Development of CNS metastases and survival in patients with inflammatory breast cancer.

BACKGROUND: Inflammatory breast cancer (IBC) is associated with a poor prognosis and high risk of central nervous system (CNS) metastases. METHODS: We retrospectively reviewed stage III-IBC patients compared with noninflammatory invasive ductal carcinoma (NI-IDC) patients treated between January 1, 1984, and December 31, 2011, who began primary treatment within 1 year of diagnosis and had been followed up for at least 1 year before the development of CNS metastasis or death. Cumulative CNS metastasis incidence and post-CNS metastasis overall survival (OS) estimates were computed. Multivariable Cox proportional hazard models explored factors for post-CNS metastasis survival. RESULTS: A total of 2323 patients were identified (589-IBC/1734-NI-IDC). Eighty-one IBC patients developed CNS metastasis, versus 154 NI-IDC patients. The 2-, 5-, and 10-year cumulative CNS metastasis incidence rates in IBC and NI-IDC were 9.8%, 15.8%, 17.4% and 6.5%, 10.1%, and 12.7%, respectively. This was significantly different between IBC and NI-IDC patients (P = .0037). Multicovariate competing risk regression models in IBC and NI-IDC patients showed no statistically significant associations with the risk of developing CNS metastasis, except neoadjuvant taxane use in NI-IDC patients (hazard ratio, 0.45; 95% confidence interval, 0.24-0.83; P = .011). The median follow-up was 7.2 years, and the median post-CNS metastasis OS was not significantly different between IBC (7.6 months) and NI-IDC (5.6 months) patients. One hundred ninety patients with CNS metastasis died. HER2-positive patients had better OS, with a median 14.1 versus 4.3 months (P < .0001). Age >50 years (P = .012) but not IBC status was a significant predictor of post-CNS metastasis survival. CONCLUSION: IBC patients demonstrated higher CNS metastasis incidence rates but OS following CNS metastases is similar in both groups. HER2 status and age may play prognostic roles. Cancer 2018;124:2299-305. © 2018 American Cancer Society.

Successful treatment of arthritis induced by checkpoint inhibitors with tocilizumab: a case series.

BACKGROUND: Immune checkpoint inhibitors (ICIs) have significantly improved outcomes for patients with numerous cancers. However, these therapies are associated with immune-related adverse events (irAEs), which are inflammatory side effects potentially affecting any organ. Cases of ICI-induced inflammatory arthritis have also been reported. In general, mild irAEs are treated with corticosteroids, while tumour necrosis factor-α (TNFα) inhibitors are reserved for refractory cases. However, prolonged use of TNFα inhibitor (TNFαi) can induce widespread, significant immunosuppression, which can negatively impact the antitumour efficacy of ICI therapy. Therefore, in clinical scenarios where patients develop severe immunotherapy-induced irAEs, an unmet need exists for alternative therapeutic strategies that are effective and without immune dampening effects. CASE REPORTS: The anti-interleukin (IL)-6 receptor antibody, tocilizumab, is a biological agent Food and Drug Administration approved for the treatment of rheumatoid arthritis and juvenile idiopathic arthritis. Here, we report on three patients who developed severe polyarthritis while receiving ICI therapy and were treated with tocilizumab. All three patients demonstrated significant clinical improvement; one patient maintained a durable antitumour response derived from checkpoint inhibition. CONCLUSIONS: These three cases suggest that anti-IL-6 receptor antibody may be an effective alternative to corticosteroids or TNFαi for the treatment of arthritis irAEs.

Retrospective study of nonmucinous appendiceal adenocarcinomas: role of systemic chemotherapy and cytoreductive surgery.

