Discordance of retroperitoneal and thoracic histologic findings in patients with metastatic germ cell tumors at postchemotherapy residual tumor resection.

INTRODUCTION AND OBJECTIVES: Postchemotherapy residual tumor resection (PC-RTR) is an important part of the multimodal treatment for patients with metastatic germ cell tumors. Simultaneous retroperitoneal and thoracic metastases often require consecutive surgical procedures. This study analyzes the histologic findings after abdominal and thoracic surgery in order to tailor the sequence and intensity of surgery. PATIENTS AND METHODS: From a total of 671 PC-RTRs from 2008 to 2021 we analyzed 50 patients with stage III non-seminomatous germ cell tumor (NSGCT) who had undergone both retroperitoneal and thoracic postchemotherapy residual tumor resection after first-line and salvage chemotherapy. RESULTS: All patients included had stage III NSGCT. 39 and 11 patients received first-line and salvage chemotherapy, respectively. 45 (90%) patients received retroperitoneal resection first, followed by thoracic surgery. Three patients (6%) underwent thoracic surgery before retroperitoneal surgery and two patients (4%) underwent simultaneous surgery. Overall, the histology of retroperitoneal and thoracic specimens was discordant in 23% of cases. After first-line chemotherapy, of fourteen patients with necrosis in retroperitoneal histology, four patients had vital carcinoma in lung histology. In patients with teratoma in the retroperitoneum, the thoracic findings were concordant in most cases (78%). When teratomatous elements were also present in the orchiectomy specimen, concordance was 100%. After salvage chemotherapy, the discordance rate was 55%. CONCLUSION: The data presented in this study underline that retroperitoneal residual masses with necrosis cannot reliably predict histologic findings of thoracic specimens. Patients with teratoma in the retroperitoneum have a high likelihood of teratoma in the thoracic specimen.

Racial Diversity and Reporting in United States Food and Drug Administration Registration Trials for Thoracic Malignancies from 2006 to 2020.

There is significant racial disparity in thoracic malignancies in terms of epidemiology and outcomes. We analyzed race reporting and racial diversity in the registration trials of drugs approved by the FDA for thoracic malignancies from 2006 to 2020. We found a significant under-representation of non-white participants in FDA drug registration trials in thoracic malignancies. Furthermore, though almost all trials report some race information, FDA guidelines are not universally followed. There is a disproportionate disease burden of lung cancer in under-represented race communities, and clinical trials should prioritize racial diversity and inclusion efforts.

Immune-Desert Tumor Microenvironment in Thoracic SMARCA4-Deficient Undifferentiated Tumors with Limited Efficacy of Immune Checkpoint Inhibitors.

BACKGROUND: Thoracic SMARCA4-deficient undifferentiated tumors (SMARCA4-UT) are aggressive neoplasms. Data linking BAF alterations with tumor microenvironment (TME) and efficacy of immune checkpoint inhibitors (ICI) are contradictory. The TME of SMARCA4-UT and their response to ICI are unknown. MATERIALS AND METHODS: Patients diagnosed with SMARCA4-UT in our institution were included. Immunostainings for tertiary lymphoid structures (TLS), immune cell markers, and checkpoints were assessed. Validation was performed using an independent transcriptome dataset including SMARCA4-UT, non-small cell lung cancers (NSCLC) with/without SMARCA4 mutations, and unclassified thoracic sarcomas (UTS). CXCL9 and PD-L1 expressions were assessed in NSCLC and thoracic fibroblast cell lines, with/without SMARCA4 knockdown, treated with/without interferon gamma. RESULTS: Nine patients were identified. All samples but one showed no TLS, consistent with an immune desert TME phenotype. Four patients received ICI as part of their treatment, but the only one who responded, had a tumor with a TLS and immune-rich TME. Unsupervised clustering of the validation cohort using immune cell scores identified 2 clusters associated with cell ontogeny and immunity (cluster 1 enriched for NSCLC independently of SMARCA4 status (n = 9/10; P = .001); cluster 2 enriched for SMARCA4-UT (n = 11/12; P = .005) and UTS (n = 5/5; P = .0005). SMARCA4 loss-of-function experiments revealed interferon-induced upregulation of CXCL9 and PD-L1 expression in the NSCLC cell line with no effect on the thoracic fibroblast cell line. CONCLUSION: SMARCA4-UT mainly have an immune desert TME with limited efficacy to ICI. TME of SMARCA4-driven tumors varies according to the cell of origin questioning the interplay between BAF alterations, cell ontogeny and immunity.

