The Equipoise Between the Treatment of Glioblastoma and the Risk of Secondary Acute Myelogenous Leukemia: An Illustrative Case Report.

We present a case report of a 56-year-old woman who was diagnosed with biopsy-proven left thalamic glioblastoma multiforme (GBM). She was treated with standard concurrent chemotherapy and radiation, as well as a 2-year period of adjuvant temozolomide. She relapsed 2 ½ years after starting her initial therapy and was treated with bevacizumab and lomustine, but she relapsed. She was then placed on a phase 1/2 clinical trial that included KHK2455 and mogamulizumab-kpkc individually and in combination for almost 4 years. She had a rapid demise due to the development of a neutropenic pneumonia and treatment-induced acute myeloid leukemia (AML) and elected for hospice care.

The inflammatory response of human pancreatic cancer samples compared to normal controls.

Pancreatic ductal adenocarcinoma (PDAC) is a poor prognosis cancer with an aggressive growth profile that is often diagnosed at late stage and that has few curative or therapeutic options. PDAC growth has been linked to alterations in the pancreas microbiome, which could include the presence of the fungus Malassezia. We used RNA-sequencing to compare 14 matched tumor and normal (tumor adjacent) pancreatic cancer samples and found Malassezia RNA in both the PDAC and normal tissues. Although the presence of Malassezia was not correlated with tumor growth, a set of immune- and inflammatory-related genes were up-regulated in the PDAC compared to the normal samples, suggesting that they are involved in tumor progression. Gene set enrichment analysis suggests that activation of the complement cascade pathway and inflammation could be involved in pro PDAC growth.

Genomic landscape of lymphatic malformations: a case series and response to the PI3Kα inhibitor alpelisib in an N-of-1 clinical trial.

Background: Lymphatic malformations (LMs) often pose treatment challenges due to a large size or a critical location that could lead to disfigurement, and there are no standardized treatment approaches for either refractory or unresectable cases. Methods: We examined the genomic landscape of a patient cohort of LMs (n = 30 cases) that underwent comprehensive genomic profiling using a large-panel next-generation sequencing assay. Immunohistochemical analyses were completed in parallel. Results: These LMs had low mutational burden with hotspot PIK3CA mutations (n = 20) and NRAS (n = 5) mutations being most frequent, and mutually exclusive. All LM cases with Kaposi sarcoma-like (kaposiform) histology had NRAS mutations. One index patient presented with subacute abdominal pain and was diagnosed with a large retroperitoneal LM harboring a somatic PIK3CA gain-of-function mutation (H1047R). The patient achieved a rapid and durable radiologic complete response, as defined in RECIST1.1, to the PI3Kα inhibitor alpelisib within the context of a personalized N-of-1 clinical trial (NCT03941782). In translational correlative studies, canonical PI3Kα pathway activation was confirmed by immunohistochemistry and human LM-derived lymphatic endothelial cells carrying an allele with an activating mutation at the same locus were sensitive to alpelisib treatment in vitro, which was demonstrated by a concentration-dependent drop in measurable impedance, an assessment of cell status. Conclusions: Our findings establish that LM patients with conventional or kaposiform histology have distinct, yet targetable, driver mutations. Funding: R.P. and W.A. are supported by awards from the Levy-Longenbaugh Fund. S.G. is supported by awards from the Hugs for Brady Foundation. This work has been funded in part by the NCI Cancer Center Support Grants (CCSG; P30) to the University of Arizona Cancer Center (CA023074), the University of New Mexico Comprehensive Cancer Center (CA118100), and the Rutgers Cancer Institute of New Jersey (CA072720). B.K.M. was supported by National Science Foundation via Graduate Research Fellowship DGE-1143953. Clinical trial number: NCT03941782.

Tumor MET expression may not predict the risk of venous thromboembolism in cancer patients.

Venous thromboembolism (VTE) occurs at an increased incidence in cancer patients. A cancer-related hypercoagulable state has been considered to play role in this phenomenon. Preclinical data suggest an association between tumor expression of MET proto-oncogene (MET) and a hypercoagulable state, resulting in VTE. We investigated this association in this retrospective study. Thirty-five cancer patients with documented VTE and no relevant predisposing factors were compared with 35 matched cancer patients without VTE who served as controls. Pathology specimens of all patients and controls were stained by immunohistochemistry (IHC) for MET protein. Intensity of reactivity to the MET antibody was read as 0 (negative), 1+ (equivocal), and 2+ (positive). The pathologists were blinded to the patient VTE status. The MET reactivity in tissue sections were compared between the two cohorts. No significant difference was observed between the two groups for MET expression. This study's findings indicate no association between the reactivity for MET protein as measured through an immunohistochemical technique, and the incidence of VTE in cancer patients.

