Perioperative Systemic Therapy for Resectable Non-Small Cell Lung Cancer.

Despite remarkable treatment advancements in patients with advanced non-small cell lung cancer (NSCLC), recurrence rates for those with resectable, early-stage disease remains high. Immune checkpoint inhibitors and targeted therapies are 2 promising treatment modalities that may improve survival outcomes for patients with resected NSCLC when moved from the advanced stage to the curable setting. There are many clinical studies that have evaluated or are currently evaluating immunotherapy or targeted therapy in the perioperative setting, and recent trials such as CheckMate 816, ADAURA, and IMpower010 have led to new approvals and demonstrated the promise of this approach. This review discusses recent and ongoing neoadjuvant and adjuvant systemic therapy trials in NSCLC, and where the field may be going in the near future.

Prediction of future imagery of lung nodule as growth modeling with follow-up computed tomography scans using deep learning: a retrospective cohort study.

Background: Risk prediction models of lung nodules have been built to alleviate the heavy interpretative burden on clinicians. However, the malignancy scores output by those models can be difficult to interpret in a clinically meaningful manner. In contrast, the modeling of lung nodule growth may be more readily useful. This study developed a CT-based visual forecasting system that can visualize and quantify a nodule in three dimensions (3D) in any future time point using follow-up CT scans. Methods: We retrospectively included 246 patients with 313 lung nodules with at least 1 follow-up CT scan. For the manually segmented nodules, we calculated geometric properties including CT value, diameter, volume, and mass, as well as growth properties including volume doubling time (VDT), and consolidation-to-tumor ratio (CTR) at follow-ups. These nodules were divided into growth and non-growth groups by thresholding their VDTs. We then developed a convolutional neural network (CNN) to model the imagery change of the nodules from baseline CT image (combined with the nodule mask) to follow-up CT image with a particular time interval. The model was evaluated on the geometric and radiological properties using either logistic regression or receiver operating characteristic (ROC) curve. Results: The lung nodules consisted of 115 ground glass nodules (GGN) and 198 solid nodules and were followed up for an average of 354 days with 2 to 11 scans. The 2 groups differed significantly in most properties. The prediction of our forecasting system was highly correlated with the ground truth with small relative errors regarding the four geometric properties. The prediction-derived VDTs had an area under the curve (AUC) of 0.857 and 0.843 in differentiating growth and non-growth nodules for GGN and solid nodules, respectively. The prediction-derived CTRs had an AUC of 0.892 in classifying high- and low-risk nodules. Conclusions: This proof-of-concept study demonstrated that the deep learning-based model can accurately forecast the imagery of a nodule in a given future for both GGNs and solid nodules and is worthy of further investigation. With a larger dataset and more validation, such a system has the potential to become a prognostication tool for assessing lung nodules.

CT derived radiomic score for predicting the added benefit of adjuvant chemotherapy following surgery in stage I, II resectable non-small cell lung cancer: a retrospective multicohort study for outcome prediction.

