Purpose. We performed a first-in-human clinical trial. The aim of this study was to determine safety and feasibility of PET imaging with 18F-PARPi in patients with head and neck cancer. Patients and Methods. Eleven patients with newly diagnosed or recurrent oral and oropharyngeal cancer were injected with 18F-PARPi (331 ± 42 MBq) and dynamic PET/CT imaging was performed between 0 min and 25 min post-injection

PURPOSE The effectiveness of immune checkpoint inhibitors (ICIs) is limited in pancreatic ductal adenocarcinoma (PDAC). We conducted a phase I study to evaluate the safety of ICI with stereotactic body radiation therapy (SBRT) in patients with metastatic PDAC. EXPERIMENTAL DESIGN Patients enrolled must have received at least one line of prior systemic chemotherapy for metastatic disease. Cohort A1

Members of the scientific and clinical neuro-oncology community met in April 2019 to discuss the current challenges and opportunities associated with translating basic science discoveries in glioblastoma to improved survival for patients. A summary of key points of these discussions is presented in this report.

PURPOSE The potential biological determinants of aggressive prostate cancer (PCa) in African American (AA) men are unknown. Here we characterize PCa genomic alterations in the largest cohort to date of AA men with clinical follow-up for metastasis, with the aim to elucidate the key molecular drivers associated with poor prognosis in this population. EXPERIMENTAL DESIGN Targeted sequencing was retrospectively

Purpose: Although cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors significantly extend tumor response in patients with metastatic ER-positive (ER+) breast cancer, relapse is almost inevitable. This may in part reflect the failure of CDK4/6 inhibitors to induce apoptotic cell death. We therefore evaluated combination therapy with ABT-199 (venetoclax), a potent and selective BCL2 inhibitor. Experimental

Purpose: NOTCH signaling is associated with tumorigenesis, mutagenesis, and immune tolerance in NSCLC, indicating its association with the clinical benefit of immune checkpoint inhibitors (ICIs). We hypothesized that NOTCH mutation in NSCLC might be a robust predictor of immunotherapeutic efficacy. Experimental Design: Multiple-dimensional data including genomic, transcriptomic, and clinical data from

Purpose: Generation of antigen-specific T cells from cancer patients employs large numbers of peripheral blood cells and/or tumor infiltrating cells to generate antigen-presenting and effector cells commonly requiring multiple rounds of re-stimulation ex vivo . We used a novel paramagnetic, nanoparticle-based artificial antigen presenting cell (nano-aAPC) that combines anti-CD28 co-stimulatory and

PURPOSE Immune checkpoint blockade has improved outcomes across tumor types; little is known about the efficacy of these agents in rare tumors. We report the results of the (non-pancreatic) neuroendocrine neoplasm cohort of SWOG S1609 Dual Anti-CTLA-4 & Anti-PD-1 blockade in Rare Tumors (DART). EXPERIMENTAL DESIGN We performed a prospective, open-label, multicenter phase 2 clinical trial of ipilimumab

PURPOSE Older patients with glioblastoma(GBM) are underrepresented in clinical trials. Several abbreviated and standard chemoradiotherapy regimens are advocated with no consensus on the optimal approach. Our objective was to quantitatively evaluate which of these regimens would provide the most favourable survival outcomes in older patients with GBM using a network meta-analysis. EXPERIMENTAL DESIGN

PURPOSE Enhanced lipogenesis and mitochondrial function are two critical metabolic characteristics in melanoma, but their crosstalk involved in tumor biology and targeted therapy remains unknown. ATP-citrate lyase (ACLY) is a crucial lipogenic enzyme that is greatly implicated in tumor development, but its role in mitochondrial function and melanoma pathogenesis has not been elucidated. EXPERIMENTAL

PURPOSE Exploitation of altered glycosylation in cancer is a major goal for the design of new cancer therapy. Here designed a novel chimeric signal peptide-Galectin-3 conjugate (sGal-3) and investigated its ability to induce cancer-specific cell death by targeting aberrantly N-glycosylated cell surface receptors in cancer cells. EXPERIMENTAL DESIGN sGal-3 was genetically engineered from Gal-3 by extending

PURPOSE Patients with recurrent or metastatic neuroendocrine neoplasms (NENs) had a poor prognosis and few treatment options. Toripalimab, a humanized IgG4 antibody specific for human PD-1 receptor, was first approved to treat 2nd line metastatic melanoma in China in 2018. EXPERIMENTAL DESIGN The multiple-center phase Ib trial enrolled patients with NENs (Ki-67≥10%) after failures of 1st line therapy

