Lactate Metabolism in Human Lung Tumors.

Cancer cells consume glucose and secrete lactate in culture. It is unknown whether lactate contributes to energy metabolism in living tumors. We previously reported that human non-small-cell lung cancers (NSCLCs) oxidize glucose in the tricarboxylic acid (TCA) cycle. Here, we show that lactate is also a TCA cycle carbon source for NSCLC. In human NSCLC, evidence of lactate utilization was most apparent in tumors with high 18fluorodeoxyglucose uptake and aggressive oncological behavior. Infusing human NSCLC patients with 13C-lactate revealed extensive labeling of TCA cycle metabolites. In mice, deleting monocarboxylate transporter-1 (MCT1) from tumor cells eliminated lactate-dependent metabolite labeling, confirming tumor-cell-autonomous lactate uptake. Strikingly, directly comparing lactate and glucose metabolism in vivo indicated that lactate's contribution to the TCA cycle predominates. The data indicate that tumors, including bona fide human NSCLC, can use lactate as a fuel in vivo.

Metabolic Heterogeneity in Human Lung Tumors.

Non-small cell lung cancer (NSCLC) is heterogeneous in the genetic and environmental parameters that influence cell metabolism in culture. Here, we assessed the impact of these factors on human NSCLC metabolism in vivo using intraoperative (13)C-glucose infusions in nine NSCLC patients to compare metabolism between tumors and benign lung. While enhanced glycolysis and glucose oxidation were common among these tumors, we observed evidence for oxidation of multiple nutrients in each of them, including lactate as a potential carbon source. Moreover, metabolically heterogeneous regions were identified within and between tumors, and surprisingly, our data suggested potential contributions of non-glucose nutrients in well-perfused tumor areas. Our findings not only demonstrate the heterogeneity in tumor metabolism in vivo but also highlight the strong influence of the microenvironment on this feature.

How I do it: robotic-assisted Ivor Lewis esophagectomy.

Advances in minimally invasive techniques, including robotic surgical technology, have led to improved outcomes in esophagectomy. In this article, we detail our approach to the robotic Ivor Lewis esophagectomy.

Esophagectomy and Gastric Pull-through Procedures: Surgical Techniques, Imaging Features, and Potential Complications.

Esophagectomy takes the center stage in the curative treatment of local and local-regional esophageal cancer. It is a complex procedure with a high postoperative complication rate. When interpreting imaging studies, radiologists must understand the surgical techniques used and their potential complications. The most common surgical techniques are transthoracic esophagectomies, such as the Ivor Lewis and McKeown techniques, and transhiatal esophagectomy. Variations of these techniques include different choices of conduit (ie, stomach, colon, or jejunum) to serve in lieu of the resected esophagus. Postoperative imaging and accurate interpretation is vital in the aftercare of these patients. Chest radiographs, esophagrams, and computed tomographic images play an essential role in early identification of complications. Pulmonary complications and anastomotic leaks are the leading causes of postoperative morbidity and mortality secondary to esophagectomy. Other complications include technical and functional problems and delayed complications such as anastomotic strictures and disease recurrence. An esophagographic technique is described that is performed by using hand injection of contrast material into an indwelling nasogastric tube. Familiarity with the various types of esophagectomy and an understanding of possible complications are of utmost importance for radiologists and allow them to be key participants in the treatment of patients undergoing these complicated procedures.

Radiation-Induced Liver Injury Mimicking Metastatic Disease in a Patient With Esophageal Cancer: Correlation of Positron Emission Tomography/Computed Tomography With Magnetic Resonance Imaging and Literature Review.

Post-radiation therapy evaluation of distal esophageal cancers with positron emission tomography/computed tomography can be problematic. Differentiation of recurrent neoplasm from postradiation changes is difficult in areas of fluorodeoxyglucose avidity in adjacent, incidentally irradiated organs. Few studies have described the magnetic resonance imaging appearance of radiation-induced hepatic injury. We report a case of focal radiation-induced liver injury with a new focus of fluorodeoxyglucose uptake on posttreatment positron emission tomography as well as masslike enhancement and signal abnormality on magnetic resonance imaging, thus mimicking new liver metastasis. Correlation with radiation planning images suggested the correct diagnosis, which was confirmed on follow-up imaging.

