Purpose Recent studies suggest that tumor-infiltrating lymphocytes (TILs) are associated with disease-free (DFS) and overall survival (OS) in operable triple-negative breast cancer (TNBC). We seek to validate the prognostic impact of TILs in primary TNBCs in two adjuvant phase III trials conducted by the Eastern Cooperative Oncology Group (ECOG). Patients and methods Full-face hematoxylin and eosin–stained sections of 506 tumors from ECOG trials E2197 and E1199 were evaluated for density of TILs in intraepithelial (iTILs) and stromal compartments (sTILs). Patient cases of TNBC from E2197 and E1199 were randomly selected based on availability of sections. For the primary end point of DFS, association with TIL scores was determined by fitting proportional hazards models stratified on study. Secondary end points were OS and distant recurrence–free interval (DRFI). Reporting recommendations for tumor marker prognostic studies criteria were followed, and all analyses were prespecified. Results The majority of 481 evaluable cancers had TILs (sTILs, 80%; iTILs, 15%). With a median follow-up of 10.6 years, higher sTIL scores were associated with better prognosis; for every 10% increase in sTILs, a 14% reduction of risk of recurrence or death (P = .02), 18% reduction of risk of distant recurrence (P = .04), and 19% reduction of risk of death (P = .01) were observed. Multivariable analysis confirmed sTILs to be an independent prognostic marker of DFS, DRFI, and OS. Conclusion In two national randomized clinical trials using contemporary adjuvant chemotherapy, we confirm that stromal lymphocytic infiltration constitutes a robust prognostic factor in TNBCs. Studies assessing outcomes and therapeutic efficacies should consider stratification for this parameter.

Prognostic Value of Tumor-Infiltrating Lymphocytes in Triple-Negative Breast Cancers From Two Phase III Randomized Adjuvant Breast Cancer Trials: ECOG 2197 and ECOG 1199

Summary Neurofibromatosis type 1 is a relatively common inherited disorder. Patients have a high predisposition to develop both benign and malignant tumours. Although many manifestations of neurofibromatosis type 1 affect the nervous system, other organs and tissues can also be affected. Because of the varying features and clinical heterogeneity inherent to this disorder, patients can present to different medical and surgical specialists and, therefore, the association of clinical symptoms with neurofibromatosis type 1 might not be appreciated. Thus, for prompt diagnosis and to provide optimum care for patients with neurofibromatosis type 1, clinicians must be aware of the diverse clinical features of this disorder. We advocate a multidisciplinary approach to care, entailing a dedicated team of specialists throughout the lifetime of the patient. As our understanding of this disorder deepens through basic laboratory and clinical investigations, swift implementation of new effective treatments becomes feasible.

/pdf/neurofibromatosis-type-1-a-multidisciplinary-approach-to-14vriz86uz.pdf

Neurofibromatosis type 1: a multidisciplinary approach to care.

mTOR: Role in cancer, metastasis and drug resistance.

Extranodal marginal zone lymphoma of the ocular adnexa.

Talazoparib inhibits PARP catalytic activity, trapping PARP1 on damaged DNA and causing cell death in BRCA1/2-mutated cells. We evaluated talazoparib therapy in this two-part, phase I, first-in-human trial. Antitumor activity, MTD, pharmacokinetics, and pharmacodynamics of once-daily talazoparib were determined in an open-label, multicenter, dose-escalation study (NCT01286987). The MTD was 1.0 mg/day, with an elimination half-life of 50 hours. Treatment-related adverse events included fatigue (26/71 patients; 37%) and anemia (25/71 patients; 35%). Grade 3 to 4 adverse events included anemia (17/71 patients; 24%) and thrombocytopenia (13/71 patients; 18%). Sustained PARP inhibition was observed at doses ≥0.60 mg/day. At 1.0 mg/day, confirmed responses were observed in 7 of 14 (50%) and 5 of 12 (42%) patients with BRCA mutation-associated breast and ovarian cancers, respectively, and in patients with pancreatic and small cell lung cancer. Talazoparib demonstrated single-agent antitumor activity and was well tolerated in patients at the recommended dose of 1.0 mg/day.Significance: In this clinical trial, we show that talazoparib has single-agent antitumor activity and a tolerable safety profile. At its recommended phase II dose of 1.0 mg/day, confirmed responses were observed in patients with BRCA mutation-associated breast and ovarian cancers and in patients with pancreatic and small cell lung cancer. Cancer Discov; 7(6); 620-9. ©2017 AACR.This article is highlighted in the In This Issue feature, p. 539.

Phase I, Dose-Escalation, Two-Part Trial of the PARP Inhibitor Talazoparib in Patients with Advanced Germline BRCA1/2 Mutations and Selected Sporadic Cancers

Triple-negative breast cancer (TNBC) is a long-lasting orphan disease in terms of little therapeutic progress during the past several decades and still the standard of care remains chemotherapy. Experimental discovery of molecular signatures including the ‘BRCAness’ highlighted the innate heterogeneity of TNBC, generating the diversity of TNBC phenotypes. As it contributes to enhancing genomic instability, it has widened the therapeutic spectrum of TNBC. In particular, unusual sensitivity to DNA damaging agents was denoted in patients with BRCA deficiency, suggesting therapeutic benefit from platinum and poly(ADP-ribose) polymerase inhibitors. However, regardless of enriched chemosensitivity and immunogenicity, majority of patients with TNBC still suffer from dismal clinical outcomes including early relapse and metastatic spread. Therefore, efforts into more precise and personalised treatment are critical at this point. Accordingly, the advance of multiomics has revealed novel actionable targets including PI3K-Akt-mTOR and epidermal growth factor receptor signalling pathways, which might actively participate in modulating the chemosensitivity and immune system. Also, TNBC has long been considered a potential protagonist of immunotherapy in breast cancer, supported by abundant tumour-infiltrating lymphocytes and heterogeneous tumour microenvironment. Despite that, earlier studies showed somewhat unsatisfactory results of monotherapy with immune-checkpoint inhibitors, consistently durable responses in responders were noteworthy. Based on these results, further combinatorial trials either with other chemotherapy or targeted agents are underway. Incorporating immune-molecular targets into combination as well as refining the standard chemotherapy might be the key to unlock the future of TNBC. In this review, we share the current and upcoming treatment options of TNBC in the framework of scientific and clinical data, especially focusing on early stage of TNBC.

