinicopathologic, blood-based, and radiographic variables were collected and included in a Cox regression analysis (CRA). Response to neoadjuvant therapy was characterized by a change in tumor thickness from pretherapy to preoperative scans using the modified RECIST criteria. Results: In this study, 99 patients met the inclusion criteria. The median age of the included patients was 64.7 years, who were predominantly men, had smoking and asbestos exposure, and who received neoadjuvant therapy. The median change in tumor thickness following neoadjuvant therapy was -16.5% (interquartile range of -49.7% to +14.2%). CRA demonstrated reduced OS associated with non-epithelioid histology [hazard ratio (HR): 3.06, 95% confidence interval (CI): 1.62-5.78, p < 0.001] and a response to neoadjuvant therapy inferior to the median (HR: 2.70, CI: 1.55-4.72, p < 0.001). Patients who responded poorly (below median) to neoadjuvant therapy had lower median survival (15.8 months compared to 38.2 months, p < 0.001). Conclusion: Poor response to neoadjuvant therapy in patients with MPM is associated with poor outcomes even following maximum surgical cytoreduction and should warrant a patient-centered discussion regarding goals of care and may therefore help guide further therapeutic decisions.
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PURPOSE: The optimal neoadjuvant treatment for resectable carcinoma of the thoracic esophagus (TE) or gastroesophageal junction (GEJ) remains a matter of debate. We performed an individual participant data (IPD) network meta-analysis (NMA) of randomized controlled trials (RCTs) to study the effect of chemotherapy or chemoradiotherapy, with a focus on tumor location and histology subgroups. PATIENTS AND METHODS: All, published or unpublished, RCTs closed to accrual before December 31, 2015 and having compared at least two of the following strategies were eligible: upfront surgery (S), chemotherapy followed by surgery (CS), and chemoradiotherapy followed by surgery (CRS). All analyses were conducted on IPD obtained from investigators. The primary end point was overall survival (OS). The IPD-NMA was analyzed by a one-step mixed-effect Cox model adjusted for age, sex, tumor location, and histology. The NMA was registered in PROSPERO (CRD42018107158). RESULTS: IPD were obtained for 26 of 35 RCTs (4,985 of 5,807 patients) corresponding to 12 comparisons for CS-S, 12 for CRS-S, and four for CRS-CS. CS and CRS led to increased OS when compared with S with hazard ratio (HR) = 0.86 (0.75 to 0.99), P = .03 and HR = 0.77 (0.68 to 0.87), P < .001 respectively. The NMA comparison of CRS versus CS for OS gave a HR of 0.90 (0.74 to 1.09), P = .27 (consistency P = .26, heterogeneity P = .0038). For CS versus S, a larger effect on OS was observed for GEJ versus TE tumors (P = .036). For the CRS versus S and CRS versus CS, a larger effect on OS was observed for women (P = .003, .012, respectively). CONCLUSION: Neoadjuvant chemotherapy and chemoradiotherapy were consistently better than S alone across histology, but with some variation in the magnitude of treatment effect by sex for CRS and tumor location for CS. A strong OS difference between CS and CRS was not identified.
Assuntos
Carcinoma , Neoplasias Esofágicas , Feminino , Humanos , Carcinoma/tratamento farmacológico , Quimiorradioterapia , Quimioterapia Adjuvante , Neoplasias Esofágicas/patologia , Junção Esofagogástrica/patologia , Terapia Neoadjuvante , Metanálise em Rede , Ensaios Clínicos Controlados Aleatórios como Assunto , MasculinoRESUMO
OBJECTIVES: To describe financial toxicity (FT) in patients with resected lung cancer and identify risk factors in this population. BACKGROUND: FT describes the financial burden associated with cancer care and its impact on the quality of survivorship. Few prior studies have examined FT in patients with lung cancer. METHODS: Patients who underwent lung cancer resection at our institution between January 1, 2016 and December 31, 2021, were surveyed to gather demographic information and evaluate FT using a validated questionnaire. A multivariable model was built to identify risk factors for FT. RESULTS: Of the total, 1477 patients were contacted, of whom 463 responded (31.3%). Most patients were stage I (n = 349, 75.4%) and lobectomy was performed often (n = 290, 62.8%). There were 196 patients (42.3%) who experienced FT. Upon multivariable analyses, divorced marital status [odds ratio (OR) = 3.658, 95% CI: 1.180-11.337], household income <$40,000 (OR = 2.544, 95% CI: 1.003-6.455), credit score below 739 (OR = 2.744, 95% CI: 1.326-5.679), clinical stage >I (OR = 2.053, 95% CI: 1.088-3.877), and change in work hours or work cessation (all P < 0.05) were associated with FT. Coping mechanisms, such as decreased spending on food or clothing and increased use of savings or borrowing money, were more likely to be reported by patients experiencing FT than those who did not ( P < 0.001). CONCLUSIONS: Patients undergoing lung cancer resection often experienced significant financial stress with several identifiable risk factors. FT should be considered early in the care of these patients to alleviate detrimental coping mechanisms and enhance their quality of survivorship.
Assuntos
Neoplasias Pulmonares , Neoplasias , Humanos , Neoplasias Pulmonares/cirurgia , Estresse Financeiro , Efeitos Psicossociais da Doença , Neoplasias/epidemiologia , Renda , Inquéritos e Questionários , Qualidade de VidaRESUMO
Osimertinib sensitive and resistant NSCLC NCI-H1975 clones are used to model osimertinib acquired resistance in humanized and non-humanized mice and delineate potential resistance mechanisms. No new EGFR mutations or loss of the EGFR T790M mutation are found in resistant clones. Resistant tumors grown under continuous osimertinib pressure both in humanized and non-humanized mice show aggressive tumor regrowth which is significantly less sensitive to osimertinib as compared with parental tumors. 3-phosphoinositide-dependent kinase 1 (PDK1) is identified as a potential driver of osimertinib acquired resistance, and its selective inhibition by BX795 and CRISPR gene knock out, sensitizes resistant clones. In-vivo inhibition of PDK1 enhances the osimertinib sensitivity against osimertinib resistant xenograft and a patient derived xenograft (PDX) tumors. PDK1 knock-out dysregulates PI3K/Akt/mTOR signaling, promotes cell cycle arrest at the G1 phase. Yes-associated protein (YAP) and active-YAP are upregulated in resistant tumors, and PDK1 knock-out inhibits nuclear translocation of YAP. Higher expression of PDK1 and an association between PDK1 and YAP are found in patients with progressive disease following osimertinib treatment. PDK1 is a central upstream regulator of two critical drug resistance pathways: PI3K/AKT/mTOR and YAP.