BACKGROUND: Use of adjuvant chemotherapy in patients with early-stage lung cancer is controversial because no definite biomarker exists to identify patients who would receive added benefit from it. We aimed to develop and validate a quantitative radiomic risk score (QuRiS) and associated nomogram (QuRNom) for early-stage non-small cell lung cancer (NSCLC) that is prognostic of disease-free survival and predictive of the added benefit of adjuvant chemotherapy following surgery. METHODS: We did a retrospective multicohort study of individuals with early-stage NSCLC (stage I and II) who either received surgery alone or surgery plus adjuvant chemotherapy. We selected patients for whom we had available pre-treatment diagnostic CT scans and corresponding survival information. We used radiomic texture features derived from within and outside the primary lung nodule on chest CT scans of patients from the Cleveland Clinic Foundation (Cleveland, OH, USA; cohort D1) to develop QuRiS. A least absolute shrinkage and selection operator-Cox regularisation model was used for data dimension reduction, feature selection, and QuRiS construction. QuRiS was independently validated on a cohort of patients from the University of Pennsylvania (Philadephia, PA, USA; cohort D2) and a cohort of patients whose CT scans were derived from The Cancer Imaging Archive (cohort D3). QuRNom was constructed by integrating QuRiS with tumour and node descriptors (according to the tumour, node, metastasis staging system) and lymphovascular invasion. The primary endpoint of the study was the assessment of the performance of QuRiS and QuRNom in predicting disease-free survival. The added benefit of adjuvant chemotherapy estimated using QuRiS and QuRNom was validated by comparing patients who received adjuvant chemotherapy versus patients who underwent surgery alone in cohorts D1-D3. FINDINGS: We included: 329 patients in cohort D1 (73 [22%] had surgery plus adjuvant chemotherapy and 256 (78%) had surgery alone); 114 patients in cohort D2 (33 [29%] had surgery plus adjuvant chemotherapy and 81 (71%) had surgery alone); and 82 patients in cohort D3 (24 [29%] had surgery plus adjuvant chemotherapy and 58 (71%) had surgery alone). QuRiS comprised three intratumoral and 10 peritumoral CT-radiomic features and was found to be significantly associated with disease-free survival (ie, prognostic validation of QuRiS; hazard ratio for predicted high-risk vs predicted low-risk groups 1·56, 95% CI 1·08-2·23, p=0·016 for cohort D1; 2·66, 1·24-5·68, p=0·011 for cohort D2; and 2·67, 1·39-5·11, p=0·0029 for cohort D3). To validate the predictive performance of QuRiS, patients were partitioned into three risk groups (high, intermediate, and low risk) on the basis of their corresponding QuRiS. Patients in the high-risk group were observed to have significantly longer survival with adjuvant chemotherapy than patients who underwent surgery alone (0·27, 0·08-0·95, p=0·042, for cohort D1; 0·08, 0·01-0·42, p=0·0029, for cohorts D2 and D3 combined). As concerns QuRNom, the nomogram-estimated survival benefit was predictive of the actual efficacy of adjuvant chemotherapy (0·25, 0·12-0·55, p<0·0001, for cohort D1; 0·13, <0·01-0·99, p=0·0019 for cohort D3). INTERPRETATION: QuRiS and QuRNom were validated as being prognostic of disease-free survival and predictive of the added benefit of adjuvant chemotherapy, especially in clinically defined low-risk groups. Since QuRiS is based on routine chest CT imaging, with additional multisite independent validation it could potentially be employed for decision management in non-invasive treatment of resectable lung cancer. FUNDING: National Cancer Institute of the US National Institutes of Health, National Center for Research Resources, US Department of Veterans Affairs Biomedical Laboratory Research and Development Service, Department of Defence, National Institute of Diabetes and Digestive and Kidney Diseases, Wallace H Coulter Foundation, Case Western Reserve University, and Dana Foundation.

Novel, non-invasive imaging approach to identify patients with advanced non-small cell lung cancer at risk of hyperprogressive disease with immune checkpoint blockade.

PURPOSE: Hyperprogression is an atypical response pattern to immune checkpoint inhibition that has been described within non-small cell lung cancer (NSCLC). The paradoxical acceleration of tumor growth after immunotherapy has been associated with significantly shortened survival, and currently, there are no clinically validated biomarkers to identify patients at risk of hyperprogression. EXPERIMENTAL DESIGN: A total of 109 patients with advanced NSCLC who underwent monotherapy with Programmed cell death protein-1 (PD1)/Programmed death-ligand-1 (PD-L1) inhibitors were included in the study. Using RECIST measurements, we divided the patients into responders (n=50) (complete/partial response or stable disease) and non-responders (n=59) (progressive disease). Tumor growth kinetics were used to further identify hyperprogressors (HPs, n=19) among non-responders. Patients were randomized into a training set (D1=30) and a test set (D2=79) with the essential caveat that HPs were evenly distributed among the two sets. A total of 198 radiomic textural patterns from within and around the target nodules and features relating to tortuosity of the nodule associated vasculature were extracted from the pretreatment CT scans. RESULTS: The random forest classifier using the top features associated with hyperprogression was able to distinguish between HP and other radiographical response patterns with an area under receiver operating curve of 0.85±0.06 in the training set (D1=30) and 0.96 in the validation set (D2=79). These features included one peritumoral texture feature from 5 to 10 mm outside the tumor and two nodule vessel-related tortuosity features. Kaplan-Meier survival curves showed a clear stratification between classifier predicted HPs versus non-HPs for overall survival (D2: HR=2.66, 95% CI 1.27 to 5.55; p=0.009). CONCLUSIONS: Our study suggests that image-based radiomics markers extracted from baseline CTs of advanced NSCLC treated with PD-1/PD-L1 inhibitors may help identify patients at risk of hyperprogressions.