PURPOSE ABBV-838 is an antibody-drug conjugate targeting a unique epitope of CD2 subset 1, a cell-surface glycoprotein expressed on multiple myeloma (MM) cells. This phase 1/1b first-in-human, dose-escalation study (Trial registration ID: NCT02462525) evaluated the safety, pharmacokinetics, and preliminary activity of ABBV-838 in patients with relapsed and refractory (RR) MM. EXPERIMENTAL DESIGN Eligible

PURPOSE Allogeneic hematopoietic stem cell transplantation (AHCT) outcomes depend on disease and patient characteristics. We previously developed a novel prognostic model, hematopoietic cell transplant composite-risk (HCT-CR) by incorporating the refined disease risk index (DRI-R) and hematopoietic cell transplant - comorbidity/age index (HCT-CI/Age) to predict post-transplant survival in patients

PURPOSE Evaluating drug responses using primary patient derived cells ex vivo represents a potentially rapid and efficient approach to screening for new treatment approaches. Here, we sought to identify neratinib combinations in HER2mutant non-small cell lung cancer (NSCLC) patient xenograft derived organotypic spheroids (XDOTS) using a short term ex vivo system. EXPERIMENTAL DESIGN We generated two

### [Varghese et al. Page 1555][1] Trifluridine/tipiracil (FTD/TPI), an oral cytotoxic agent, has previously led to improved survival in patients with pretreated, refractory metastatic colorectal cancer. Varghese and colleagues conducted a phase I evaluation of the combination of FTD/TPI,

The present ReACT trial provides data from a small randomized controlled vaccination trial that in addition to other recent immunotherapy trials in glioblastoma allows sketching a rational, advanced trial design for the development of (immune) therapies in glioblastoma elaborating on but not restricting to biological monitoring and endpoints.See related article by Reardon et al., p. XXX.

KRAS G12C inhibitors have shown promise in KRAS G12C-mutant lung cancer but intrinsic and acquired resistance are common. Cotreatment with inhibitors of the protein phosphatase SHP2 can abrogate the adaptive response of cancer cells to KRAS inhibitors resulting in greater suppression of MAPK signaling and enhanced tumor growth inhibition.See related article by Ryan et al., p. xxx.

The progression of multiple myeloma, a hematologic malignancy characterized by unregulated plasma cell growth, is associated with increasing innate and adaptive immune system dysfunction, notably in the T-cell repertoire. Although treatment advances in multiple myeloma have led to deeper and more durable clinical responses, the disease remains incurable for most patients. Therapeutic strategies aimed

PURPOSE This two-part phase Ib trial determined the maximum tolerated dose (MTD) of the combination of trifluridine/tipiracil (FTD/TPI) and irinotecan in patients with advanced gastrointestinal tumors, and evaluated the safety, pharmacokinetics, and antitumor activity of the FTD/TPI, irinotecan, and bevacizumab triplet combination in previously treated metastatic colorectal cancer (mCRC). PATIENTS

Purpose: To characterize the population pharmacokinetics of cyclophosphamide, active 4-hydroxy-cyclophosphamide (4OH-CTX), and inactive carboxyethylphosphoramide mustard (CEPM), and their associations with hematologic toxicities in infants and young children with brain tumors. To use this information to provide cyclophosphamide dosing recommendations in this population. Patients and Methods: Patients

PURPOSE The STAKT study examined short-term exposure (4.5 days) to the oral selective pan-AKT inhibitor capivasertib (AZD5363) to determine if this drug can reach its therapeutic target in sufficient concentration to significantly modulate key biomarkers of the AKT pathway and tumor proliferation. METHODS STAKT was a two-stage, double-blind, randomized, placebo-controlled, "window-of-opportunity" study

PURPOSE Rindopepimut is a vaccine targeting the tumor-specific EGF driver mutation, EGFRvIII. The ReACT study investigated whether the addition of rindopepimut to standard bevacizumab improved outcome for patients with relapsed, EGFRvIII-positive glioblastoma. PATIENTS AND METHODS In this double-blind, randomized, phase II study (NCT01498328) conducted at 26 hospitals in the United States, bevacizumab-naïve

PURPOSE To evaluate the safety and feasibility of preoperative locoregional cytokine therapy (IRX-2 regimen) in early-stage breast cancer, and to evaluate for intratumoral and peripheral immunomodulatory activity. EXPERIMENTAL DESIGN Sixteen patients with stage I-III early-stage breast cancer (any histology type) indicated for surgical lumpectomy or mastectomy were enrolled to receive preoperative