A phase 2 cooperative group adjuvant trial using a biomarker-based decision algorithm in patients with stage I non-small cell lung cancer (SWOG-0720, NCT00792701).

BACKGROUND: This cooperative group adjuvant phase 2 trial in patients with completely resected stage I non-small cell lung cancer with tumor diameters measuring ≥ 2 cm was designed to assess the feasibility and preliminary efficacy of assigning patients to therapy or observation using a molecularly based decision algorithm. METHODS: At least a lobectomy and sampling of recommended mediastinal lymph node stations, good Zubrod performance status, adequate organ function, and a formalin-fixed and paraffin-embedded tumor specimen were required. Excision repair cross-complementing group 1 (ERCC1) and ribonucleotide reductase M1 (RRM1) were analyzed using immunofluorescence-based in situ automated quantitative image analysis and categorized as high or low using prespecified cutoff values. Patients with high ERCC1 and RRM1 were assigned to observation and all others to 4 cycles of cisplatin and gemcitabine. Feasibility was defined as treatment assignment within 84 days from surgery in > 85% of patients. Secondary objectives were to estimate the 2-year survival. RESULTS: Treatment assignment met the feasibility criteria in 88% of eligible patients (71 of 81 patients). The collective 2-year disease-free and overall survival rates were 80% and 96%, respectively. Protein levels for RRM1 fell within the previously established range, ERCC1 levels were slightly lower than expected, and they were significantly correlated (correlation coefficient, 0.4). The rates of assignment of patients to observation (22%) and chemotherapy (78%) were as expected. CONCLUSIONS: Gene expression analysis for treatment assignment is feasible. Survival results are encouraging and require future validation. Real-time performance of quantitative in situ ERCC1 and RRM1 analysis requires further development.

Fen1 mutations result in autoimmunity, chronic inflammation and cancers.

Functional deficiency of the FEN1 gene has been suggested to cause genomic instability and cancer predisposition. We have identified a group of FEN1 mutations in human cancer specimens. Most of these mutations abrogated two of three nuclease activities of flap endonuclease 1 (FEN1). To demonstrate the etiological significance of these somatic mutations, we inbred a mouse line harboring the E160D mutation representing mutations identified in human cancers. Selective elimination of nuclease activities led to frequent spontaneous mutations and accumulation of incompletely digested DNA fragments in apoptotic cells. The mutant mice were predisposed to autoimmunity, chronic inflammation and cancers. The mutator phenotype results in the initiation of cancer, whereas chronic inflammation promotes the cancer progression. The current work exemplifies the approach of studying the mechanisms of individual polymorphisms and somatic mutations in cancer development, and may serve as a reference in developing new therapeutic regimens through the suppression of inflammatory responses.

Metabolic signatures of thymomas: potential biomarkers and treatment targets.

OBJECTIVES: A study of tumour metabolic reprogramming has revealed disease biomarkers and avenues for therapeutic intervention. Metabolic reprogramming in thymoma is currently understudied and largely unknown. This study utilized metabolomics and isotope tracing with 13C-glucose to metabolically investigate thymomas, adjacent thymic tissue and benign thymic lesions. METHODS: From 2017 to 2021, 20 patients with a suspected thymoma were recruited to this prospective Institutional Review Board approved clinical trial. At the time of surgery, 11 patients were infused with 13C-glucose, a stable, non-radioactive tracer which reports the flow of carbon through metabolic pathways. Samples were analysed by mass spectrometry to measure the abundance of >200 metabolites.13C enrichment was measured in patients who received 13C-glucose infusions. RESULTS: Histological analysis showed that 9 patients had thymomas of diverse subtypes and 11 patients had benign cysts. In our metabolomic analysis, thymomas could be distinguished from both adjacent thymus tissue and benign lesions by metabolite abundances. Metabolites in pyrimidine biosynthesis and glycerophospholipid metabolism were differentially expressed across these tissues.13C-glucose infusions revealed differential labelling patterns in thymoma compared to benign cysts and normal thymus tissue. The lactate/3PG labelling ratio, a metabolic marker in aggressive lung tumours correlated with lactate uptake, was increased in thymomas (1.579) compared to normal thymus (0.945) and benign masses (0.807) (thymic tissue versus tumour P = 0.021, tumour versus benign P = 0.013). CONCLUSIONS: We report metabolic biomarkers, including differential 13C labelling of metabolites from central metabolism, that distinguish thymomas from benign tissues. Altered glucose and lactate metabolism warrant further investigation and may provide novel therapeutic targets for thymoma.