Cases from the Immune-Related Adverse Event Tumor Board: Diagnosis and Management of Immune Checkpoint Blockade-Induced Diabetes.

The addition of immune checkpoint inhibitors to the armamentarium of cancer therapies has resulted in unprecedented improvement in clinical outcomes for a vast range of malignancies. Because they interfere with the physiologic function of immune checkpoints, such as programmed cell death protein 1 or cytotoxic T-lymphocyte-associated protein 4, to promote self-tolerance, these agents are associated with a unique spectrum of immune-related adverse events (irAEs). Immune-mediated endocrinopathies are among the most commonly noted irAEs. Immune-mediated diabetes is an uncommon irAE but can be associated with significant morbidity if it is not recognized and treated in a time-sensitive manner. In this manuscript, we present a case based discussion and review of the literature pertaining to immune-mediated diabetes associated with immune checkpoint blockade. KEY POINTS: Immune checkpoint inhibitor associated diabetes mellitus often resembles type 1 diabetes mellitus (DM) in its pathophysiology and clinical manifestations. However, some patients may present with type 2 DM or worsening hyperglycemia in the setting of pre-existent DM. Early recognition and management is key to preventing life-threatening events such as diabetic ketoacidosis. Endocrinology referral and interdisciplinary management should be considered for every patient to optimize glycemic control and to ensure optimal monitoring for long-term microvascular complications.

Cases from the irAE Tumor Board: A Multidisciplinary Approach to a Patient Treated with Immune Checkpoint Blockade Who Presented with a New Rash.

Immune checkpoint inhibitors (ICIs) have revolutionized the treatment paradigms for a broad spectrum of malignancies. Because immune checkpoint inhibitors rely on immune reactivation to eliminate cancer cells, they can also lead to the loss of immune tolerance and result in a wide range of phenomena called immune-related adverse events (irAEs). At our institution, the management of irAEs is based on multidisciplinary input obtained at an irAE tumor board that facilitates expedited opinions from various specialties and allows for a more uniform approach to these patients. In this article, we describe a case of a patient with metastatic urothelial carcinoma who developed a maculopapular rash while being treated with a programmed death-ligand 1 inhibitor. We then describe the approach to management of dermatologic toxicities with ICIs based on the discussion at our irAE Tumor Board. KEY POINTS: Innocuous symptoms such as pruritis or a maculopapular rash may herald potentially fatal severe cutaneous adverse reactions (SCARs); therefore, close attention must be paid to the symptoms, history, and physical examination of all patients.Consultation with dermatology should be sought for patients with grade 3 or 4 toxicity or SCARs and prior to resumption of immune checkpoint inhibitors for patients with grade 3 or higher toxicity.A multidisciplinary immune-related adverse events (irAE) tumor board can facilitate timely input and expertise from various specialties, thereby ensuring a streamlined approach to management of irAEs.

Incidental extensive adenocarcinoma in lungs explanted from a transplant recipient with an idiopathic pulmonary fibrosis flare-up: A clinical dilemma.

Patients under consideration for lung transplantation as treatment for end-stage lung diseases such as idiopathic pulmonary fibrosis (IPF) often have risk factors such as a history of smoking or concomitant emphysema, both of which can predispose the patient to lung cancer. In fact, IPF itself increases the risk of lung cancer development by 6.8% to 20%. Solid organ malignancy (non-skin) is an established contraindication for lung transplantation. We encountered a clinical dilemma in a patient who presented with an IPF flare-up and underwent urgent evaluation for lung transplantation. After transplant, the patient's explanted lungs showed extensive adenocarcinoma in situ, with the foci of invasion and metastatic adenocarcinoma in N1-level lymph nodes, as well as usual interstitial pneumonia. Retrospectively, we saw no evidence to suggest malignancy in addition to the IPF flare-up. Clinical diagnostic dilemmas such as this emphasize the need for new noninvasive testing that would facilitate malignancy diagnosis in patients too sick to undergo invasive tissue biopsy for diagnosis. Careful pathological examination of explanted lungs in patients with IPF is critical, as it can majorly influence immunosuppressive regimens, surveillance imaging, and overall prognosis after lung transplant.