PURPOSE Immunogenicity derived from the murine scFv, a major molecular compomemt of chimeric antigen receptors (CARs), may limit the persistence of CAR T cells, resulting in tumor relapse of patients in complete remission (CR). In this study, we developed a humanized anti-CD19 scFv CAR-T (hCAR-T) to treat patients with relapsed/refractory acute lymphoblastic leukemia (r/r ALL). EXPERIMENTAL DESIGN

PURPOSE To determine the efficacy of the therapeutic DNA vaccine GX-188E for inducing regression of cervical intraepithelial neoplasia (CIN) 3. PATIENTS AND METHODS We conducted a prospective, randomized, multicenter, open-label, phase II clinical trial of GX-188E in CIN3 patients positive for human papillomavirus (HPV) type 16/18. The primary endpoint was to determine the histopathologic regression

PURPOSE TRK inhibitors achieve marked tumor-agnostic efficacy in TRK fusion-positive cancers and consequently are now an established standard of care. Little is known, however, about the demographics, outcomes, response to alternative standard therapies, or genomic characteristics of TRK fusion-positive cancers. EXPERIMENTAL DESIGN Utilizing a center-wide screening program involving more than 26,000

PURPOSE Although KRAS represents the most commonly mutated oncogene, it has long been considered an "undruggable" target. Novel covalent inhibitors selective for the KRASG12C mutation offer the unprecedented opportunity to target KRAS directly. However, prior efforts to target the RAS-MAPK pathway have been hampered by adaptive feedback, which drives pathway reactivation and resistance. EXPERIMENTAL

PURPOSE Immune-checkpoint inhibitors have shown therapeutic efficacy in various malignant diseases. However, anti-programmed death (PD)-1 therapy has not shown clinical efficacy in multiple myeloma. EXPERIMENTAL DESIGN Bone marrow (BM) mononuclear cells were obtained from 77 newly diagnosed multiple myeloma patients. We examined the expression of immune-checkpoint receptors in BM CD8+ T cells and their

PURPOSE Tumor cells from patients with lung cancer are expelled from the primary tumor into the blood, but difficult to detect in the peripheral circulation. We studied the release of circulating tumor cells (CTCs) during surgery to test the hypothesis that CTC counts are influenced by hemodynamic changes (caused by surgical approach) and manipulation. EXPERIMENTAL DESIGN Patients undergoing video-assisted

PURPOSE Small-cell neuroendocrine prostate cancer (SCNPC) exhibits an aggressive clinical course and incidence rates seem to be increasing following resistance to potent androgen receptor (AR) antagonists. Currently, treatment options are limited and few model systems are available to identify new approaches for treatment. We sought to evaluate commonalities between SCNPC and other aggressive neuroendocrine

PURPOSE Metastatic prostate cancer (PCa) patients are increasingly presenting with treatment-resistant, androgen receptor-Negative/Low (AR-/Low) tumors, with or without neuroendocrine characteristics, in processes attributed to tumor cell plasticity. This plasticity has been modeled by Rb1/p53 knockdown/knockout and is accompanied by overexpression of the pluripotency factor, Sox2. Here we explore

PURPOSE Emergence of mismatch repair (MMR) deficiency is a frequent mechanism of acquired resistance to the alkylating chemotherapeutic temozolomide (TMZ) in gliomas. Poly(ADP-ribose) polymerase inhibitors (PARPi) have been shown to potentiate TMZ cytotoxicity in several cancer types, including gliomas. We tested whether PARP inhibition could re-sensitize MSH6-null MMR-deficient gliomas to TMZ, and

Purpose: PI3K signaling is a common feature of B-cell neoplasms, including chronic lymphocytic leukemia (CLL) and diffuse large B-cell lymphoma (DLBCL), and PI3K inhibitors have been introduced into the clinic. However, there remains a clear need to develop new strategies to target PI3K signaling. PI3K activity is countered by Src homology domain 2-containing inositol-5′-phosphatase 1 (SHIP1) and,

PURPOSE Despite its enormous successes, the overall response rate of cancer immunotherapy remains suboptimal, especially in breast cancer. There is an increased interest in combining immune checkpoint inhibitor with targeted agents to enhance antitumor effect. Anti-angiogenic drugs have been shown to synergize with immune checkpoint blockades, but the optimal setting for combining these two modalities