BACKGROUND: Mucinous appendiceal adenocarcinomas (AAs) are the most common histological subset of AAs. Nonmucinous AAs have been infrequently studied. We performed a single-center retrospective study to investigate this histological subtype. METHODS: We reviewed 172 patient records with nonmucinous AAs treated at MD Anderson Cancer Center from Jan, 1990 to Jun, 2015 and recorded patient demographics, tumor characteristics, treatment, and outcomes. Response rate (RR) was assessed semi-quantitatively (response/no response) according to the treating physician's findings. Survival outcomes were calculated using the Kaplan-Meier product-limit method and compared using the log-rank test. RESULTS: Median age at diagnosis was 52.9 years. Most patients presented with advanced-stage disease: stage I-II (35%), stage III (15%), and stage IV (50%). Moderate and poorly differentiated histology was seen in 56% and 44% tumors, respectively. Median overall survival (OS) of all patients was stage-dependent and was 88.5, 39.2, and 28.3 months for stages I-II, stage III, and stage IV disease, respectively (p < 0.0001). In patients with metastatic disease, only 10% had extraperitoneal disease without peritoneal involvement. Cytoreductive surgery (CRS) was attempted in 31/69 (45%) patients with disease confined to the peritoneum. Complete CRS was achieved in 18. Median OS for patients receiving complete CRS was 48.6 months. Systemic chemotherapy was administered to 109 (86%) patients with metastatic disease; a large majority of patients received either an oxaliplatin-based (55%) or irinotecan-based (27%) regimen. Chemotherapy resulted in a semi-quantitative RR of 54% and median time to progression (TTP) of 9.4 months (95% CI, 8.03-11.50). Patients who received combination chemotherapy (either oxaliplatin or irinotecan-based) showed significantly longer median OS (p = 0.003), compared to those receiving fluoropyrimidine monotherapy. CONCLUSIONS: This is one of the first studies to report specifically on nonmucinous AAs. Nonmucinous AAs presented with moderate or poorly differentiated histology with a predilection for peritoneal metastasis. Systemic chemotherapy is active in this AA subtype. Though CRS was infrequently used, complete CRS appears beneficial and warrants further investigation.

Imaging of effector memory T cells during a delayed-type hypersensitivity reaction and suppression by Kv1.3 channel block.

Effector memory T (Tem) cells are essential mediators of autoimmune disease and delayed-type hypersensitivity (DTH), a convenient model for two-photon imaging of Tem cell participation in an inflammatory response. Shortly (3 hr) after entry into antigen-primed ear tissue, Tem cells stably attached to antigen-bearing antigen-presenting cells (APCs). After 24 hr, enlarged Tem cells were highly motile along collagen fibers and continued to migrate rapidly for 18 hr. Tem cells rely on voltage-gated Kv1.3 potassium channels to regulate calcium signaling. ShK-186, a specific Kv1.3 blocker, inhibited DTH and suppressed Tem cell enlargement and motility in inflamed tissue but had no effect on homing to or motility in lymph nodes of naive and central memory T (Tcm) cells. ShK-186 effectively treated disease in a rat model of multiple sclerosis. These results demonstrate a requirement for Kv1.3 channels in Tem cells during an inflammatory immune response in peripheral tissues. Targeting Kv1.3 allows for effector memory responses to be suppressed while central memory responses remain intact.

Erythema nodosum-like panniculitis mimicking disease recurrence: A novel toxicity from immune checkpoint blockade therapy-Report of 2 patients.

Immunotherapies targeting cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) and the programmed cell death 1 (PD-1) receptor and its ligand (PD-L1) have showed substantial therapeutic benefit in patients with clinically advanced solid malignancies. However, autoimmune toxicities are common and often significant adverse events with these agents. While rash and pruritus remain the most common cutaneous complications in treated patients, novel dermatologic toxicities related to immune checkpoint blockade continue to emerge as the number of patients exposed to immunotherapy increases. Here, we describe 2 patients treated with combination immunotherapy with ipilimumab and nivolumab who developed painful subcutaneous nodules. Although the findings were clinically concerning for disease recurrence, histopathologic examination of biopsies from the lesions revealed a subcutaneous mixed septal and lobular erythema nodosum-like panniculitis. Notably, neither patient received immunosuppressive therapy for these lesions, which subsequently remained stable, and both patients' cancer remained controlled. These cases show that the dermatologic toxicity profile of immune checkpoint blockade is diverse and continues to expand, and illustrates that recognition of such toxicities is critical to optimal patient management.

Enhancing quality improvements in cancer care through CME activities at a nationally recognized cancer center.

Changing healthcare policy will undoubtedly affect the healthcare environment in which providers function. The current Fee for Service reimbursement model will be replaced by Value-Based Purchasing, where higher quality and more efficient care will be emphasized. Because of this, large healthcare organizations and individual providers must adapt to incorporate performance outcomes into patient care. Here, we present a Continuing Medical Education (CME)-based initiative at the City of Hope National Cancer Center that we believe can serve as a model for using CME as a value added component to achieving such a goal.

Tilsotolimod with Ipilimumab Drives Tumor Responses in Anti-PD-1 Refractory Melanoma.