A 47-Year-Old Man With Fever, Dry Cough, and a Lung Mass After Redo Lung Transplantation.

CASE PRESENTATION: A 47-year-old man who was a redo double lung transplant recipient (cytomegalovirus [CMV] status: donor positive/recipient positive; Epstein-Barr virus status: donor positive/recipient positive) presented to the hospital with 1 week of generalized malaise, low-grade fevers, and dry cough. His redo lung transplantation was necessitated by bronchiolitis obliterans syndrome, and his previous lung transplantation 5 years earlier was for silicosis-related progressive massive fibrosis. He denied any difficulty breathing or chest pain. There was no history of GI or urinary symptoms, and the patient had no anorexia, weight loss, night sweats, sick contacts, or history of travel. He had a history of 1 earlier episode of CMV viremia that was treated with valganciclovir. His immunosuppressive regimen included tacrolimus, mycophenolate mofetil, and prednisone, and his infection prophylaxis included trimethoprim-sulfamethoxazole, itraconazole, and valganciclovir. Results of a chest radiograph 8 weeks earlier were normal.

A 68-Year-Old Lung Transplant Recipient With Shortness of Breath, Weight Loss, and Abnormal Chest CT.

CASE PRESENTATION: A 68-year-old man presented to our ED with shortness of breath, weakness, and a 25-lb unintentional weight loss. He had undergone bilateral lung transplantation (cytomegalovirus [CMV]: donor+, recipient+; Epstein-Barr virus: donor+; recipient+) for idiopathic pulmonary fibrosis (IPF) 18 months prior. His posttransplant course was fairly unremarkable until 1 month earlier, when he was admitted for breathlessness and weakness. CT of the chest during that admission revealed mild intralobular and interlobular septal thickening. A bronchoscopy with BAL and transbronchial biopsies did not show acute cellular rejection, but the BAL fluid was positive for coronavirus. His cortisol level was undetectable; he was diagnosed with adrenal insufficiency and fludrocortisone was initiated. He was taking prednisone, tacrolimus, and everolimus for immunosuppression and valganciclovir, itraconazole, and trimethoprim-sulfamethoxazole for antimicrobial prophylaxis. His 25-lb weight loss occurred over the span of just one month.

Pulmonary Artery Pseudoaneurysm: A Rare Cause of Fatal Massive Hemoptysis.

Pulmonary artery pseudoaneurysm (PAPA), an uncommon complication of pyogenic bacterial and fungal infections and related septic emboli, is associated with high mortality. The pulmonary artery (PA) lacks an adventitial wall; therefore, repeated endovascular seeding of the PA with septic emboli creates saccular dilations that are more likely to rupture than systemic arterial aneurysms. The most common clinical presentation of PAPA is massive hemoptysis and resultant worsening hypoxemia. Computed tomography angiography is the preferred diagnostic modality for PAPA; typical imaging patterns include focal outpouchings of contrast adjacent to a branch of the PA following the same contrast density as the PA in all phases of the study. In mycotic PAPAs, multiple synchronous lesions are often seen in segmental and subsegmental PAs due to ongoing embolic phenomena. The recommended approach for a mycotic PAPA is prolonged antimicrobial therapy; for massive hemoptysis, endovascular treatment (e.g., coil embolization, stenting, or embolization of the feeding vessel) is preferred. PAPA resection and lobectomy are a last resort, generally reserved for patients with uncontrolled hemoptysis or pleural hemorrhage. We present a case of a 28-year-old woman with necrotizing pneumonia from intravenous drug use who ultimately died from massive hemoptysis and shock after a ruptured PAPA.

