An oral care self-management support protocol (OrCaSS) to reduce oral mucositis in hospitalized patients with acute myeloid leukemia and allogeneic hematopoietic stem cell transplantation: a randomized controlled pilot study.

INTRODUCTION: Oral mucositis (OM) is a common and debilitating side effect of chemoradiotherapy in patients awaiting allogeneic hematopoietic stem cell transplantation (aHSCT). PURPOSE: The aim of this pilot RCT was to compare an oral care self-management support protocol (OrCaSS) to usual pre-aHSCT care. Feasibility was tested, effect sizes calculated for OM (primary outcome), and patient adherence was measured (secondary outcome). METHODS: Eighteen AML patients awaiting aHSCT and hospitalized between August 2012 and April 2013 were randomized 1:1 to usual care (UCG) and intervention (IG) groups. The OrCaSS protocol consisted of two sessions of educational and behavioral interventions, the first delivered 1 week pre-admission (T1), the second on admission day (T2). Via field notes, practicability and acceptability were evaluated to explore the feasibility of intervention and study procedures. OM data were collected at T1, T2, and daily for 28 days using the WHO scale. The effect size r was calculated (r less than -0.1 ≙ small and greater than or equal to -0.3 ≙ medium). Patients' adherence to the protocol was assessed at T1, T2, and 8-10 days post-HSCT (T3). RESULTS: Research and intervention procedures were feasible. OM incidence was 100 %. The IG's median highest OM grade was 2.0 (IQR = 2); the UCGs was 3.0 (IQR = 2; r = -0.1). Median OM durations were 12 days in the IG and 14 days in the UCG (r = -0.1). OM onset was 2 days later in the IG than in the UCG (r = -0.1). Over the course of the study, patient adherence decreased in both groups. CONCLUSIONS: OrCaSS is a promising intervention to delay and reduce OM. These results can serve to plan a larger RCT.

Clinical Activity of Selpercatinib in RET-mutant Pheochromocytoma.

INTRODUCTION: Activating RET alterations have been reported in a variety of solid tumors, including pheochromocytoma where they occur both sporadically and as part of familial multiple endocrine neoplasia type 2 (MEN2) syndromes. Selpercatinib is a first-in-class, highly selective, and potent small molecule RET kinase inhibitor that has demonstrated marked and durable anti-tumor activity in diverse RET-activated solid tumors in the LIBRETTO-001 study (NCT03157128). METHODS: We describe the first six pheochromocytoma cases treated with selpercatinib in the LIBRETTO-001 study. RESULTS: Of the six patients (one sporadic and five reported as part of MEN2 syndromes) in this case report, four had a partial response/complete response and two had stable disease per independent review committee. Treatment duration ranged from 9.2 months to more than 56.4 months. The safety profile of treatment was consistent with selpercatinib in other indications. CONCLUSION: These data support selpercatinib as an effective therapy against RET-mutant pheochromocytoma, adding to the diversity of RET-activated tumor types that may benefit from targeted RET inhibition.

A phase 2, multicenter, open-label study of anti-LAG-3 ieramilimab in combination with anti-PD-1 spartalizumab in patients with advanced solid malignancies.

Ieramilimab, a humanized anti-LAG-3 monoclonal antibody, was well tolerated in combination with the anti-PD-1 antibody spartalizumab in a phase 1 study. This phase 2 study aimed to further investigate the efficacy and safety of combination treatment in patients with selected advanced (locally advanced or metastatic) solid malignancies. Eligible patients with non-small cell lung cancer (NSCLC), melanoma, renal cell carcinoma (RCC), mesothelioma, and triple-negative breast cancer (TNBC) were grouped depending on prior anti-PD-1/L1 therapy (anti-PD-1/L1 naive or anti-PD-1/L1 pretreated). Patients received ieramilimab (400 mg) followed by spartalizumab (300 mg) every 3 weeks. The primary endpoint was objective response rate (ORR), along with safety, pharmacokinetics, and biomarker assessments. Of 235 patients, 142 were naive to anti-PD-1/L1 and 93 were pretreated with anti-PD-1/L1 antibodies. Durable responses (>24 months) were seen across all indications for patients naive to anti-PD-1/L1 and in melanoma and RCC patients pretreated with anti-PD1/L1. The most frequent study drug-related AEs were pruritus (15.5%), fatigue (10.6%), and rash (10.6%) in patients naive to anti-PD-1/L1 and fatigue (18.3%), rash (14.0%), and nausea (10.8%) in anti-PD-1/L1 pretreated patients. Biomarker assessment indicated higher expression of T-cell-inflamed gene signature at baseline among responding patients. Response to treatment was durable (>24 months) in some patients across all enrolled indications, and safety findings were in accordance with previous and current studies exploring LAG-3/PD-1 blockade.

