Response-adapted, time-limited venetoclax, umbralisib, and ublituximab for relapsed/refractory chronic lymphocytic leukemia.

Many patients with chronic lymphocytic leukemia (CLL) will develop treatment resistance to Bruton tyrosine kinase (BTK) inhibitors. Phosphatidylinositol-3-kinase (PI3K) inhibitors, including umbralisib, have significant clinical activity in relapsed/refractory CLL, but prolonged exposure is associated with potential toxicities. Owing to the synergistic antitumor effects of combined PI3K and BCL-2 inhibition, we sought to explore the feasibility of response-adapted, time-limited therapy to optimize disease control while mitigating the risks of prolonged treatment.

Patient-reported impact of symptoms in lung cancer (PRISM-LC).

Background: Individuals with lung cancer (LC) face a variety of symptoms that significantly impact their lives. We use extensive patient input to determine the relative importance and prevalence of these symptoms and identify which demographic features are associated with a higher level of disease burden.

Methods: We performed semi-structured qualitative interviews with participants with LC to identify potentially important symptoms.

Heterogeneity of neuroendocrine transcriptional states in metastatic small cell lung cancers and patient-derived models.

Molecular subtypes of small cell lung cancer (SCLC) defined by the expression of key transcription regulators have recently been proposed in cell lines and limited number of primary tumors. The clinical and biological implications of neuroendocrine (NE) subtypes in metastatic SCLC, and the extent to which they vary within and between patient tumors and in patient-derived models is not known. We integrate histology, transcriptome, exome, and treatment outcomes of SCLC from a range of metastatic sites, revealing complex intra- and intertumoral heterogeneity of NE differentiation.

Notch signaling and efficacy of PD-1/PD-L1 blockade in relapsed small cell lung cancer.

Immune checkpoint blockade (ICB) benefits only a small subset of patients with small cell lung cancer (SCLC), yet the mechanisms driving benefit are poorly understood. To identify predictors of clinical benefit to ICB, we performed immunogenomic profiling of tumor samples from patients with relapsed SCLC. Tumors of patients who derive clinical benefit from ICB exhibit cytotoxic T-cell infiltration, high expression of antigen processing and presentation machinery (APM) genes, and low neuroendocrine (NE) differentiation.

Erratum: Anterior mediastinal large cell neuroendocrine carcinoma with elevated AFP: A case report and review.

[This corrects the article DOI: 10.3892/mco.2020.

Anterior mediastinal large cell neuroendocrine carcinoma with elevated AFP: A case report and review.

Large cell neuroendocrine carcinoma (LCNEC) is a rare and aggressive cancer that typically presents in the lung. The current case report describes a 56 year old male who presented to Strong Memorial Hospital with progressive dyspnea and was revealed to have a large anterior mediastinal tumor with metastases to axillary, hilar and mediastinal lymph nodes. Tumor marker results revealed an elevated plasma level of α-fetoprotein (AFP), which initially pointed towards a diagnosis of teratoma, but the tumor stained positive for neuroendocrine markers CD56, chromogranin, and synaptophysin on biopsy, consistent with LCNEC.

Atorvastatin is associated with reduced cisplatin-induced hearing loss.

BACKGROUNDCisplatin is widely used to treat adult and pediatric cancers. It is the most ototoxic drug in clinical use, resulting in permanent hearing loss in approximately 50% of treated patients. There is a major need for therapies that prevent cisplatin-induced hearing loss.

Risk of brain metastases in T1-3N0 NSCLC: a population-based analysis.

Aim: Several consensus guidelines recommend against routine brain imaging at diagnosis of T1-3N0 non-small cell lung cancer (NSCLC).

Methods: From the Surveillance, Epidemiology and End Results registry, patients with pathologically confirmed T1-3N0 NSCLC were identified. Risks of brain metastases at time of initial diagnosis were analyzed.

-Paclitaxel-Based Therapy in Underserved Patient Populations: The ABOUND.PS2 Study in Patients With NSCLC and a Performance Status of 2.