Metastatic Pancreatic Cancer with BRAF and P53 Mutations: Case Report of Therapeutic Response to Doublet Targeted Therapy.

We report on the clinical history of a 49-year-old female with metastatic pancreatic cancer. She was initially treated with standard chemotherapy as per current guidelines. She was found to have both a BRAF and P53 mutation, and received dabrafenib and trametinib with deep responses, both radiographically and biochemically (CA19-9). Her response has been more clinically relevant than responses in previous case reports of patients with BRAF-positive pancreatic cancer treated with targeted therapy. To the best of our knowledge, this is the first case report showing a dramatic therapeutic response to combination therapy with dabrafenib and trametinib in metastatic pancreatic cancer.

First-Line Nivolumab Plus Ipilimumab in Advanced Non-Small-Cell Lung Cancer (CheckMate 568): Outcomes by Programmed Death Ligand 1 and Tumor Mutational Burden as Biomarkers.

PURPOSE: CheckMate 568 is an open-label phase II trial that evaluated the efficacy and safety of nivolumab plus low-dose ipilimumab as first-line treatment of advanced/metastatic non-small-cell lung cancer (NSCLC). We assessed the association of efficacy with programmed death ligand 1 (PD-L1) expression and tumor mutational burden (TMB). PATIENTS AND METHODS: Two hundred eighty-eight patients with previously untreated, recurrent stage IIIB/IV NSCLC received nivolumab 3 mg/kg every 2 weeks plus ipilimumab 1 mg/kg every 6 weeks. The primary end point was objective response rate (ORR) in patients with 1% or more and less than 1% tumor PD-L1 expression. Efficacy on the basis of TMB (FoundationOne CDx assay) was a secondary end point. RESULTS: Of treated patients with tumor available for testing, 252 patients (88%) of 288 were evaluable for PD-L1 expression and 98 patients (82%) of 120 for TMB. ORR was 30% overall and 41% and 15% in patients with 1% or greater and less than 1% tumor PD-L1 expression, respectively. ORR increased with higher TMB, plateauing at 10 or more mutations/megabase (mut/Mb). Regardless of PD-L1 expression, ORRs were higher in patients with TMB of 10 or more mut/Mb (n = 48: PD-L1, ≥ 1%, 48%; PD-L1, < 1%, 47%) versus TMB of fewer than 10 mut/Mb (n = 50: PD-L1, ≥ 1%, 18%; PD-L1, < 1%, 5%), and progression-free survival was longer in patients with TMB of 10 or more mut/Mb versus TMB of fewer than 10 mut/Mb (median, 7.1 v 2.6 months). Grade 3 to 4 treatment-related adverse events occurred in 29% of patients. CONCLUSION: Nivolumab plus low-dose ipilimumab was effective and tolerable as a first-line treatment of advanced/metastatic NSCLC. TMB of 10 or more mut/Mb was associated with improved response and prolonged progression-free survival in both tumor PD-L1 expression 1% or greater and less than 1% subgroups and was thus identified as a potentially relevant cutoff in the assessment of TMB as a biomarker for first-line nivolumab plus ipilimumab.

Phase II studies of antiangiogenic four drug regimens for the treatment of advanced renal cell carcinoma: FUNIL-retinoid and the FUNIL-thalidomide protocols.

BACKGROUND AND PURPOSE: The objective of these studies was to determine the activity of two alternative 4- drug combinations using cis-retinoic acid or thalidomide administered with a previously developed combination of 5 fluorouracil, interferon-alpha, and interleukin 2 (FUNIL), for patients with metastatic renal cell carcinoma (RRC). METHODS: Patients enrolled in these studies had progressive measurable metastatic renal cell cancer and signed an informed consent. Treatments included continuous infusions of 5-fluorouracil, interferon-alpha, 6 MIU/m2 given subcutaneous on days 1, 3, and 5 every week, interleukin-2 6 MIU/m2/day given by continuous infusion days 2 to 5 every week, and either cis-retinoic acid at a dose of 1 mg/kg/day orally in two divided doses or thalidomide given at an initial dose of 200 mg per day. Each cycle consisted of 6 or 4 weeks of the combinations, respectively, followed by a 2-week rest. Patients were evaluated for response prior to each successive cycle. A 2-step mini-max statistical design was used. RESULTS: In the cis-retinoid study, 20 patients were enrolled. One patient was ineligible. There were 1 complete and 2 partial responses (one confirmed and one unconfirmed) (15.8%), 1 stable disease, and 15 disease progression. In the thalidomide combination study, 20 patients were enrolled, but only 19 are assessable. One patient progressed early and was never treated. There were 2 partial responses (10.5%), 4 stable disease, and 13 progressive disease. CONCLUSION: Neither the FUNIL-cis-retinoid nor the FUNIL-thalidomide regimens met their primary objective first step endpoint of 3 confirmed responses. Both regimens had significant adverse effects and neither is considered promising for further study.