Comparative Effectiveness of First-Line Selpercatinib versus Standard Therapies in Patients with RET-Activated Cancers: An Exploratory Interpatient Analysis of LIBRETTO-001.

Selpercatinib is indicated for locally advanced/metastatic RET-activated solid tumors after progression or following prior systemic therapies. Until the recently published data from LIBRETTO-431 and LIBRETTO-531, there were limited effectiveness data comparing selpercatinib with other first-line treatments in RET-activated non-small cell lung cancer (NSCLC), medullary thyroid cancer (MTC), and thyroid cancer (TC). This study analyzed patient data from LIBRETTO-001 and compared the outcomes (time to treatment discontinuation {TTD}, time to next treatment or death {TTNT-D}, time to progression {TTP}, and the objective response rate {ORR}) of first-line selpercatinib (selpercatinib arm) use with the outcomes of first-line standard therapies in patients who then received selpercatinib in later lines of treatment (comparator arm). Overall, the first-line selpercatinib arm had a longer TTD, TTNT-D, and TTP versus the first-line comparator arm. The hazard ratios (HRs) for TTD were 0.29 (NSCLC), 0.15 (MTC), 0.08 (TC); for TTNT-D, the HRs were 0.48 (NSCLC), 0.11 (MTC), 0.09 (TC); and for TTP, the HRs were 0.54 (NSCLC), 0.15 (MTC), and 0.12 (TC). The ORR was higher for first-line selpercatinib versus the first-line comparator (NSCLC: 85.3% vs. 39.7%; MTC: 82.6% vs. 15.2%; and TC: 81.8% vs. 31.8%). First-line selpercatinib use is associated with improved outcomes compared to first-line comparator therapies for patients with advanced/metastatic RET-activated cancers.

Visualization of Tumor Heterogeneity in Advanced Medullary Thyroid Carcinoma by Dual-Tracer Molecular Imaging: Revealing the Theranostic Potential of SSTR- and PSMA-Directed Endoradiotherapy.

ABSTRACT: We present the case of a 60-year-old man with medullary thyroid carcinoma and hepatic, osseous, and lymph node metastases who underwent peptide receptor radionuclide therapy with 177Lu-DOTATOC. After 2 cycles, 68Ga-DOTATOC PET/CT revealed multiple nonavid lesions. To assess whether the patient would be eligible for prostate-specific membrane antigen (PSMA)-targeted radioligand therapy, a PSMA PET/CT was conducted. PSMA PET/CT identified increased PSMA expression in both 68Ga-DOTATOC-avid and nonavid lesions. As such, dual-radiotracer PET/CT may allow for insights into the complexities of tumor heterogeneity in patients with medullary thyroid carcinoma, which may pave the way for subsequent therapeutic algorithms.

Phase I/II study of the LAG-3 inhibitor ieramilimab (LAG525) ± anti-PD-1 spartalizumab (PDR001) in patients with advanced malignancies.