Introduction: The phase II ABOUND.PS2 study (NCT02289456) assessed safety/tolerability of a first-line modified -paclitaxel/carboplatin regimen for patients with advanced non-small cell lung cancer (NSCLC) and Eastern Cooperative Oncology Group (ECOG) performance status (PS) 2.

Methods: Chemotherapy-naive patients with stage IIIB/IV NSCLC and ECOG PS 2 received four cycles of -paclitaxel 100 mg/m days 1 and 8 plus carboplatin area under the curve 5 day 1 q3w (induction).

SWOG0919: a Phase 2 study of idarubicin and cytarabine in combination with pravastatin for relapsed acute myeloid leukaemia.

Inhibition of cholesterol synthesis and uptake sensitizes acute myeloid leukaemia (AML) blasts to chemotherapy. A Phase 1 study demonstrated the safety of high dose pravastatin given with idarubicin and cytarabine in patients with AML and also demonstrated an encouraging response rate. The Southwestern Oncology Group (SWOG) trial, SWOG S0919, was a Phase 2 trial evaluating the complete remission (CR) rate in a larger number of patients with relapsed AML treated with idarubicin, cytarabine and pravastatin.

A phase I study of decitabine and rapamycin in relapsed/refractory AML.

A phase I study utilizing decitabine (DAC) followed by the mammalian target of rapamycin (mTOR) inhibitor, rapamycin, in patients with relapsed/refractory adult AML was undertaken to assess safety and feasibility. Patients received DAC 20mg/m(2) intravenously daily for 5 days followed by rapamycin from day 6 to day 25 at doses of 2 mg, 4 mg, and 6 mg/day in a standard 3+3 dose escalation design. Twelve patients completed treatment for safety evaluation.

Phase 1 dose-ranging study of ezatiostat hydrochloride in combination with lenalidomide in patients with non-deletion (5q) low to intermediate-1 risk myelodysplastic syndrome (MDS).

Background: Ezatiostat, a glutathione S-transferase P1-1 inhibitor, promotes the maturation of hematopoietic progenitors and induces apoptosis in cancer cells.

Results: Ezatiostat was administered to 19 patients with non-deletion(5q) myelodysplastic syndrome (MDS) at one of two doses (2000 mg or 2500 mg/day) in combination with 10 mg of lenalidomide on days 1-21 of a 28-day cycle. No unexpected toxicities occurred and the incidence and severity of adverse events (AEs) were consistent with that expected for each drug alone.

A phase 2 randomized multicenter study of 2 extended dosing schedules of oral ezatiostat in low to intermediate-1 risk myelodysplastic syndrome.

Background: Ezatiostat is a glutathione analog prodrug glutathione S-transferase P1-1 (GSTP1-1) inhibitor. This study evaluated 2 extended dose schedules of oral ezatiostat in 89 heavily pretreated patients with low to intermediate-1 risk myelodysplastic syndrome (MDS).

Methods: Patients were randomized by 1 stratification factor-baseline cytopenia (anemia only vs anemia with additional cytopenias)-to 1 of 2 extended dosing schedules.

Proteasome inhibition in myelodysplastic syndromes and acute myelogenous leukemia cell lines.

In this work, effects of bortezomib on apoptosis, clonal progenitor growth, cytokine production, and NF-κB expression in patients with MDS with cytopenias requiring transfusion support are examined. Bortezomib increased apoptosis in marrow mononuclear cells but had no effects on CFU-GM, BFU-E, or CFU-L content. No consistent effects on NF-κB activation in vivo were noted.

A phase 2 study of lenalidomide monotherapy in patients with deletion 5q acute myeloid leukemia: Southwest Oncology Group Study S0605.

Older acute myeloid leukemia (AML) patients with a chromosome 5q deletion have poor outcomes with conventional chemotherapy. This phase 2 study explored the safety and efficacy of single-agent lenalidomide in previously untreated older AML patients with del(5q) who declined standard chemotherapy. Patients were treated with lenalidomide 50 mg daily for 28 days as induction therapy and 10 mg daily for 21 days of a 28-day cycle as maintenance until disease progression or unacceptable toxicity.