Unresectable thoracic neuroblastic tumors: Changes in image-defined risk factors after chemotherapy and impact on surgical management.

PURPOSE: Neuroblastoma management in children is multimodal and depends on multiple factors, including the possibility of complete surgical resection. Image-defined risk factors (IDRFs) are used to assess the feasibility of primary surgery. We studied the changes in IDRFs after neoadjuvant chemotherapy for thoracic neurogenic tumors. METHODS: We performed a multicenter review of 27 patients presenting with unresectable thoracic neurogenic tumors. Patients received neoadjuvant chemotherapy, according to their risk group. IDRF at diagnosis and before surgery were retrospectively analyzed by a radiologist and a surgeon, blind to the initial assessment. Surgical and oncologic outcomes were reviewed. RESULTS: None of the patients presented MYCN amplification, and 78 IDRFs were identified at diagnosis. Vascular IDRFs were the most frequent, with 28 vascular IDRFs detected in 18 patients, 22 of which disappeared after chemotherapy. Reductions of tumor volume were associated with a regression of IDRFs. Patients undergoing minimally invasive surgery had smaller tumor volumes than those undergoing open surgery, and no vascular IDRF. Two patients received two additional courses of chemotherapy to reduce tumor volume sufficiently for surgery. One patient with ganglioneuroblastoma underwent early surgery due to a lack of response to initial chemotherapy. CONCLUSION: Tumor volume reduction with neoadjuvant chemotherapy eliminates most IDRF in thoracic neurogenic tumors. Vascular IDRF are rapidly resolved at this site, making surgical resection and minimally invasive surgery possible.

Rapid Response to Lorlatinib in a Patient With TFG-ROS1 Fusion Positive Inflammatory Myofibroblastic Tumor of the Chest Wall Metastatic to the Brain and Refractory to First and Second Generation ROS1 Inhibitors.

Most inflammatory myofibroblastic tumors (IMTs) harbor ALK fusions but oncogene fusions involving ROS1, RET, NTRK, and PDGFR also occur. The recognition that most IMTs harbor receptor tyrosine kinase fusions has provided a rationale for the use of tyrosine kinase inhibitors to target these oncogenic drivers in advanced IMTs. Crizotinib has been effective in ALK and ROS1-positive IMTs but resistance eventually develops. Here we report the successful use of lorlatinib in a patient with heavily pretreated ROS1-positive IMT of the chest wall with acquired crizotinib-resistance and metastasis to the brain.

Novel fusion sarcomas including targetable NTRK and ALK.