The International Association for the Study of Lung Cancer Lung Cancer Staging Project: Proposals for Revision of the TNM Stage Groups in the Forthcoming (Ninth) Edition of the TNM Classification for Lung Cancer.

INTRODUCTION: The TNM classification of lung cancer is periodically revised. The International Association for the Study of Lung Cancer collected and analyzed a new database to inform the forthcoming ninth edition of the TNM classification. The results are herewith presented. METHODS: After exclusions, 76,518 patients from a total of 124,581 registered patients were available for analyses: 58,193 with clinical stage, 39,192 with pathologic stage, and 62,611 with best stage NSCLC. The proposed new N2 subcategories (N2a, involvement of single ipsilateral mediastinal or subcarinal nodal station, and N2b, involvement of multiple ipsilateral mediastinal nodal stations with or without involvement of the subcarinal nodal station) and the new M1c subcategories (M1c1, multiple extrathoracic metastases in one organ system, and M1c2, multiple extrathoracic metastases in multiple organ systems) were considered in the survival analyses. Several potential stage groupings were evaluated, using multiple analyses, including recursive partitioning, assessment of homogeneity within and discrimination between potential groups, clinical and statistical significance of survival differences, multivariable regression, and broad assessment of generalizability. RESULTS: T1N1, T1N2a, and T3N2a subgroups are assigned to IIA, IIB, and IIIA stage groups, respectively. T2aN2b and T2bN2b subgroups are assigned to IIIB. M1c1 and M1c2 remain in stage group IVB. Analyses reveal consistent ordering, discrimination of prognosis, and broad generalizability of the proposed ninth edition stage classification of lung cancer. CONCLUSIONS: The proposed stages for the ninth edition TNM improve the granularity of nomenclature about anatomic extent that has benefits as treatment approaches become increasingly differentiated and complex.

Clinical and radiological septic joint analysis of spontaneous sternoclavicular joint infections: achieving the best outcomes-a systems engineering approach.

OBJECTIVES: Spontaneous sternoclavicular joint infection (SSCJI) is a rare and poorly understood disease process. This study aims to identify factors guiding effective management strategies for SSCJI by using data mining. METHODS: An Institutional Review Board-approved retrospective review of patients from 2 large hospitals (2010-2022) was conducted. SSCJI is defined as a joint infection without direct trauma or radiation, direct instrumentation or contiguous spread. An interdisciplinary team consisting of thoracic surgeons, radiologists, infectious disease specialists, orthopaedic surgeons, hospital information experts and systems engineers selected relevant variables. Small set data mining algorithms, utilizing systems engineering, were employed to assess the impact of variables on patient outcomes. RESULTS: A total of 73 variables were chosen and 54 analysed against 11 different outcomes. Forty-seven patients [mean age 51 (22-82); 77% male] met criteria. Among them, 34 underwent early joint surgical resection (<14 days), 5 patients received delayed surgical intervention (>14 days) and 8 had antibiotic-only management. The antibiotic-only group had comparable outcomes. Indicators of poor outcomes were soft tissue fluid >4.5 cm, previous SSCJI, moderate/significant bony fragments, HgbA1c >13.9% and moderate/significant bony sclerosis. CONCLUSIONS: This study suggests that targeted antibiotic-only therapy should be considered initially for SSCJI cases while concurrently managing comorbidities. Patients displaying indicators of poor outcomes or no symptomatic improvement after antibiotic-only therapy should be considered for surgical joint resection.