BACKGROUND: Lymphocyte-activation gene 3 (LAG-3) is an inhibitory immunoreceptor that negatively regulates T-cell activation. This paper presents preclinical characterization of the LAG-3 inhibitor, ieramilimab (LAG525), and phase I data for the treatment of patients with advanced/metastatic solid tumors with ieramilimab ±the anti-programmed cell death-1 antibody, spartalizumab. METHODS: Eligible patients had advanced/metastatic solid tumors and progressed after, or were unsuitable for, standard-of-care therapy, including checkpoint inhibitors in some cases. Patients received ieramilimab ±spartalizumab across various dose-escalation schedules. The primary objective was to assess the maximum tolerated dose (MTD) or recommended phase II dose (RP2D). RESULTS: In total, 255 patients were allocated to single-agent ieramilimab (n=134) and combination (n=121) treatment arms. The majority (98%) had received prior antineoplastic therapy (median, 3). Four patients experienced dose-limiting toxicities in each treatment arm across various dosing cohorts. No MTD was reached. The RP2D on a 3-week schedule was declared as 400 mg ieramilimab plus 300 mg spartalizumab and, on a 4-week schedule (once every 4 weeks; Q4W), as 800 mg ieramilimab plus 400 mg spartalizumab; tumor target (LAG-3) suppression with 600 mg ieramilimab Q4W was predicted to be similar to the Q4W, RP2D schedule. Treatment-related adverse events (TRAEs) occurred in 75 (56%) and 84 (69%) patients in the single-agent and combination arms, respectively. Most common TRAEs were fatigue, gastrointestinal, and skin disorders, and were of mild severity; seven patients experienced at least one treatment-related serious adverse event in the single-agent (5%) and combination group (5.8%). Antitumor activity was observed in the combination arm, with 3 (2%) complete responses and 10 (8%) partial responses in a mixed population of tumor types. In the combination arm, eight patients (6.6%) experienced stable disease for 6 months or longer versus six patients (4.5%) in the single-agent arm. Responding patients trended towards having higher levels of immune gene expression, including CD8 and LAG3, in tumor tissue at baseline. CONCLUSIONS: Ieramilimab was well tolerated as monotherapy and in combination with spartalizumab. The toxicity profile of ieramilimab in combination with spartalizumab was comparable to that of spartalizumab alone. Modest antitumor activity was seen with combination treatment. TRIAL REGISTRATION NUMBER: NCT02460224.

Pasotuxizumab, a BiTE® immune therapy for castration-resistant prostate cancer: Phase I, dose-escalation study findings.

Aim: We report results of a first-in-human study of pasotuxizumab, a PSMA bispecific T-cell engager (BiTE®) immune therapy mediating T-cell killing of tumor cells in patients with advanced castration-resistant prostate cancer. Patients & methods: We assessed once-daily subcutaneous (SC) pasotuxizumab. All SC patients developed antidrug antibodies; therefore, continuous intravenous (cIV) infusion was assessed. Results: A total of 47 patients received pasotuxizumab (SC: n = 31, 0.5-172 µg/d; cIV: n = 16, 5-80 µg/d). The SC maximum tolerated dose was 172.0 µg/d. A sponsor change stopped the cIV cohort early; maximum tolerated dose was not determined. PSA responders occurred (>50% PSA decline: SC, n = 9; cIV, n = 3), including two long-term responders. Conclusion: Data support pasotuxizumab safety in advanced castration-resistant prostate cancer and represent evidence of BiTE monotherapy efficacy in solid tumors. Clinical trial registration: NCT01723475 (ClinicalTrials.gov).

Gene signatures of pulmonary metastases of renal cell carcinoma reflect the disease-free interval and the number of metastases per patient.