Transient monoclonal gammopathy induced by Candida fungemia.

A 41-year-old woman was admitted for Candida fungemia. On hospital day 4, a routine complete blood count and peripheral smear showed circulating plasma cells. Initial workup showed an M-component on serum protein electrophoresis with 6% λ-predominate plasma cells by flow cytometry. The patient was treated with intravenous antifungal therapy. Her 6-month follow-up laboratory evaluation revealed resolution of the M-component and only rare polyclonal plasma cells in peripheral blood by flow cytometry. This case illustrates that transient monoclonal gammopathy can be induced by fungal infection. It is important to exclude a plasma cell neoplasm or a B-cell lymphoma and to follow the patient until resolution of abnormal findings.

Amplification patterns of three genomic regions predict distant recurrence in breast carcinoma.

Currently used clinical and histopathological parameters imprecisely define the risk of distant recurrence in breast cancer, underscoring the need for more informative prognostic markers. In the present fluorescence in situ hybridization study of archived surgical specimens, we derived an algorithm for computing a prognostic index (PI) from DNA copy numbers of three genomic regions (CYP24, PDCD6IP, and BIRC5) for estrogen/progesterone receptor-positive (ER/PR+) cancers and a distinct PI (based on NR1D1, SMARCE1, and BIRC5) for estrogen/progesterone receptor-negative (ER/PR-) cancers. Among independent test cases stratified by PI, recurrence rates were significantly higher among high-risk patients than low-risk patients for both ER/PR+ (odds ratio = 9.52, 95% confidence interval >2.12, P = 0.0024) and ER/PR- (odds ratio = 12.3, 95% confidence interval >1.45, P = 0.0188) cancers. Among the entire population, recurrences were significantly more prevalent for cases with PI above the medians for both ER/PR+ (Fisher's exact, P = 1.19 x 10(-5)) and ER/PR- (P = 0.0025) patients and for the node-negative subsets (ER/PR+ node-negative, P = 0.042 and ER/PR- node-negative, P = 0.039). In conclusion, these markers perform well in comparison with other criteria for recurrence risk assessment and can be used with routinely formalin-fixed, paraffin-embedded surgical specimens.

Antioxidants Abrogate Alpha-Tocopherylquinone-Mediated Down-Regulation of the Androgen Receptor in Androgen-Responsive Prostate Cancer Cells.

Tocopherylquinone (TQ), the oxidation product of alpha-tocopherol (AT), is a bioactive molecule with distinct properties from AT. In this study, AT and TQ are investigated for their comparative effects on growth and androgenic activity in prostate cancer cells. TQ potently inhibited the growth of androgen-responsive prostate cancer cell lines (e.g., LAPC4 and LNCaP cells), whereas the growth of androgen-independent prostate cancer cells (e.g., DU145 cells) was not affected by TQ. Due to the growth inhibitory effects induced by TQ on androgen-responsive cells, the anti-androgenic properties of TQ were examined. TQ inhibited the androgen-induced activation of an androgen-responsive reporter and inhibited the release of prostate specific antigen from LNCaP cells. TQ pretreatment was also found to inhibit AR activation as measured using the Multifunctional Androgen Receptor Screening assay. Furthermore, TQ decreased androgen-responsive gene expression, including TM4SF1, KLK2, and PSA over 5-fold, whereas AT did not affect the expression of androgen-responsive genes. Of importance, the antiandrogenic effects of TQ on prostate cancer cells were found to result from androgen receptor protein down-regulation produced by TQ that was not observed with AT treatment. Moreover, none of the androgenic endpoints assessed were affected by AT. The down-regulation of androgen receptor protein by TQ was abrogated by co-treatment with antioxidants. Overall, the biological actions of TQ were found to be distinct from AT, where TQ was found to be a potent inhibitor of cell growth and androgenic activity in androgen-responsive prostate cancer cells.

Alternative administration of camptothecin analogues.