BACKGROUND: Challenging emerging entities with distinctive molecular signatures may benefit from algorithms for diagnostic work-up. METHODS: Fusion sarcomas (2020-2021, during pandemic) were diagnosed by clinicoradiology, morphology, phenotype, and next-generation sequencing (NGS). RESULTS: Six fusion sarcomas in two males and four females involved the chest-wall, neck, or extremities; ages ranged 2-73, median 18 years. Sizes ranged 5.3-25.0, median 9.1 cm. These include high grade 1) TPR-NTRK1 of proximal femur with a larger rounded soft tissue mass, previously considered osteosarcoma yet without convincing tumor matrix. A pathologic fracture necessitated emergency hemipelvectomy (NED) and 2) novel KANK1-NTRK2 sarcoma of bone and soft tissue with spindled pleomorphic to epithelioid features (AWD metastases). 3) Novel ERC1-ALK unaligned fusion, a low grade infiltrative deep soft tissue hand sarcoma with prominent-vascularity, myopericytoid/lipofibromatosis-like ovoid cells, and collagenized stroma, was successfully treated with ALK-inhibitor (Crizotinib), avoiding amputation. These NTRK and ALK tumors variably express S100 and CD34 and were negative for SOX10. 4) and 5) CIC-DUX4 round cell tumors (rapid metastases/demise), one with COVID superinfection, were previously treated as Ewing sarcoma. These demonstrated mild pleomorphism and necrosis, variable myxoid change and CD99 reactivity, and a distinctive dot-like-Golgi WT1 immunostaining pattern. 6) A chest wall/thoracic round cell sarcoma, focal CD34/ keratins/CK7, revealed nuclear-STAT6, STAT6-NAB2 by NGS, confirming malignant solitary fibrous tumor, intermediate-risk-stratification (AWD metastases). CONCLUSIONS: Recent fusion sarcomas include new KANK1-NTRK2 and ERC1-ALK, the latter successfully treated by targeted-therapy. ALK/NTRK fusion partners TPR and KANK1 suggest unusual high-grade morphology/behavior. Clinicoradiologic, morphologic, and phenotypic algorithms can prompt molecular-targeted immunostains or NGS for final classification and promising inhibitor therapy.

Severe Hepatotoxicity of Mithramycin Therapy Caused by Altered Expression of Hepatocellular Bile Transporters.

Mithramycin demonstrates preclinical anticancer activity, but its therapeutic dose is limited by the development of hepatotoxicity that remains poorly characterized. A pharmacogenomics characterization of mithramycin-induced transaminitis revealed that hepatotoxicity is associated with germline variants in genes involved in bile disposition: ABCB4 (multidrug resistance 3) rs2302387 and ABCB11 [bile salt export pump (BSEP)] rs4668115 reduce transporter expression (P < 0.05) and were associated with ≥grade 3 transaminitis developing 24 hours after the third infusion of mithramycin (25 mcg/kg, 6 hours/infusion, every day ×7, every 28 days; P < 0.0040). A similar relationship was observed in a pediatric cohort. We therefore undertook to characterize the mechanism of mithramycin-induced acute transaminitis. As mithramycin affects cellular response to bile acid treatment by altering the expression of multiple bile transporters (e.g., ABCB4, ABCB11, sodium/taurocholate cotransporting polypeptide, organic solute transporter α/ß) in several cell lines [Huh7, HepaRG, HepaRG BSEP (-/-)] and primary human hepatocytes, we hypothesized that mithramycin inhibited bile-mediated activation of the farnesoid X receptor (FXR). FXR was downregulated in all hepatocyte cell lines and primary human hepatocytes (P < 0.0001), and mithramycin inhibited chenodeoxycholic acid- and GW4046-induced FXR-galactose-induced gene 4 luciferase reporter activity (P < 0.001). Mithramycin promoted glycochenodeoxycholic acid-induced cytotoxicity in ABCB11 (-/-) cells and increased the overall intracellular concentration of bile acids in primary human hepatocytes grown in sandwich culture (P < 0.01). Mithramycin is a FXR expression and FXR transactivation inhibitor that inhibits bile flow and potentiates bile-induced cellular toxicity, particularly in cells with low ABCB11 function. These results suggest that mithramycin causes hepatotoxicity through derangement of bile acid disposition; results also suggest that pharmacogenomic markers may be useful to identify patients who may tolerate higher mithramycin doses. SIGNIFICANCE STATEMENT: The present study characterizes a novel mechanism of drug-induced hepatotoxicity in which mithramycin not only alters farnesoid X receptor (FXR) and small heterodimer partner gene expression but also inhibits bile acid binding to FXR, resulting in deregulation of cellular bile homeostasis. Two novel single-nucleotide polymorphisms in bile flow transporters are associated with mithramycin-induced liver function test elevations, and the present results are the rationale for a genotype-directed clinical trial using mithramycin in patients with thoracic malignancies.