PURPOSE Immune components of the tumor microenvironment (TME) have been associated with disease outcome. We prospectively evaluated the association of an immune-related gene signature (GS) with clinical outcome in melanoma and non-small cell lung cancer (NSCLC) tumor samples from two phase III studies. EXPERIMENTAL DESIGN The GS was prospectively validated using an adaptive signature design to optimize

PURPOSE Long noncoding RNAs (lncRNA) have been observed in various cancer types. Our bioinformatic analysis of existing databases demonstrated overexpression of lncRNA THAP9-AS1 in pancreatic ductal adenocarcinoma (PDAC). We aimed to investigate the roles and mechanisms of THAP9-AS1 in PDAC. EXPERIMENTAL DESIGN The overexpression of THAP9-AS1 in samples of patients with pancreatic cancer was characterized

PURPOSE Glioblastoma (GBM) is one of the most aggressive and lethal cancer types in humans. The standard treatment approach is surgery followed by chemoradiation. However, the molecular mechanisms of innate tumor radioresistance remain poorly understood. EXPERIMENTAL DESIGN We tested the expression of Smoothened (Smo) in primary and recurrent GBM tissues and cells. Then, we determined radiation effectiveness

PURPOSE This study aims to provide comprehensive insights into longitudinal immune landscape in acute myeloid leukemia (AML) development and treatment, which may contribute to predict prognosis and guide clinical decisions. EXPERIMENTAL DESIGN Periphery blood samples from 79 patients with AML (at diagnosis or/and after chemotherapy or at relapse) and 24 healthy controls were prospectively collected

I read with great interest the recent article by Parseghian and colleagues ([1][1]), presenting a review of the mechanisms underlying the innate and acquired resistance to anti-EGFR therapy. This “in-depth review” of the resistance mechanisms, however, does not include the possible host antibody

In the METROS trial, Landi and colleagues evaluated the efficacy of crizotinib in advanced non–small cell lung cancer (NSCLC) harboring ROS1 rearrangements or MET dysregulation ([1][1]). A total of 505 patients were screened and 10 patients entered the trial with cancers harboring MET exon 14

We thank the authors for their interest in our study and for their comments. Wiesweg and colleagues correctly reported that the minor allele frequency of both p.T1010I and p.R988C MET variants is close to 1% in the European population, but these mutations were described also as somatic (T1010I:

The editors are publishing this note to alert readers to a concern about [this article][1] ([1][2]). In the actin row of Fig. 3B, there is a missing splice line between samples 12 and 35, and the sets of actin blots in samples 12 and 35 appear to be duplicates. 1. 1.[↵][3]1. Van Den Broeck A

[This article][1] ([1][2]) has been retracted at the request of the authors. During their efforts to advance related compounds and analogues, the authors were not able to reproduce the in vivo efficacy results represented in Fig. 5. The authors apologize to the scientific community and deeply regret

Poly-ADP-ribose-polymerase inhibitors (PARPi) are promising in BRCA2-altered prostate cancer. Data were presented on PARPi efficacy in prostate cancers with alterations in other DNA damage repair genes which suggest low response rates in ATM-, CHEK2-, CDK12-altered tumors and promising results in PALB2-, RAD51B-, FANCA-, and BRIP1-altered tumors.

The impact on survival of steroids and TNF-alpha blockade to treat immune-related toxicity from checkpoint blockade with ipilimumab, nivolumab/pembrolizumab or combined ipilimumab and nivolumab was assessed using data from a large national database. Using steroids was associated with better survival than the use of TNF-alpha blocking antibodies such as infliximab.

Purpose: Adults with T-cell lymphoblastic lymphoma (T-LBL) generally benefit from treatment with acute lymphoblastic leukemia (ALL)-like regimens, but approximately 40% will relapse after such treatment. We evaluated the value of CpG methylation in predicting relapse for adults with T-LBL treated with ALL-like regimens. Experimental Design: A total of 549 adults with T-LBL from 27 medical centers were

Purpose: Over 60% of melanoma patients respond to immune checkpoint inhibitor (ICI) therapy, but many subsequently progress on these therapies. Second-line targeted therapy is based on BRAF mutation status, but no available agents are available for NRAS, CDKN2A, PTEN, and TP53 mutations. Over 70% of melanoma tumors have activation of the MAPK pathway due to BRAF or NRAS mutations, while loss or mutation