In order to improve the therapeutic index of camptothecin (CPT) analogues, alternative administration of CPT analogues is being evaluated. Topotecan, irinotecan, rubitecan, lurtotecan and 9-aminocamptothecin have been administered orally with response rates equivalent to that seen after intravenous administration, where applicable. Oral availability and administration of some of the newer CPT analogues, including diflomotecan (BN80915) and grimatecan (ST1481), have also shown promising results. Aerosolisation of liposomal 9-nitrocamptothecin has been studied in patients with advanced malignancies involving the lung, demonstrating systemic antitumour activity. Intrathecal administration of topotecan has been studied in children with refractory neoplastic meningitis. It is well tolerated and associated with some antitumour activity. Intraperitoneal administration of topotecan as consolidation therapy in patients with ovarian cancer has shown promising results. Transdermal administration of rubitecan has been studied in mice. So far, no CPT has been approved for an alternative route of administration.

Octreotide scans are positive in a subset of patients with hepatocellular carcinoma.

PURPOSE: In vitro data suggest that a proportion of hepatocellular carcinomas express the somatostatin receptor. However, in vivo data are lacking. There has been little reported use of octreotide scans in hepatocellular carcinomas. This study was performed to determine the percentage of positive results of octreotide scanning in patients with hepatocellular carcinoma. MATERIALS AND METHODS: In-111 octreotide scans were performed in the standard manner in eight patients with unresectable hepatocellular carcinoma. Computer fusion imaging of the nuclear medicine and computed tomographic scans was performed in selected patients. RESULTS: Five of eight (63%) patients tested had hepatocellular carcinomas that displayed focal tracer uptake. CONCLUSIONS: This is the first report of positive uptake of octreotide scans in patients with hepatocellular carcinoma. These findings may have implications for the treatment of hepatocellular carcinoma with octreotide. Furthermore, these results may broaden the differential diagnosis in patients with positive results of octreotide scanning.

Sorafenib-Induced Grade Four Hepatotoxicity in a Patient with Recurrent Gastrointestinal Stromal Tumor (GIST): A Case Report and Review of Literature.

Gastrointestinal stromal tumor is a rare mesenchymal tumor. Sorafenib is an effective medication in these tumors based on two phase II clinical trials and a retrospective analysis. We report a rare case of a 57-year-old male with acute hepatotoxicity from sorafenib. He was treated conservatively with IV fluids and prednisolone. Liver function tests improved over 2 months. We conclude that sorafenib could cause life-threatening hepatotoxicity and patients taking sorafenib need to be closely monitored.

Disease-specific survival for patients with multiple myeloma: significant improvements over time in all age groups.

This study analyzed the survival of patients with multiple myeloma. Surveillance, Epidemiology, and End Results (SEER) and Centers for Disease Control and Prevention (CDC) databases were queried to calculate myeloma cause-specific survival curves by the Kaplan and Meier product-limit method. The Cox proportional hazards model was used to assess univariate and multivariate predictors of myeloma cause-specific survival. The outcome of interest was death due to myeloma. Results from a Cox proportional hazards model restricted to age and time period at diagnosis demonstrated that the magnitude of improvement in survival by time period varied by age at diagnosis. Among patients under 60 years at diagnosis, hazard ratios for myeloma cause-specific death decreased by more 50% from the first interval of observation to the last. Hazard ratios decreased during the study period by 39% among patients 60-69 years of age and by 27% among patients who were 70 years of age and older. Survival is improving in patients with myeloma of all ages.

A Phase I Protocol of Hydralazine and Valproic Acid in Advanced, Previously Treated Solid Cancers.

Smokers experience aberrant gene promoter methylation in their bronchial cells, which may predispose to the development of neoplasia. Hydralazine is a DNA demethylating agent, and valproic acid is a histone deacetylase inhibitor, and both have modest but synergistic anticancer activity in vitro. We conducted a phase I trial combining valproic acid and hydralazine to determine the maximally tolerated dose (MTD) of hydralazine in combination with a therapeutic dose of valproic acid in patients with advanced, unresectable, and previously treated solid cancers. Twenty females and nine males were enrolled, with a median age of 57 years and a median ECOG performance status of 0. Grade 1 lymphopenia and fatigue were the most common adverse effects. Three subjects withdrew for treatment-related toxicities occurring after the DLT observation period, including testicular edema, rash, and an increase in serum lipase accompanied by hyponatremia in one subject each. A true MTD of hydralazine in combination with therapeutic doses of valproic acid was not reached in this trial, and the planned upper limit of hydralazine investigated in this combination was 400 mg/day without grade 3 or 4 toxicities. A median number of two treatment cycles were delivered. One partial response by Response Evaluation Criteria In Solid Tumors criteria was observed, and five subjects experienced stable disease for 3 to 6 months. The combination of hydralazine and valproic acid is simple, nontoxic, and might be appropriate for chemoprevention or combination with other cancer treatments. This trial supports further investigation of epigenetic modification as a new therapeutic strategy.