Clinical Impact of the Location of Lymph Node Metastases After Neoadjuvant Chemotherapy for Middle and Lower Thoracic Esophageal Cancer.

BACKGROUND: In the current cancer staging systems, the location of lymph node (LN) metastases is not considered, although LN status is defined according to the number of LN metastases. OBJECTIVES: This study aimed to investigate the clinical impact of the location of LN metastases in esophageal cancer and to evaluate the relevance of minimizing the extent of lymphadenectomy after neoadjuvant therapy. METHODS: In 561 patients with esophageal cancer who underwent neoadjuvant chemotherapy, the therapeutic value of each LN dissection was estimated by multiplying the incidence of metastasis by the 5-year survival rate of patients with positive nodes. In addition, we examined whether the value was affected by the response to neoadjuvant therapy. RESULTS: Metastasis to the celiac LN and middle mediastinal LN regions was identified as an independent prognostic factor by multivariate analysis, together with the number of LN metastases; however metastasis to the cervical LN and upper mediastinal LN regions was not identified as an independent prognostic factor. The therapeutic value was high in recurrent nerve LNs, paraesophageal LNs, paracardial LNs, and left gastric LNs. The therapeutic value for each LN dissection did not change according to the response to neoadjuvant therapy, excluding the lower mediastinal LN and perigastric LN stations for which the value was relatively high in patients with a poor response. CONCLUSION: The present study shows that the location and number of LN metastases have a prognostic impact in patients with esophageal cancer undergoing neoadjuvant chemotherapy. Limited lymphadenectomy according to the response to neoadjuvant therapy cannot be justified.

Correlation of prechemotherapy urinary megalin ectodomain (A-megalin) levels with the development of cisplatin-induced nephrotoxicity: a prospective observational study.

BACKGROUND: Cisplatin is a potent chemotherapeutic agent used to treat a variety of solid tumors. One of the major side effects of cisplatin is dose-limiting nephrotoxicity. We recently demonstrated that the renal uptake of cisplatin and resultant cisplatin-induced nephrotoxicity are mediated in part by megalin, an endocytic receptor in proximal tubule epithelial cells (PTECs). We also developed sandwich enzyme-linked immunosorbent assays to measure the megalin ectodomain (A-megalin) and full-length megalin (C-megalin) in urine using monoclonal antibodies against the amino- and carboxyl-termini of megalin, respectively. The present study examined the correlation of urinary megalin level with cisplatin-induced nephrotoxicity and its utility as a biomarker in patients with thoracic cancer. METHODS: This prospective observational study involved 45 chemotherapy-naïve patients scheduled to receive chemotherapy with ≥60 mg/m2 cisplatin for histologically diagnosed small cell lung cancer, non-small cell lung cancer, or malignant pleural mesothelioma. Before and after the first course of chemotherapy, we measured urinary A- and C-megalin and other markers of PTEC injury, such as N-acetyl-ß-D-glucosaminidase, α1-microglobulin, ß2-microglobulin, neutrophil gelatinase-associated lipocalin, and liver-type fatty acid-binding protein, and compared the values with the change in the estimated glomerular filtration rate (eGFR) and clinical risk factors for renal impairment. RESULTS: A negative correlation was found between baseline urinary A-megalin levels and change in eGFR (r = - 0.458, P = 0.002). According to Kaplan-Meier survival curves, eGFR decline was associated with the baseline urinary A-megalin quartile (P = 0.038). In addition, according to the hazard ratios (HRs) for eGFR decline > 10 mL/min/1.73 m2 calculated using a Cox proportional hazard model, the highest quartile had a significantly higher risk of eGFR decline compared with the lowest quartile (HR 7.243; 95% confidence interval 1.545-33.962). Other baseline urinary markers showed no correlation with eGFR decline. CONCLUSIONS: This is the first report demonstrating that prechemotherapy urinary A-megalin levels are correlated with the development of cisplatin-induced nephrotoxicity. This finding has clinical implications for the identification of patients at risk for cisplatin-induced nephrotoxicity and the development of possible prophylactic therapies.