Coexistent Non-Small Cell Carcinoma and Small Cell Carcinoma in a Patient Presenting with Hyponatremia.

Despite recent advances in screening methods, lung cancer remains the leading cause of cancer-related deaths worldwide. By the time lung cancer becomes symptomatic and patients seek treatment, it is often too advanced for curative measures. Low-dose computed tomography (CT) screening has been shown to reduce mortality in patients at high risk of lung cancer. We present a 66-year-old man with a 50-pack-year smoking history who had a right upper lobe (RUL) pulmonary nodule and left lower lobe (LLL) consolidation on a screening CT. He reported a weight loss of 45 pounds over 3 months, had recently been hospitalized for hyponatremia, and was notably cachectic. A CT of the chest showed a stable LLL mass-like consolidation and a 9 × 21 mm subsolid lesion in the RUL. Navigational bronchoscopy biopsy of the RUL lesion revealed squamous non-small cell lung cancer (NSCLC). Endobronchial ultrasound-guided transbronchial needle aspiration of the LLL lesion revealed small cell lung cancer (SCLC). The final diagnosis was a right-sided Stage I NSCLC (squamous) and a left-sided limited SCLC. The RUL NSCLC was treated with stereotactic radiation; the LLL SCLC was treated with concurrent chemotherapy and radiation. In patients with multiple lung nodules, a diagnosis of synchronous multiple primary lung cancers (MPLCs) is crucial, as inadvertent upstaging of patients with MPLC (to T3 and/or T4 tumors) can lead to erroneous staging, inaccurate prognosis, and improper treatment. Recent advances in the diagnosis of small pulmonary nodules via navigational bronchoscopy and management of these lesions dramatically affect a patient's overall prognosis.

Primary Nocardia Infection Causing a Fluorodeoxyglucose-Avid Right Renal Mass in a Redo Lung Transplant Recipient.

Immunosuppression after lung transplantation may increase susceptibility to opportunistic infection and is associated with early and delayed deaths in lung transplant recipients. Factors that may predispose lung transplant recipients to opportunistic bacterial and fungal infections include prolonged corticosteroid use, renal impairment, treatment of acute rejection, and post-transplant diabetes mellitus. We present a unique case of a 63-year-old woman with diabetes mellitus who underwent redo lung transplantation. Three years after her right-sided single redo lung transplant, she presented with right-sided abdominal pain, nausea, and vomiting. Upon examination, computed tomography showed a 4.5 × 3.3 cm heterogeneous, enhancing right renal mass with a patent renal vein. Magnetic resonance imaging confirmed a T1/T2 hypointense, diffusion-restricting, right mid-renal mass that was fluorodeoxyglucose-avid on positron emission tomography. We initially suspected primary renal cell carcinoma. However, after a right nephrectomy, no evidence of neoplasia was observed; instead, a renal abscess containing filamentous bacteria was noted, raising suspicion for infection of the Nocardia species. Special stains confirmed a diagnosis of Nocardia renal abscess. Computed tomography of the chest and brain revealed no lesions consistent with infection. We initiated a long-term therapeutic regimen of anti-Nocardia therapy with imipenem and trimethoprim-sulfamethoxazole.

Biomarkers for immune-related toxicities of checkpoint inhibitors: current progress and the road ahead.

INTRODUCTION: Immune checkpoint pathways are key immune regulatory pathways that play a physiologic role in maintaining immune-homeostasis and are often co-opted by cancer cells to evade the host immune system. Recent developments in cancer immunotherapy, mainly drugs blocking the immune checkpoint pathways, have revolutionized the treatment paradigm for many solid tumors. A wide spectrum of immune-related adverse events (irAEs) have been described with the use of these agents which necessitate treatment with immunosuppression, lead to disruption of therapy and can on occasion be life-threatening. There are currently no clinically validated biomarkers to predict the risk of irAEs. Areas covered: In this review, the authors describe the current progress in identifying biomarkers for irAEs and potential future directions. Literature search was conducted using PubMed-MEDLINE, Embase and Scopus. In addition, abstracts from major conference proceedings were reviewed for relevant content. Expert commentary: The discovery of biomarkers for irAEs is currently in its infancy, however there are a lot of promising candidate biomarkers that are currently being investigated. Biomarkers that can identify patients at a higher risk of developing irAEs or lead to early detection of autoimmune toxicities are crucial to optimize patient selection for immune-oncology agents and to minimize toxicity with their use.