Many patients with advanced melanoma are resistant to immune checkpoint inhibition. In the ILLUMINATE-204 phase I/II trial, we assessed intratumoral tilsotolimod, an investigational Toll-like receptor 9 agonist, with systemic ipilimumab in patients with anti-PD-1- resistant advanced melanoma. In all patients, 48.4% experienced grade 3/4 treatment-emergent adverse events. The overall response rate at the recommended phase II dose of 8 mg was 22.4%, and an additional 49% of patients had stable disease. Responses in noninjected lesions and in patients expected to be resistant to ipilimumab monotherapy were observed. Rapid induction of a local IFNα gene signature, dendritic cell maturation and enhanced markers of antigen presentation, and T-cell clonal expansion correlated with clinical response. A phase III clinical trial with this combination (NCT03445533) is ongoing. SIGNIFICANCE: Despite recent developments in advanced melanoma therapies, most patients do not experience durable responses. Intratumoral tilsotolimod injection elicits a rapid, local type 1 IFN response and, in combination with ipilimumab, activates T cells to promote clinical activity, including in distant lesions and patients not expected to respond to ipilimumab alone.This article is highlighted in the In This Issue feature, p. 1861.

IL17A Blockade Successfully Treated Psoriasiform Dermatologic Toxicity from Immunotherapy.

Dermatologic toxicities are the most common immune-related adverse events (irAE) secondary to immune checkpoint inhibitors (ICI). First-line treatment for grade 3 or 4 skin irAEs is high-dose corticosteroids, which have their own side effects. Prolonged treatment with corticosteroids may abrogate antitumor ICI activity. The cellular causes of these dermatologic toxicities, which can manifest as a variety of clinical presentations, remain unclear. Beyond steroids, recommended treatment options are limited. We report a case of psoriasiform dermatologic toxicity, induced by inhibition of PD-1 with the mAb pembrolizumab, which resolved after treatment with systemic interleukin IL17A blockade. Introduction of IL17A blockade did not alter the patient's melanoma response to pembrolizumab. This case suggests a possible pathogenic role of Th17 cells the irAE of the skin in this metastatic melanoma patient.

Molecular Profiling of Hepatocellular Carcinoma Using Circulating Cell-Free DNA.

PURPOSE: Molecular profiling has been used to select patients for targeted therapy and determine prognosis. Noninvasive strategies are critical to hepatocellular carcinoma (HCC) given the challenge of obtaining liver tissue biopsies. EXPERIMENTAL DESIGN: We analyzed blood samples from 206 patients with HCC using comprehensive genomic testing (Guardant Health) of circulating tumor DNA (ctDNA). RESULTS: A total of 153/206 (74.3%) were men; median age, 62 years (range, 18-91 years). A total of 181/206 patients had ≥1 alteration. The total number of alterations was 680 (nonunique); median number of alterations/patient was three (range, 1-13); median mutant allele frequency (% cfDNA), 0.49% (range, 0.06%-55.03%). TP53 was the common altered gene [>120 alterations (non-unique)] followed by EGFR, MET, ARID1A, MYC, NF1, BRAF, and ERBB2 [20-38 alterations (nonunique)/gene]. Of the patients with alterations, 56.9% (103/181) had ≥1 actionable alterations, most commonly in MYC, EGFR, ERBB2, BRAF, CCNE1, MET, PIK3CA, ARID1A, CDK6, and KRAS. In these genes, amplifications occurred more frequently than mutations. Hepatitis B (HBV)-positive patients were more likely to have ERBB2 alterations, 35.7% (5/14) versus 8.8% HBV-negative (P = 0.04). CONCLUSIONS: This study represents the first large-scale analysis of blood-derived ctDNA in HCC in United States. The genomic distinction based on HCC risk factors and the high percentage of potentially actionable genomic alterations suggests potential clinical utility for this technology.

Correction to: Infliximab associated with faster symptom resolution compared with corticosteroids alone for the management of immune-related enterocolitis.

Following publication of the original article [1], the authors reported an error in their listed affiliations.

Infliximab associated with faster symptom resolution compared with corticosteroids alone for the management of immune-related enterocolitis.

BACKGROUND: Immune-related enterocolitis (irEC) is the most common serious complication from checkpoint inhibitors (CPIs). The current front-line treatment for irEC, high-dose corticosteroids (CS), have significant side effects and prolonged therapy may reduce CPI-anti-tumor activity. Early addition of TNF-α inhibitors such as infliximab (IFX) may expedite symptom resolution and shorten CS duration. Thus, we conducted the first retrospective study, to our knowledge, evaluating symptom resolution in patients with irEC treated with and without IFX. METHODS: Data were collected from the medical records of patients diagnosed with irEC. The primary endpoint was time to symptom resolution for irEC for cases managed with IFX plus CS (IFX group) versus CS alone (CS group). Duration of CS, overall survival (OS), and time to treatment failure (TTF) were secondary endpoints. RESULTS: Among 75 patients with irEC, 52% received CS alone, and 48% received IFX. Despite higher grade colitis in the IFX group (grade 3/4: 86% vs. 34%; p < 0.001), median times to diarrhea resolution (3 vs. 9 days; p < 0.001) and to steroid titration (4 vs. 13 days; p < 0.001) were shorter in the IFX group than in the CS group without a negative impact on TTF or OS. Total steroid duration (median 35 vs. 51 days; p = 0.150) was numerically lower in the IFX group. CONCLUSIONS: Despite higher incidence of grade 3/4 colitis, IFX added to CS for the treatment of patients with irEC was associated with a significantly shorter time to symptom resolution. The data suggest that early introduction of IFX should be considered for patients with irEC until definitive prospective clinical trials are conducted.