Congenital spindle cell rhabdomyosarcoma.

Spindle cell and sclerosing rhabdomyosarcoma (ssRMS) is a rare variant of rhabdomyosarcoma, which includes three distinct subtypes. In infants, these tumors are commonly associated with recurring fusions involving VGLL2 or NCOA2 and have a favorable prognosis. We present four cases of ssRMS and 16 additional cases from the literature, which show that these patients present with localized disease and have an excellent prognosis regardless of surgical margin or lack of radiation therapy. Molecularly defined spindle cell rhabdomyosarcoma in infants is likely a biologically distinct entity which may not require the aggressive multimodal treatment used for other subtypes of rhabdomyosarcoma.

Presumptive primary intrathoracic mast cell tumours in two dogs.

BACKGROUND: Mast cell tumours are the most common cutaneous neoplasms in dogs. Other primary sites include visceral organs, such as the gastrointestinal tract, liver, or spleen, and the oral cavity. Frequent metastatic sites include the local lymph nodes, skin, spleen, liver and bone marrow. The thorax is rarely affected by metastatic disease and no such cases have been reported in dogs. Mast cell tumours are usually not considered as a differential diagnosis for lung and intrathoracic chest wall masses in dogs. Chest wall tumours can be primary tumours of the ribs and sternum, an invasion of adjacent tumours into the chest wall, and metastasis from distant tumours. CASES PRESENTATION: A German Shepherd dog presented with a history of persistent cough and a large mass involving the thoracic wall and a small round pulmonary mass. The dog had a history of mammary tumours that were surgically excised. Thoracoscopy revealed a thoracic wall mass involving the internal intercostal muscle and a small mass in the left cranial lung lobe. Cytology and histopathology of the intrathoracic mass confirmed the large mass as a mast cell tumour and the small mass as a carcinoma. Cytology of the sternal lymph nodes showed no involvement. The dog received toceranib for 3 months, which failed to alleviate persistent cough. Radiology indicated that the large mass had a partial response to toceranib. The dog was euthanasied. A Maltese dog presented with a history of chronic regurgitation and cough, and a large mass involving the left caudal lung lobe. Cytology and histopathology of mass confirmed a mast cell tumour. The dog received toceranib for 2 months. Radiology indicated that the large mass had no response to toceranib. The dog was euthanasied. Confirmation of lungs mast cell tumour and the absence of any other Mast cell tumour was achieved by postmortem examination. CONCLUSIONS: The cases discussed are two unusual presentations of intrathoracic mast cell tumours, in the absence of cutaneous mast cell tumours, in dogs.

Perioperative chemotherapy is not associated with improved survival in high-grade truncal sarcoma.

BACKGROUND: The treatment benefit of perioperative chemotherapy (CTX) for truncal soft tissue sarcoma (STS) is not well established. This study evaluates the association of CTX with survival for patients with resected primary high-grade truncal STS. MATERIALS AND METHODS: Adult patients with high-grade truncal STS who had curative-intent resection from 2000 to 2016 at seven U.S. institutions were evaluated retrospectively. Patients were stratified by receipt of CTX. Kaplan-Meier curves with log-rank tests were used to compare overall survival (OS) and recurrence-free survival. Logistic regression models were used to evaluate characteristics associated with OS. RESULTS: Of patients with primary high-grade truncal STS, 235 underwent curative-intent resections. The most common histology was undifferentiated pleomorphic sarcoma and mean tumor size was 7.8 cm. Thirty percent of the patients received CTX (n = 70). Among patients receiving CTX, 34% (n = 24) had neoadjuvant CTX, 44% (n = 31) adjuvant CTX, and 21% (n = 15) had neoadjuvant and adjuvant CTX. Patients receiving CTX were more likely to receive radiation (51% versus 34%, P = 0.01), have deep tumors (86% versus 73%, P = 0.037) and solid organ invasion (14% versus 3%, P = 0.001). On univariate analysis, patients who received CTX had worse OS (P < 0.01) and a trend toward worse recurrence-free survival (P = 0.08). Margin status was the only variable associated with improved OS on multivariate analysis (odds ratio 4.36, 95% confidence interval 1.56, 12.13, P < 0.01). CONCLUSIONS: In this multi-institutional retrospective analysis of resected high-grade truncal STS, receipt of perioperative CTX was not associated with improved OS, which may be related to selection bias. Microscopically negative margin status was the only independent factor associated with OS.