Purpose: Fulvestrant, the first-in-class selective estrogen receptor (ER) degrader (SERD), is clinically effective in patients with ER+ breast cancer, but it has administration and pharmacokinetic (PK) limitations. Pharmacodynamic (PD) data suggests complete ER degradation is not achieved at fulvestrant's clinically feasible dose. This pre-surgical study ([NCT03236974][1]) compared the PD effects of

PURPOSE: We performed next-generation sequencing (NGS) in the CONKO-001 phase-3 trial to identify clinically relevant prognostic and predictive mutations and conducted a functional validation in TCGA sequencing data. PATIENTS AND METHODS: Patients of the CONKO-001 trial received curatively intended surgery for pancreatic adenocarcinoma (PDAC) followed by adjuvant chemotherapy with gemcitabine (Gem)

Purpose: Pancreatic ductal adenocarcinoma (PDAC) is a lethal disease with dismal survival rates. Tumor microenvironment (TME), comprising of immune cells and cancer-associated fibroblasts, plays a key role in driving poor prognosis and resistance to chemotherapy. Herein, we aimed to identify a TME-associated, risk-stratification gene biomarker signature in PDAC. Experimental Design: The initial biomarker

Background Unleashing the immune system by PD-1 and/or CTLA-4 blockade can cause severe immune-related toxicity necessitating immunosuppressive treatment. Whether immunosuppression for toxicity impacts survival is largely unknown. Patients and methods Using data from the prospective nationwide Dutch Melanoma Treatment Registry (DMTR), we analysed the association between severe toxicity and overall

PURPOSE Copy number changes and translocations have been studied extensively in many datasets with long term follow-up. The impact of mutations remains debated given the short time to follow-up of most datasets. METHODS we performed targeted panel sequencing covering 125 myeloma-specific genes and the loci involved in translocations in 223 newly diagnosed myeloma samples recruited into one of the Total

PURPOSE Treatment failure from drug resistance is the primary reason for relapse in acute lymphoblastic leukemia. Improving outcomes by targeting mechanisms of drug resistance is a potential solution. EXPERIMENTAL DESIGN We report results investigating the epigenetic modulators decitabine and vorinostat with vincristine, dexamethasone, mitoxantrone and PEG-asparaginase for pediatric patients with relapsed

PURPOSE Although stereotactic body radiation therapy (SBRT) is effective in early stage non-small cell lung cancer (NSCLC), ~10-15% of patients will fail regionally and 20-25% distantly. We evaluate a novel circulating tumor cell (CTC) assay as a prognostic marker for increased risk of recurrence following SBRT. EXPERIMENTAL DESIGN 92 subjects (median age 71y) with T1a (64%), T1b (23%), or T2a (13%)

PURPOSE Pancreatic cancer remains a disease of high mortality despite advanced diagnostic techniques. Mucins (MUC) play crucial roles in carcinogenesis and tumor invasion in pancreatic cancers. MUC1 and MUC4 expression are related to the aggressive behavior of human neoplasms and a poor patient outcome. In contrast, MUC2 is a tumor suppressor, and we have previously reported that MUC2 is a favorable

Purpose: We assessed plasma circulating tumor DNA (ctDNA) level as a prognostic marker for progression-free survival (PFS) following first-line metastatic colorectal cancer (mCRC) therapy. Experimental Design: STEAM was a randomized, phase II trial investigating efficacy of bevacizumab (BEV) plus 5-fluorouracil/leucovorin/oxaliplatin (FOLFOX) and 5-fluorouracil/leucovorin/irinotecan (FOLFIRI), administered

Purpose: Children with Down syndrome (DS, constitutive trisomy 21) that develop acute lymphoblastic leukemia (DS-ALL) have a 3-fold increased likelihood of treatment-related mortality coupled with a higher cumulative incidence of relapse, compared to other children with B-cell acute lymphoblastic leukemia (B-ALL). This highlights the lack of suitable treatment for DS children with B-ALL. Experimental

Purpose: The emergence of secondary mutations is a cause of resistance to current KIT inhibitors used in the treatment of patients with gastrointestinal stromal tumors (GIST). AZD3229 is a selective inhibitor of wild-type KIT and a wide spectrum of primary and secondary mutations seen in GIST patients. The objective of this analysis is to establish the pharmacokinetic-pharmacodynamic (PKPD) relationship

Purpose: Translocation renal cell carcinoma (tRCC) is a rare, aggressive RCC subtype. There is currently limited understanding on the role of molecular alterations in the pathogenesis and progression of these tumors. We investigated the association between somatic alterations and clinical outcomes in two independent cohorts profiled using DNA-sequencing. Experimental Design: Twenty-two tRCCs underwent