A 54-Year-Old Man With Anasarca, Dyspnea, and Recurrent Bilateral Pleural Effusions.

CASE PRESENTATION: A 54-year-old African-American man presented with 2 years of progressively worsening dyspnea and anasarca. Over the past 6 months he gained 30 lbs with worsening lower extremity, abdominal wall, and scrotal edema. A recent workup for cardiac, renal, and liver disease, including two-dimensional echocardiogram, liver and renal function tests, and abdominal ultrasound, was unremarkable. He reported a 15-pack year history of smoking and quit 3 years ago. Chest radiograph at that time revealed bilateral pleural effusions that were both reportedly milky in appearance when drained by thoracenteses.

Metastasis to the Lung From Carcinomas of Nonpulmonary Sites After Prolonged Disease-free Intervals.

BACKGROUND: Most carcinomas of nonpulmonary sites that metastasize to the lung do so within 5 years of diagnosis. Although examples of late metastasis to the lung after prolonged disease-free intervals (>5 y) have been reported sporadically, this phenomenon has not been systematically analyzed. The aim of this study was to describe the clinical and pathologic features of metastases to the lung from carcinomas of nonpulmonary origin after prolonged disease-free intervals. METHODS: We searched our pathology archives to identify lung biopsies/resections containing metastases from carcinomas of nonpulmonary origin. Medical records were reviewed to determine the interval between resection of the nonpulmonary primary and subsequent detection of lung metastasis. Cases were included if the disease-free interval between initial diagnosis and lung metastasis exceeded 5 years and the site of origin could be verified by pathologic examination. RESULTS: Of 195 consecutive lung metastases from carcinomas of nonpulmonary sites, the recurrence-free interval before lung metastasis was >5 years in 20 (10.3%). Primary sites (number of cases, recurrence-free interval) included kidney (5, 6 to 33 y), endometrium (5, 8 to 10 y), colon (3, 6 to 13 y), breast (2, 8 y, 12 y), esophagus (1, 8 y), thyroid (1, 10 y), epiglottis (1, 12 y), prostate (1, 12 y), and ovary (1, 15 y). At diagnosis of lung metastasis, lung nodules/masses were multiple in 12 and solitary in 8. CONCLUSIONS: Carcinomas of nonpulmonary sites can metastasize to the lung after prolonged disease-free intervals and present as a solitary lung mass. The most common culprits are carcinomas of the kidney and endometrium.

A Rare Presentation of Sarcoidosis as a Pancreatic Head Mass.

Sarcoidosis is a multisystem granulomatous syndrome of unknown etiology with noncaseating epithelioid granulomas being the pathognomonic pathological finding. Sarcoidosis most commonly involves the lungs and involvement of the gastrointestinal (GI) tract is uncommon. Pancreatic sarcoidosis is very rare, especially when it is the presenting feature of sarcoidosis and can masquerade as pancreatic cancer. Tissue infiltration in pancreatic sarcoidosis can lead to either a diffuse nodular appearance or a mass-like lesion. We present an interesting case of a 47-year-old woman with a 10-pack-year history of smoking who presented with sharp epigastric pain, weight loss, and elevated lipase level. CT and MRI imaging showed a 4 cm × 5 cm heterogeneous pancreatic mass with a dilated pancreatic duct and peripancreatic lymphadenopathy. Endoscopic ultrasound guided FNA revealed noncaseating granulomas with no evidence of malignancy or atypical infection. CT of the chest revealed bilateral mediastinal and hilar adenopathy with calcification, without any parenchymal abnormalities, and her angiotensin-converting enzyme level was elevated at 170 U/L. The clinical picture pointed to the diagnosis of pancreatic sarcoidosis. Given the severity of gastrointestinal symptoms related to pancreatic sarcoidosis, prednisone therapy at 0.5 mg/kg/day was initiated with complete resolution of symptoms at 8 weeks.