The International Association for the Study of Lung Cancer (IASLC) Staging Project for Lung Cancer: Recommendation to Introduce Spread Through Air Spaces as a Histologic Descriptor in the Ninth Edition of the TNM Classification of Lung Cancer. Analysis of 4061 Pathologic Stage I NSCLC.

INTRODUCTION: Spread through air spaces (STAS) consists of lung cancer tumor cells that are identified beyond the edge of the main tumor in the surrounding alveolar parenchyma. It has been reported by meta-analyses to be an independent prognostic factor in the major histologic types of lung cancer, but its role in lung cancer staging is not established. METHODS: To assess the clinical importance of STAS in lung cancer staging, we evaluated 4061 surgically resected pathologic stage I R0 NSCLC collected from around the world in the International Association for the Study of Lung Cancer database. We focused on whether STAS could be a useful additional histologic descriptor to supplement the existing ones of visceral pleural invasion (VPI) and lymphovascular invasion (LVI). RESULTS: STAS was found in 930 of 4061 of the pathologic stage I NSCLC (22.9%). Patients with tumors exhibiting STAS had a significantly worse recurrence-free and overall survival in both univariate and multivariable analyses involving cohorts consisting of all NSCLC, specific histologic types (adenocarcinoma and other NSCLC), and extent of resection (lobar and sublobar). Interestingly, STAS was independent of VPI in all of these analyses. CONCLUSIONS: These data support our recommendation to include STAS as a histologic descriptor for the Ninth Edition of the TNM Classification of Lung Cancer. Hopefully, gathering these data in the coming years will facilitate a thorough analysis to better understand the relative impact of STAS, LVI, and VPI on lung cancer staging for the Tenth Edition TNM Stage Classification.

The International Association for the Study of Lung Cancer Staging Project for Lung Cancer: Proposals for the Revision of the N Descriptors in the Forthcoming Ninth Edition of the TNM Classification for Lung Cancer.

INTRODUCTION: The accurate assessment of nodal (N) status is crucial to the management and prognostication of nonmetastatic NSCLC. We sought to determine whether the current N descriptors should be maintained or revised for the upcoming ninth edition of the international TNM lung cancer staging system. METHODS: Data were assembled by the International Association for the Study of Lung Cancer on patients with NSCLC, detailing both clinical and pathologic N status, with information about anatomical location and individual station-level identification. Survival was calculated by the Kaplan-Meier method and prognostic groups were assessed by a Cox regression analysis. RESULTS: Data for clinical N and pathologic N status were available in 45,032 and 35,009 patients, respectively. The current N0 to N3 descriptors for both clinical N and pathologic N categories reflect prognostically distinct groups. Furthermore, single-station N2 involvement (N2a) exhibited a better prognosis than multistation N2 involvement (N2b) in both clinical and pathologic classifications, and the differences between all neighboring nodal subcategories were highly significant. The prognostic differences between N2a and N2b were robust and consistent across resection status, histologic type, T category, and geographic region. CONCLUSIONS: The current N descriptors should be maintained, with the addition of new subdescriptors to N2 for single-station involvement (N2a) and multiple-station involvement (N2b).

DNA methylation biomarkers for lung cancer.