Our understanding of metastatic spread is limited and molecular mechanisms causing particular characteristics of metastasis are largely unknown. Herein, transcriptome-wide expression profiles of a unique cohort of 20 laser-resected pulmonary metastases (Mets) of 18 patients with clear-cell renal cell carcinoma (RCC) were analyzed to identify expression patterns associated with two important prognostic factors in RCC: the disease-free interval (DFI) after nephrectomy and the number of Mets per patient. Differentially expressed genes were identified by comparing early (DFI < or = 9 months) and late (DFI > or = 5 years) Mets, and Mets derived from patients with few (< or =8) and multiple (> or =16) Mets. Early and late Mets could be separated by the expression of genes involved in metastasis-associated processes, such as angiogenesis, cell migration and adhesion (e.g., PECAM1, KDR). Samples from patients with multiple Mets showed an elevated expression of genes associated with cell division and cell cycle (e.g., PBK, BIRC5, PTTG1) which indicates that a high number of Mets might result from an increased growth potential. Minimal sets of genes for the prediction of the DFI and the number of Mets per patient were identified. Microarray results were confirmed by quantitative PCR by including nine further pulmonary Mets of RCC. In summary, we showed that subgroups of Mets are distinguishable based on their expression profiles, which reflect the DFI and the number of Mets of a patient. To what extent the identified molecular factors contribute to the development of these characteristics of metastatic spread needs to be analyzed in further studies.

[Management of adverse events in immune oncology - Practical aspects of immune-related adverse events during immune oncological treatment]. / Nebenwirkungsmanagement in der Immunonkologie.

The immune oncological treatment approach uses immune checkpoint inhibitors to prevent tumor cells from shutting down the immune system, and thus from escaping immune response. Following the clinical success of immune checkpoint inhibitors, the number of approved immune oncological therapies continues to increase. Response rates and overall survival with anti-PD-1/PD-L1 and CTLA-4 blockade could be further improved by combining both treatment approaches. However, checkpoint inhibition is associated with a unique spectrum of side effects termed immune-related adverse events. These typically occur 3 to 6 months after treatment start and resolve with adequate management procedures if detected early on. Therefore, profound patient education, sensitizing and monitoring are mandatory. We describe in this article selected frequent and rare adverse events that are clinically relevant. Furthermore, using case reports, interdisciplinary experts share their practice-based experience in the management of frequent pneumonic, endocrine, and gastro-intestinal immune-related adverse events.

Genomic Profiling Identifies Outcome-Relevant Mechanisms of Innate and Acquired Resistance to Third-Generation Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Therapy in Lung Cancer.

PURPOSE: Third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are effective in acquired resistance (AR) to early-generation EGFR TKIs in EGFR-mutant lung cancer. However, efficacy is marked by interindividual heterogeneity. We present the molecular profiles of pretreatment and post-treatment samples from patients treated with third-generation EGFR TKIs and their impact on treatment outcomes. METHODS: Using the databases of two lung cancer networks and two lung cancer centers, we molecularly characterized 124 patients with EGFR p.T790M-positive AR to early-generation EGFR TKIs. In 56 patients, correlative analyses of third-generation EGFR TKI treatment outcomes and molecular characteristics were feasible. In addition, matched post-treatment biopsy samples were collected for 29 patients with progression to third-generation EGFR TKIs. RESULTS: Co-occurring genetic aberrations were found in 74.4% of EGFR p.T790-positive samples (n = 124). Mutations in TP53 were the most frequent aberrations detected (44.5%; n = 53) and had no significant impact on third-generation EGFR TKI treatment. Mesenchymal-epithelial transition factor (MET) amplifications were found in 5% of samples (n = 6) and reduced efficacy of third-generation EGFR TKIs significantly (eg, median progression-free survival, 1.0 months; 95% CI, 0.37 to 1.72 v 8.2 months; 95% CI, 1.69 to 14.77 months; P ≤ .001). Genetic changes in the 29 samples with AR to third-generation EGFR TKIs were found in EGFR (eg, p.T790M loss, acquisition of p.C797S or p.G724S) or in other genes (eg, MET amplification, KRAS mutations). CONCLUSION: Additional genetic aberrations are frequent in EGFR-mutant lung cancer and may mediate innate and AR to third-generation EGFR TKIs. MET amplification was strongly associated with primary treatment failure and was a common mechanism of AR to third-generation EGFR TKIs. Thus, combining EGFR inhibitors with TKIs targeting common mechanisms of resistance may delay AR.