How shall we treat early triple-negative breast cancer (TNBC): from the current standard to upcoming immuno-molecular strategies

Ocular adnexal lymphoma (OAL) is a mostly extranodal marginal zone lymphoma (EMZL). Recent findings have suggested an association between Chlamydia psittaci (Cp) infection and OAL. We sought to confirm this issue and to analyze the clinicopathologic characteristics of OAL in Korea. Between 1993 and 2004, 33 OAL cases were identified at the Asan Medical Center, Seoul, Korea. DNA was extracted from paraffin-embedded tissues, and touchdown enzyme time release polymerase chain reaction was performed to identify three Chlamydia species (Cp, C. tracomatis, and C. pneumoniae). The same procedures were also performed in 21 samples from patients with non-neoplastic ocular adnexal disease (NNOAD). All OAL cases were EMZL. Cp DNA was detected in 26/33 (79%) OAL samples compared with 5/21 (23%) NNOAD samples (P < 0.001). With a median follow-up of 38.5 months (range: 1-105 months), the 5-year progression-free survival (PFS) and overall survival (OS) rates of OAL patients were 72% and 93%, respectively. Clinicopathologic characteristics, recurrence rate, PFS, and OS were not associated with Cp infection. Our study demonstrates an association between OAL and Cp infection in Korea, suggesting that Cp plays a role as a causative antigen in Korean OAL patients.

Chlamydia psittaci infection and clinicopathologic analysis of ocular adnexal lymphomas in Korea.

https://www.annalsthoracicsurgery.org/article/S0003-4975(12)01654-2/pdf

Salvage Esophagectomy for Locoregional Failure After Chemoradiotherapy in Patients With Advanced Esophageal Cancer

Historically, gastrointestinal stromal tumors (GISTs) were considered pathological oddities and were somewhat neglected by oncologists as chemoresistant sarcomas. However, GISTs have now emerged as distinct pathogenetic entities that reinforce the concept of molecular targeted therapy (1). Imatinib therapy has produced dramatic results in the management of metastatic and unresectable GIST. However, this response to imatinib is usually confined to GISTs harboring detectable KIT or platelet-derived growth factor receptor α (PDGFRA) gene mutations (2). Interestingly, GISTs arise at least 500 times more frequently in patients with neurofibromatosis type 1 (NF1) compared to the general population (3, 4), and nearly all GISTs associated with NF1 lack a detectable KIT gene mutation. Despite these observations, there have been only a limited number of studies on NF1-associated GISTs (3, 5), and no studies have reported on the GIST response to imatinib in such patients. The present study reports a case of metastatic GIST in an NF1 patient. The patient responded favorably to imatinib despite the absence of any mutations in not only the KIT but also the PDGFRA gene.

Response to imatinib in KIT- and PDGFRA-wild type gastrointestinal stromal associated with neurofibromatosis type 1.

BACKGROUND Severe inflammation and acute kidney injury (AKI) are serious adverse events after burn injuries. The neutrophil/lymphocyte ratio (NLR) is a marker of inflammation. We evaluated the independent risk factors for postoperative AKI, including NLR, in burn-injured patients. METHODS The preoperative, intraoperative, and postoperative variables of 473 burn-injured patients were collected. The risk factors for AKI after burn surgery were evaluated using univariate and multivariate logistic regression analyses. The receiver operating characteristic (ROC) curve analysis of preoperative NLR was performed. The 3-month mortality after surgery was also compared between AKI and non-AKI groups using Kaplan-Meier analysis with a log-rank test. RESULTS Postoperative AKI occurred in 71 of 473 (15.0%) burn patients. The total body surface area burned (odds ratio (OR), 1.013; 95% confidence interval (CI), 1.001-1.026; P = 0.037), inhalation injury (OR, 1.821; 95% CI, 1.008-3.292; P = 0.047), and preoperative NLR (OR, 1.094; 95% CI, 1.064-1.125; P < 0.001) were risk factors for AKI after surgery. The area under the ROC curve was 0.767, with an optimal cut-off value of 11.7. Moreover, the 3-month mortality after surgery was significantly higher in the AKI group than in the non-AKI group (49.3% vs 14.9%, P < 0.001). CONCLUSION Total body surface area burned, inhalation injury, and preoperative NLR are risk factors for AKI after burn surgery, which is associated with early postoperative mortality. Preoperative NLR can provide useful information for the early detection of postoperative AKI and subsequent mortality in burn-injured patients.

Ji Hyun Park

Papers

How shall we treat early triple-negative breast cancer (TNBC): from the current standard to upcoming immuno-molecular strategies

Chlamydia psittaci infection and clinicopathologic analysis of ocular adnexal lymphomas in Korea.

Salvage Esophagectomy for Locoregional Failure After Chemoradiotherapy in Patients With Advanced Esophageal Cancer

Response to imatinib in KIT- and PDGFRA-wild type gastrointestinal stromal associated with neurofibromatosis type 1.

Acute kidney injury after burn surgery: Preoperative neutrophil/lymphocyte ratio as a predictive factor