Changes in DNA methylation patterns are an important characteristic of human cancer including lung cancer. In particular, hypermethylation of CpG islands is a signature of malignant progression. Methylated CpG islands are promising diagnostic markers for the early detection of cancer. However, the full extent and sequence context of DNA hypermethylation in lung cancer has remained unknown. We have used the methylated CpG island recovery assay and high-resolution microarray analysis to find hypermethylated CpG islands in squamous cell carcinomas (SCC) and adenocarcinomas of the lung. Each tumor contained several hundred hypermethylated CpG islands. In an initial microarray screen, 36 CpG islands were methylated in five of five (=100%) of the SCC tumors tested and 52 CpG islands were methylated in at least 75% of the adenocarcinomas tested (n=8). Using sodium-bisulfite-based approaches, 12 CpG islands (associated with the BARHL2, EVX2, IRX2, MEIS1, MSX1, NR2E1, OC2, OSR1, OTX1, PAX6, TFAP2A, and ZNF577 genes) were confirmed to be methylated in 85% to 100% of the squamous cell carcinomas and 11 CpG islands (associated with the CHAD, DLX4, GRIK2, KCNG3, NR2E1, OSR1, OTX1, OTX2, PROX1, RUNX1, and VAX1 genes) were methylated in >80% of the adenocarcinomas. From the list of genes that were methylated in lung adenocarcinomas, we identified the gene FAT4 and found that this gene was methylated in 39% of the tumors. FAT4 is the closest mammalian homologue of the Drosophila tumor suppressor Fat which is an important component of the Hippo growth control pathway. Many of these newly discovered methylated CpG islands hold promise for becoming biomarkers for the early detection of lung cancer.

A case of diffuse large B-cell lymphoma in association with paraesophageal leiomyoma: highlighting false-positivity of PET scan and importance of tissue diagnosis.

PET scan and PET/CT scans are being widely used for staging of diffuse large B-cell lymphoma (DLBCL) and Hodgkin lymphoma. They are sensitive and specific imaging techniques available for lymphoma. However, practicing hematologists must be aware of false-positive tests, which can upgrade the stage of the lymphoma significantly and may alter the treatment paradigm for an individual patient. This report describes a case of DLBCL that was upgraded with PET/CT scan to stage IVA from stage IA. Pursuit of tissue biopsy with minimally invasive surgery eventually confirmed it to be stage IA DLBCL and paraesophageal leiomyoma. This case highlights the potential pitfalls of modern imaging techniques and the need for histologic diagnosis.

Predictors of finding benefit after lung cancer diagnosis.

OBJECTIVE: We examined benefit finding in patients with lung cancer, including level of benefit finding and change in benefit finding over time, and tested a predictive model postulating that greater impact of and engagement with the stressor promotes benefit finding. METHODS: Patients diagnosed with a primary lung cancer within the past 6 months (M=16 weeks post-diagnosis) completed measures of benefit finding, cancer-related intrusions, perceived stressfulness, coping, and demographic and medical information at study entry (T1; n = 118) and 3 months later (T2; n = 79). RESULTS: Level of benefit finding at both assessments was to a 'mild-to-moderate degree'. Benefit finding increased over time for patients with small cell carcinoma, but not for those with nonsmall cell carcinoma. The proposed model explained 33% of the variance in T1 benefit finding, and 64% (using T1 coping measures) and 71% (using T2 coping measures) of the variance in T2 benefit finding. Greater benefit finding was associated with having small cell lung cancer, higher cancer-related intrusions, lower perceived cancer-related stress, and greater approach-oriented coping. Positive reframing coping emerged as the single unique approach-oriented coping scale predicting benefit finding at T1, and emotional approach coping was the single unique approach-oriented coping scale predicting benefit finding at T2. CONCLUSION: Findings provide general support for a theoretical model positing that stressor impact and engagement with the stressor contribute to the development of benefit finding after cancer. Future research with larger, more diverse samples is needed to confirm and extend these findings.

Serological antibodies against LY6K as a diagnostic biomarker in esophageal squamous cell carcinoma.

OBJECTIVES: To evaluate the diagnostic values of autoantibodies against lymphocyte antigen 6 complex locus K (LY6K) in esophageal squamous cell carcinoma (ESCC). METHODS: After cloning, expressing, and purifying LY6K as fusion proteins, LY6K autoantibodies were measured in 62 patient and 58 control serum samples using enzyme-linked immunosorbent assay (ELISA). Reverse transcription polymerase chain reaction (RT-PCR) was used to measure the LY6K mRNA levels in ESCC and adjacent tissues. RESULTS: LY6K autoantibodies were found significantly higher in patients than controls. The area under the receiver-operating characteristic (ROC) curve (AUC) was 0.85, and the optimal sensitivity and specificity for ESCC detection were 80.6 and 78.7%, respectively. LY6K mRNA expressions in patients were upregulated. CONCLUSIONS: Autoantibodies against LY6K may be a good diagnostic biomarker for ESCC.