Erratum to: A case report of Grover's disease from immunotherapy-a skin toxicity induced by inhibition of CTLA-4 but not PD-1.

[This corrects the article DOI: 10.1186/s40425-016-0157-6.].

Metastatic Melanoma Patient Had a Complete Response with Clonal Expansion after Whole Brain Radiation and PD-1 Blockade.

We report here on a patient with metastatic melanoma who had extensive brain metastases. After being treated with the sequential combination of whole brain radiation therapy followed by the PD-1-inhibitory antibody, pembrolizumab, the patient had a durable complete response. Retrospective laboratory studies of T cells revealed that, after treatment with anti-PD-1 commenced, effector CD8+ T cells in the blood expanded and the ratio of CD8+:Treg T cells increased. A CD8+ T-cell clone present in the initial brain metastases was expanded in the blood after anti-PD-1 treatment, which suggested an antitumor role for this clone. Immunohistochemical analysis confirmed the presence of CD8+ T cells and low PD-L1 expression in the brain metastases before immunotherapy initiation. This sequence of therapy may provide an option for melanoma patients with unresponsive brain metastases. Cancer Immunol Res; 5(2); 100-5. ©2017 AACR.

Selective inhibition of autoimmune exacerbation while preserving the anti-tumor clinical benefit using IL-6 blockade in a patient with advanced melanoma and Crohn's disease: a case report.

BACKGROUND: Novel immunotherapies, or checkpoint inhibitors, targeting programmed cell death protein-1 (PD-1) and cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) have significantly improved outcomes for patients with numerous different cancer types. However, owing to their exclusion from clinical trials and risk for autoimmune exacerbation on these treatments, the impact on safety and degree of toxicity of these potentially life-prolonging therapies is not well characterized in patients with an underlying autoimmune disease or previous organ transplant. CASE PRESENTATION: We report a case of a patient with advanced melanoma and refractory Crohn's disease who was treated concurrently with pembrolizumab (anti-PD-1 antibody) and tocilizumab (anti-interluekin-6 receptor antibody). This novel treatment strategy was well tolerated and did not result in Crohn's disease exacerbation for at least 16 weeks. Importantly, this treatment resulted in marked, durable antitumor responses. CONCLUSIONS: This outcome suggests that targeted immunosuppression combined with checkpoint inhibitors may hold promise as a treatment strategy for this unique patient population and may warrant additional study.

A case report of Grover's disease from immunotherapy-a skin toxicity induced by inhibition of CTLA-4 but not PD-1.

BACKGROUND: Immune related adverse events (irAEs) are common side effects of checkpoint inhibitory (CPI) therapies targeting CTLA-4 and PD-1/PD-L1. Grover's disease is an uncommon dermatologic condition with unclear pathogenesis previously reported as an irAE with ipilimumab. CASE PRESENTATION: We report an additional case of ipilimumab-induced Grover's disease. Interestingly, this dermatologic side effect did not appear with use of anti-PD-1 therapy in our patient. Immune analysis was performed and suggests a possible role of Th2 cells in its patholgenesis. CONCLUSION: This case suggests that Grover's disease is an irAE induced by Ipilimumab. Our immune analysis suggests that Th2 cells may be pathogenic mediators which warrants further study.

Hemophagocytic Lymphohistiocytosis Complicating T-Cell Lymphoma in a Patient with HIV Infection.

Hemophagocytic lymphohistiocytosis (HLH), while uncommon, may be a devastating complication of lymphoma and/or human immunodeficiency virus (HIV) infection. While several of the diagnostic criteria for HLH are relatively nonspecific, particularly in the setting of a systemic inflammatory response, more diagnostic specificity may be achieved with marked elevations in serum ferritin (e.g., >100,000 ng/mL). Increased suspicion of HLH, particularly in the setting of persistent, unexplained fevers, pancytopenia, and transaminitis, should prompt consideration of HLH. Earlier diagnosis and initiation of therapy have the potential to alter the natural history and poor prognosis of this disorder. We present a patient with HIV infection who developed relapsed T-cell lymphoma complicated by hemophagocytic lymphohistiocytosis.