Association between Radiotherapy and Anatomic Severity of Coronary Artery Disease: A Propensity Score Matching Comparison Among Adult-Onset Thoracic Cancer Survivors.

OBJECTIVE: To investigate the association between radiotherapy and anatomic severity of coronary artery disease (CAD) using the SYNTAX scores (SXscores) of coronary angiograms in adult-onset thoracic cancer survivors. METHODS: A total of 152 patients who previously had thoracic cancer and underwent coronary angiography between 2010 and 2016 were examined. Propensity score matching (PSM) was used to identify 27 well-matched pairs of patients. Characteristics and coronary angiograms were collected from each patient. Coronary artery abnormalities were assessed using SXscores of coronary angiograms. RESULTS: Among the 152 patients, the SXscores and percentage of high SXscores were higher in the radiotherapy group than in the non-radiotherapy group; however, the latter was not significantly different (p = 0.0266 and p = 0.064, respectively). After PSM, the SXscores and percentage of high SXscores were significantly higher in the radiotherapy group than in the non-radiotherapy group (22 [interquartile range (IQR) 10.00-30.00] vs. 15.00 [IQR 4.00-26.00], p = 0.0459), (70.07 vs. 44.44%, p = 0.027), respectively. After adjusting for related risk factors and chemotherapy, the OR of radiotherapy for a high SXscore was 3.674 (95% CI 1.094-12.343) by logistic regression analysis. CONCLUSION: Thoracic cancer survivors who underwent radiotherapy have higher SXscores and are at a higher risk of developing anatomically severe CAD, independent of chemotherapy.

Severe esophagitis associated with cytomegalovirus during concurrent chemoradiotherapy for esophageal cancer.

Although radiation esophagitis is one of the most common adverse events that occurs during chemoradiotherapy (CRT) in patients with esophageal cancer, CRT-associated cytomegalovirus (CMV) esophagitis is rare. CMV esophagitis typically occurs in patients with an immunosuppressed status. Here we report a case of CMV esophagitis during CRT initially treated as radiation esophagitis. A 64-year-old man with mid-thoracic esophageal cancer was admitted to our hospital with clinical stage cT4bN1M1 (supraclavicular lymph node metastasis) Stage IV according to the UICC ver. 7 guidelines, and he was administered definitive concurrent CRT. From the 39th day of CRT onwards, he presented with a sustained fever and severe odynophagia that was resistant to antibiotic therapy. An esophagoscopy revealed severe esophagitis with a circumferential ulcer throughout the entire esophagus, and CMV esophagitis was clinically suspected because of positive result of CMV antigenemia. Subsequently, antiviral therapy for CMV provided dramatic relief of his symptoms. Later, CMV DNA was confirmed with a polymerase chain reaction in the biopsy specimen.The symptoms of CMV esophagitis resemble those of radiation esophagitis and can make the diagnosis difficult. Thus, CMV esophagitis associated CRT may be overlooked or masked by radiation esophagitis and can cause a delay in healing. Therefore, CMV esophagitis may be considered when severe intractable esophagitis is observed during CRT.