Retrospective survival analysis of 237 consecutive patients with multiple pulmonary metastases from advanced renal cell carcinoma exclusively resected by a 1318-nm laser.

OBJECTIVES: Despite the introduction of new target drugs to treat pulmonary metastatic renal cell carcinoma (mRCC), complete surgical resection still generates significantly longer survival. We analysed the survival outcome for patients with pulmonary mRCC after extended laser metastasectomy with up to 110 metastases and systematic lymphadenectomy to assess the utility and value of laser resection in the respective patient groups even with high number of metastases. METHODS: Between 1996 and 2012, 237 patients (150 men, 87 women) underwent curative intended pulmonary laser metastasectomy of mRCC. A total of 2996 metastases (range: 1-110) were resected. Kaplan-Meier analysis was performed to assess overall survival in all 237 patients and for sub-groups. Multivariate analysis of prognostic factors was performed using Cox regression models. RESULTS: Two hundred and eight patients with R0-resection (88%) had 5-year overall survival rate and median overall survival of 54% and 69 months, respectively, significantly better than 7% and 19 months in those with incomplete resections (log-rank P < 0.00001). A mean of 13 metastases per patient were resected. Five-year survival for patients with 1, 2-5, 6-9, 10-29 or 30-110 metastases resected was 62, 59, 60, 43 and 40%, respectively. In multivariate Cox-regression of all 237 patients, only completeness of resection (P < 0.0001) and number of metastases (P = 0.0029) were independent factors. CONCLUSIONS: If complete resection is achieved, laser resection can remove even high numbers of metastases with considerable and comparable long-term survival known from previous reports. This tissue-saving technique allows repeated resections in case of recurrence.

Laser resection technique and results of multiple lung metastasectomies using a new 1,318 nm Nd:YAG laser system.

BACKGROUND AND OBJECTIVES: Advantages of a new 1,318 nm Nd:YAG laser based on multiple lung metastasectomies are shown. STUDY DESIGN/MATERIALS AND METHODS: Ninety-three percent of 328 patients with metastases (8/patient, range 1-124) had precision laser resections (lobectomy-rate reduced to 7%); this laser delivers 20 kW/cm(2) 1,318 nm power densities with 400 microm fibers, and a focussing handpiece. Absorption in water is tenfold higher. RESULTS AND CONCLUSIONS: Between 1/1996 and 12/2003 in 328 patients (164 males/females, 61 years) 3,267 nodules were removed. Pathologic examination revealed 2,546 metastases (range 3-80 mm) from kidney (n = 112), colorectal (n = 91), and breast cancers (n = 35). In 85% of patients where the complete resection was achieved the 5-year survival was 41%. For remaining 15% (incomplete resection) the 5-year survival was 7%. Five-year survival for patients with 10 (and more) metastases was 28%, for patients with 20 (and more) was 26%. No 30-day mortality was observed. CONCLUSION: This new laser system facilitates any kind of parenchymal lung resection in lobe-sparing manner and in case of complete resection improves significantly the survival.

Is surgery for multiple lung metastases reasonable? A total of 328 consecutive patients with multiple-laser metastasectomies with a new 1318-nm Nd:YAG laser.

OBJECTIVE: Our objective was to define the role of a new 1318-nm Nd:YAG laser for lobe- and parenchyma-saving resection of multiple lung metastases. PATIENTS AND METHODS: From January 1996 to December 2003, a total of 3267 nodules (10/patient) were removed from 328 patients (164 men/164 women, mean age 61 years). Criteria for eligibility were expanded to any primary tumors with no upper limit of metastases given. All parenchymal resections were performed with a new 1318-nm Nd:YAG laser whose effect on lung tissue differs significantly from that of the 1064-nm wavelength owing to a 10-fold higher absorption in water and one-third extinction in blood. In 93%, precision laser resection was achieved. The lobectomy rate was only 7%. RESULTS: Pathologic examination revealed 2546 metastases (8/patient) and lymph node disease in 19%. Complete resections (R0) were achieved in 93% of 177 patients undergoing unilateral procedures with a mean of 3 metastases (range 1%-29%) and 75% of 151 patients having bilateral operations with a mean of 13 metastases (range 2-124). The 5-year survival after R0 was 55% for solitary nodules, 41% for all patients, 28% for 10 metastases, and 26% for 20 or more metastases resected. Outcome was significantly poorer after incomplete resection (7%). No 30-day mortality was observed. Major postoperative complications included prolonged air leaks (n = 2), intrapleural bleeding (n = 2), and late pneumothorax (n = 2); all were treated successfully with a chest tube. CONCLUSION: This new 1318-nm Nd:YAG laser facilitates complete resection of multiple bilateral centrally located metastases and thus is lobe sparing. Resection of 20 or more metastases is reasonable because long-term survival was significantly better than that observed with incomplete resection.