Sequential cytarabine and alpha-particle immunotherapy with bismuth-213-lintuzumab (HuM195) for acute myeloid leukemia.

Purpose: Lintuzumab (HuM195), a humanized anti-CD33 antibody, targets myeloid leukemia cells and has modest single-agent activity against acute myeloid leukemia (AML). To increase the potency of the antibody without the nonspecific cytotoxicity associated with β-emitters, the α-particle-emitting radionuclide bismuth-213 ((213)Bi) was conjugated to lintuzumab. This phase I/II trial was conducted to determine the maximum tolerated dose (MTD) and antileukemic effects of (213)Bi-lintuzumab, the first targeted α-emitter, after partially cytoreductive chemotherapy.

Phase I study of cladribine, cytarabine (Ara-C), granulocyte colony stimulating factor (G-CSF) (CLAG Regimen) and simultaneous escalating doses of imatinib mesylate (Gleevec) in relapsed/refractory AML.

Receptor activated tyrosine kinases such as c-kit, c-fms and PDGFR are known targets of inhibition by imatinib mesylate (Gleevec) and are expressed on AML blasts. Marrow stromal cells and monocytes express KIT ligand, M-CSF and PDGF and are therefore capable of activating survival pathways in these leukemic cells. Given the synergy in vitro between Ara-C and imatinib mesylate on AML cell growth inhibition, we initiated a Phase I study combining CLAG+imatinib mesylate in AML patients.

Rapid method for detection of mutations in the nucleophosmin gene in acute myeloid leukemia.

Mutations in exon 12 of the nucleophosmin gene (NPM1) that cause the encoded protein to abnormally relocate to the cytoplasm are found at diagnosis in about 50% of karyotypically normal acute myeloid leukemias and are associated with a more favorable outcome. We have devised a PCR-based assay for NPM1 exon 12 mutations using differential melting of an oligo probe labeled with a fluorescent dye. The nucleobase quenching (NBQ) phenomenon was used to detect probe hybridization, and an oligonucleotide containing locked nucleic acid (LNA) nucleotides was used as a PCR clamp to suppress amplification of the normal sequence and enhance the analytical sensitivity of the assay.

Antibody therapy for acute myeloid leukemia.

Due to the high rate of relapse in younger patients and the overall poor outcome in older patients, novel therapies are needed for the treatment of acute myeloid leukemia (AML). Monoclonal antibodies have become an important treatment modality in cancer therapy. Gemtuzumab ozogamicin (GO), an anti-CD33 immunoconjugate, was approved by the US Food and Drug Administration (FDA) for the treatment of elderly patients with relapsed AML who are not candidates for standard chemotherapy.

The promise of targeted {alpha}-particle therapy.

The use of monoclonal antibodies to deliver radioisotopes directly to tumor cells has become a promising strategy to enhance the antitumor effects of native antibodies. Since the alpha- and beta-particles emitted during the decay of radioisotopes differ in significant ways, proper selection of isotope and antibody combinations is crucial to making radioimmunotherapy a standard therapeutic modality. Because of the short pathlength (50-80 microm) and high linear energy transfer ( approximately 100 keV/microm) of alpha-emitting radioisotopes, targeted alpha-particle therapy offers the potential for more specific tumor cell killing with less damage to surrounding normal tissues than beta-emitters.

Antibody-based treatment of acute myeloid leukaemia.

Monoclonal antibodies have become an important treatment modality in cancer therapy. Genetically engineered chimaeric and humanised antibodies have demonstrated activity against a variety of tumours. Whereas the humanised anti-CD33 monoclonal antibody HuM195 has only modest activity against overt acute myeloid leukaemia (AML), it can eliminate minimal residual disease detectable by reverse transcription-polymerase chain reaction in acute promyelocytic leukaemia.