A Phase II study of palonosetron, aprepitant, dexamethasone and olanzapine for the prevention of cisplatin-based chemotherapy-induced nausea and vomiting in patients with thoracic malignancy.

BACKGROUND: The three-drug combination of a 5-hydroxytryptamine type 3 receptor antagonist, a neurokinin 1 receptor antagonist and dexamethasone is recommended for patients receiving highly emetogenic chemotherapy. However, standard antiemetic therapy is not completely effective in all patients. METHODS: We conducted an open-label, single-center, single-arm Phase II study to evaluate the efficacy of olanzapine in combination with standard antiemetic therapy in preventing chemotherapy-induced nausea and vomiting in patients with thoracic malignancy receiving their first cycle of cisplatin-based chemotherapy. Patients received 5 mg oral olanzapine on Days 1-5 in combination with standard antiemetic therapy. The primary endpoint was complete response (no vomiting and no use of rescue therapy) during the overall Phase (0-120 h post-chemotherapy). RESULTS: Twenty-three men and seven women were enrolled between May and October 2015. The median age was 64 years (range: 36-75 years). The most common chemotherapy regimen was 75 mg/m2 cisplatin and 500 mg/m2 pemetrexed, which was administered to 14 patients. Complete response rates in acute (0-24 h post-chemotherapy), delayed (24-120 h post-chemotherapy) and overall phases were 100%, 83% and 83% (90% confidence interval: 70-92%; 95% confidence interval: 66-93%), respectively. There were no Grade 3 or Grade 4 adverse events. Although four patients (13%) experienced Grade 1 somnolence, no patients discontinued olanzapine. CONCLUSIONS: The addition of 5 mg oral olanzapine to standard antiemetic therapy demonstrates promising efficacy in preventing cisplatin-based chemotherapy-induced nausea and vomiting and an acceptable safety profile in patients with thoracic malignancy.

[PD1/PD-L1 immunohistochemistry in thoracic oncology: Where are we?] / Immunohistochimie PD-1/PD-L1 en oncologie thoracique : où en sommes-nous ?

The assays for the assessment of the PD-L1 status by immunohistochemistry are available in clinical studies in thoracic oncology to predict response to immunotherapies targeting the PD-1/PD-L1 pathway. With the arrival of this new class of molecules in second line and very soon in first line of treatment for patients with advanced or metastatic non-small cell lung cancer, these tests will certainly be required in routine once these new drugs will be granted marketing authorization. The rapid introduction of these "companion" or "complementary" tests seems essential to select patients to benefit from these effective but also expensive and sometimes toxic therapies. Although challenged by some oncologists (as some patients not expressing PD-L1 may sometimes respond to PD-1/PD-L1 blockade), the anti-PD-L1 immunohistochemically approach seems inevitable in 2017. This new activity developed in the pathology laboratories raises several questions: which anti-PD-L1 clone should be used? On which device? What threshold of positivity should be considered? Should PD-L1 expression be assessed on tumor cells as well as on the immune cells? What controls should be used? Comparative studies are underway or have been already implemented in order to answer some of these questions. This review addresses the different evaluation criteria for immunohistochemistry using the main anti-PD-L1 antibodies used to date as well the recently published studies using these antibodies in thoracic oncology.

[Efficacy of PD-1/PD-L1 immune checkpoint inhibitors and PD-L1 testing in thoracic cancers]. / Efficacité des inhibiteurs du checkpoint immunitaire PD-1/PD-L1 et testing PD-L1 dans les cancers thoraciques.