Epstein-Barr virus latent membrane protein 2A mimics B-cell receptor-dependent virus reactivation.

Latent membrane protein 2A (LMP2A) of Epstein-Barr virus (EBV) shares protein motifs with the B-cell receptor that play a role in B-cell receptor signalling and has been shown to mimic an activated B-cell receptor by providing a survival signal for mature B cells in transgenic mice. Conversely, LMP2A has been reported not to support but to inhibit B-cell receptor signalling with respect to virus reactivation and to block lytic virus induction after anti-Ig treatment of EBV-infected B cells. To solve this apparent paradox, the role of LMP2A in lytic-cycle induction was re-examined in B cells conditionally immortalized by EBV. It was shown that, in the absence of other stimuli, LMP2A expression alone could lead to induction of the virus lytic cycle. Similarly to B-cell receptor stimulation by anti-Ig treatment, this LMP2A-mediated reactivation was dependent on the mitogen-activated protein kinase pathway and could be inhibited by the viral LMP1. Our data reinforce the notion that LMP2A is a functional homologue of the B-cell receptor, not only with respect to B-cell survival but also with respect to regulation of the lytic cycle.

Control of Epstein-Barr virus reactivation by activated CD40 and viral latent membrane protein 1.

In humans, Epstein-Barr virus (EBV) establishes a persistent latent infection in peripheral resting B lymphocytes. Virus reactivation is highly restricted. Whereas in healthy humans the infection usually is benign, immunocompromised patients show an increased risk for EBV-associated malignancies, accompanied by an increase in virus replication and in the number of virus-infected cells. To search for viral and host factors regulating virus reactivation, we used conditionally EBV-immortalized B cells. We found that CD40-CD40 ligand interaction and the viral mimic of activated CD40, EBV latent membrane protein 1, suppress virus reactivation. Both inhibit anti-IgM or phorbolester-induced transcription of the viral immediate early protein BZLF1, which controls entry into the viral lytic cycle. The finding that latent membrane protein 1 and CD40 contribute to the regulation of latency may have important implications for the balance between EBV and its host in normal as well as in immunocompromised individuals.

Elevated expression of c-myc in lymphoblastoid cells does not support an Epstein-Barr virus latency III-to-I switch.

Epstein-Barr virus (EBV) transforms primary B cells in vitro. Established cell lines adopt a lymphoblastoid phenotype (LCL). In contrast, EBV-positive Burkitt's lymphoma (BL) cells, in which the proto-oncogene c-myc is constitutively activated, do not express a lymphoblastoid phenotype in vivo. The two different phenotypes are paralleled by two distinct programmes of EBV latent gene expression termed latency type I in BL cells and type III in LCL. Human B cell lines were established from a conditional LCL (EREB2-5) by overexpression of c-myc and inactivation of EBV nuclear protein 2 (EBNA2). These cells (A1 and P493-6) adopted a BL phenotype in the absence of EBNA2. However, the EBV latency I promoter Qp was not activated. Instead, the latency III promoter Cp remained active. These data suggest that the induction of a BL phenotype by overexpression of c-myc in an LCL is not necessarily paralleled by an EBV latency III-to-I switch.