Combined robotic lobectomy and adrenalectomy for lung cancer and solitary adrenal metastasis.

BACKGROUND AND OBJECTIVES: Surgical resection of isolated adrenal metastasis in primary lung cancer is associated with improved survival. We report a combined robotic lobectomy and adrenalectomy for resection of a primary lung cancer and metastasis to the adrenal gland. METHODS: A 69-year-old male with a significant smoking history and shortness of breath was found to have a 3-cm left upper lobe mass with an enlarged left adrenal gland measuring 1.5cm. The adrenal gland was biopsied confirming metastatic poorly differentiated carcinoma, likely lung cancer. Computed tomography, positron emission tomography, and mediastinoscopy revealed no evidence of disease outside the adrenal gland. RESULTS: Following induction chemotherapy, the patient underwent combination robotic lobectomy, lymphadenectomy, and adrenalectomy while in the same lateral decubitus position. Thoracic and urologic oncology teams performed their respective portions of the operation. Overall operative time was 4 hours, and length of hospital stay was 3 days. Estimated blood loss was 150mL with no narcotic requirements beyond the first postoperative day. Final pathology revealed large cell carcinoma of the lung with metastasis to the adrenal. All surgical margins were negative. CONCLUSIONS: Combination robotic lobectomy and adrenalectomy is feasible and can be associated with a short convalescence, minimal pain, and an oncologically sound approach.

Putative multifunctional signature of lung metastases in dedifferentiated chondrosarcoma.

Chondrosarcomas are among the most malignant skeletal tumors. Dedifferentiated chondrosarcoma is a highly aggressive subtype of chondrosarcoma, with lung metastases developing within a few months of diagnosis in 90% of patients. In this paper we performed comparative analyses of the transcriptomes of five individual metastatic lung lesions that were surgically resected from a patient with dedifferentiated chondrosarcoma. We document for the first time a high heterogeneity of gene expression profiles among the individual lung metastases. Moreover, we reveal a signature of "multifunctional" genes that are expressed in all metastatic lung lesions. Also, for the first time, we document the occurrence of massive macrophage infiltration in dedifferentiated chondrosarcoma lung metastases.

Training Cardiothoracic Residents in Robotic Lobectomy Is Cost-Effective With No Change in Clinical Outcomes.

Objective: Our objective was to evaluate for any changes in quality or cost when robotic lung resection is used with significant trainee participation. Methods: All anatomic lung resections between January 2006 and June 2016 were identified from a prospectively maintained database. Clinical data were recorded by double entry. Cost and cancer-related data were gathered from the business analytics department and tumor registry. Robotic outcomes were compared to an ongoing thoracotomy and video-assisted thoracic surgery (VATS) experience. Propensity scores using age, sex, and comorbidities were assigned for statistical analysis. Survival was evaluated using the Kaplan-Meier method. Results: Of 523 consecutive cases, 483 were included (211 robotic, 210 thoracotomy, 62 VATS). There were 74 robotic cases (35%) performed by trainees as the console surgeon. Length of stay was shortest for robotics (3 days) compared to thoracotomy (7 days, P < 0.001) and VATS (5 days, P = 0.010). Complications occurred in 33% of robotic cases, 42% of VATS cases (P = 0.854), and 52% of thoracotomy cases (P < 0.001). Stage I non-small cell lung cancer 3-year overall survival for robotics, thoracotomy, and VATS was 79.5%, 74.3%, and 74.0%, respectively (P > 0.25). There was no significant difference in negative margin rates. Total cost related to the hospitalization for surgery was $5,721 less for robotics compared to thoracotomy (P = 0.003) but comparable to VATS. Trainees served as console surgeon in 0% of cases in the first 2 years of robotics but increased to 79% in the last year of the study. Conclusions: Robotic lung resection can be safely performed and taught in an academic medical center without sacrificing quality or cost.