Tumoral immune environment is a major component of cancer. Its composition and its organization represent a reproducible characteristic of tumors and a validated prognostic factor. In non-small cell lung cancer (NSCLC), cytotoxic T CD8+ lymphocyte density, associated with a Th1 environment and tertiary lymphoid structures impacts survival. Tumor cell-immune cell interaction is targeted by PD1/PD-L1 inhibitors. In advanced NSCLC, PD1/PD-L1 inhibitors are more effective than second-line chemotherapy. Pembrolizumab outperforms first-line chemotherapy in NSCLC strongly positive for PD-L1. PD1/PD-L1 inhibitors are currently tested in mesothelioma and thymic tumors. PD-L1 expression evaluated with immunochemistry is the most studied predictive biomarker of PD1/PD-L1 inhibitor efficacy. Tumor and immune cell expression of PD-L1 is still difficult to evaluate because of intra-tumoral heterogeneity and expression modulation by the microenvironment. Four commercial diagnostic antibodies are in development, with differences concerning recognized epitopes, methodology of evaluation of PD-L1 expression, positivity threshold, kit and platforms used. Clinical trials in NSCLC have shown that patients with tumors strongly positive for PD-L1 derived the best clinical benefit with PD1/PD-L1 inhibitors whereas clinical benefit is less common in tumors negative for PD-L1. PD-L1 expression is not a perfect biomarker since some PD-L1 negative NSCLC respond to PD1/PD-L1 inhibitors and some PD-L1 positive NSCLC do not. PD-L1 testing is likely to be implemented in daily practice for selection of advanced NSCLC that will be treated with pembrolizumab, underscoring the relevance of ongoing harmonization studies of the use of the different antibodies available for PD-L1 testing.

Nephrotoxicity of cisplatin combination chemotherapy in thoracic malignancy patients with CKD risk factors.

BACKGROUND: Nephrotoxicity is the major side effect that limits the dose of cisplatin that can be safely administered, and it is a clinical problem in cancer patients who received cisplatin combination chemotherapy. Recent evidence has demonstrated that patients with chronic kidney disease (CKD) have an increased risk of developing acute kidney injury (AKI). The present study was conducted to evaluate the prevalence of CKD risk factors in patients who received cisplatin and to assess the correlation between CKD risk factors and cisplatin-induced AKI. METHODS: We retrospectively analyzed 84 patients treated with cisplatin combination chemotherapy for thoracic malignancies. AKI was defined as a decrease in the estimated glomerular filtration rate (eGFR) > 25% from base line, an increase in the serum creatinine (sCre) level of > 0.3 mg/dl or ≥ 1.5 times the baseline level. RESULTS: Eighty of the 84 patients (95.2%) had at least one risk factor for CKD. All enrolled patients received cisplatin with hydration, magnesium supplementation and mannitol. Cisplatin-induced AKI was observed in 18 patients (21.4%). Univariate analysis revealed that cardiac disease and use of non-steroidal anti-inflammatory drugs (NSAIDs) were associated with cisplatin-induced nephrotoxicity (odds ratios [OR] 6 and 3.56, 95% confidence intervals [CI] 1.21-29.87 and 1.11-11.39, p = 0.04 and p = 0.04, respectively). Multivariate analysis revealed that cisplatin nephrotoxicity occurred significantly more often in patients with both risk factors (OR 13.64, 95% CI 1.11-326.83, p = 0.04). Patients with more risk factors for CKD tended to have a greater risk of developing cisplatin-induced AKI. CONCLUSIONS: We should consider avoiding administration of cisplatin to patients with CKD risk factors, particularly cardiac disease and NSAID use.

Pembrolizumab for the treatment of thoracic malignancies: current landscape and future directions.

New insights into the interaction between the immune system and the tumor microenvironment have led to the development of checkpoint inhibitors that target the PD-1/PD-L1 pathway. Pembrolizumab (MK-3475, lambrolizumab, Keytruda(®)) is a PD-1 inhibitor that has shown clinical activity in a variety of solid tumors and is currently approved for the second-line treatment of PD-L1-positive non-small-cell lung cancer and for unresectable/metastatic melanoma. This article will discuss the results of early-phase trials of pembrolizumab in thoracic malignancies as well as ongoing studies aimed to confirm clinical benefit.