Sio, Terence T.

Abstract Background Most oncology therapeutics have limited distribution into the brain, and developing strategies to overcome this limitation would be clinically impactful. While therapeutic radiation is often cited as a strategy to accomplish this, there are no published studies demonstrating the effect of radiation on drug distribution into the brain or brain tumors. Methods Mice were treated with brain radiation (6 Gy × 5, 4 Gy × 10; 40 Gy × 1) and dosed with drugs (levetiracetam, cefazolin, nedisertib, brigimadlin, apitolisib, or GNE-317) at times ranging from just prior to months after radiation. Plasma and tissue drug concentrations were measured by LC-MS/MS. Results Radiation did not significantly enhance drug delivery into brain tissue for levetiracetam, cefazolin, GNE-317, apitolisib, or nedisertib at any time post-radiation. Even a single, supra-therapeutic dose of radiation (40 Gy) did not significantly affect brain distribution of GNE-317 or apitolisib (P ≥ .07) from 16 to 160 hours post-radiation. For brigimadlin, radiation (6 Gy × 5) was associated with a modest but significant increase in drug accumulation only at 72 hours post-radiation (brain-to-plasma ratio 0.014 ± 0.006 vs. 0.025 ± 0.010, respectively; P = .04), but not at any other timepoint (24 hours, 15, 28, 94, 133, 183 days; P > .05). Similarly, radiation (6 Gy × 5) of orthotopic tumors did not increase levels of brigimadlin in GBM10 or GBM108 or nedisertib in GBM108 (P > .05). Conclusions Radiation had no meaningful impact on drug delivery into brain or brain tumors for the drugs tested.

Few cases of B-cell acute lymphoblastic leukemia (B-ALL)-eosinophilia (ALL-eo) association have been reported. The lack or absence of blasts in the peripheral blood smear (PBS) along with urticarial rash, fever, arthralgia, myalgia, sweating, and dyspnea are common features of this condition. Herein, we report a 16-year-old male patient admitted to the emergency department with urticaria and generalized itching. PBS was examined, and eosinophils (90%) were seen in different fields. However, blast cells were not seen in PBS. In a bone marrow examination, terminal deoxynucleotidyl transferase-positive and CD20-positive lymphoid blasts were reported along with eosinophilia. Eventually, the B-ALL diagnosis was confirmed for the patient, and he was started on the Berlin-Frankfurt-Münster chemotherapy regimen. The association of B-ALL with hypereosinophilia is a rare condition. We hope this case report and literature review can help clinicians to manage this rare condition properly.

Few cases of eosinophilia associated with B cell acute lymphoblastic leukemia (B-ALL) have been reported. This study reported a 16-year-old male patient diagnosed with B-ALL and hypereosinophilia. He was admitted to the emergency department (ED) with urticaria and generalized itching. On initial examination, the skin was wholly erythematous, and urticarial lesions were scattered throughout the body. Peripheral blood smear (PBS) was examined, and eosinophils were seen in different fields. However, blast cells were not seen in the PBS. In bone marrow examination, terminal deoxynucleotidyl transferase (TdT)-positive and CD20-positive lymphoid blasts were reported along with eosinophilia. In immunohistochemical (IHC) staining, results were within normal limits for the fibroblast growth factor receptor 1 (FGFR1), platelet-derived growth factor receptor alpha (PDGFRα), and platelet-derived growth factor receptor beta (PDGFRβ) genes expressions. Moreover, no breakpoint cluster region (BCR)/Abelson murine leukemia 1 (ABL1) mRNA transcripts and no Janus kinase 2 (JAK2) V617F mutation were detected. Eventually, the B-ALL diagnosis was confirmed for the patient, and he was started on the Berlin-Frankfurt-Münster (BFM) chemotherapy regimen. The patient was transferred to another facility and is continuing his treatment there.

Introduction: Thoracic external beam radiation therapy (XRT) for cancer is associated with a multitude of long-term cardiotoxic side effects. Previous studies have suggested worse outcomes in XRT-treated cancer survivors who undergo revascularization with CABG, but sample sizes have been small. In addition, XRT after CABG is thought to portend decreased patency and survival. We aimed to examine outcomes after CABG in patients with XRT compared with to those without XRT. Methods: We identified all patients who were treated with both CABG (between 1999 and 2013) and curative thoracic XRT for cancer (between 1971 and 2013) (>30 Gray). Baseline clinical characteristics and comorbidities at time of CABG, as well as long-term outcomes after CABG and XRT were compared with propensity matched control cohorts. Results: A total of 38 patients underwent CABG following XRT [Group 1] (mean age 67.9, 63% female) and 43 patients underwent XRT after CABG [Group 2] (mean age 69.3, 63% female). Compared with propensity-matched controls (Group 1: n=141; Group 2: n=167), baseline clinical and demographic characteristics between cases and controls were similar in both groups, except a lower incidence of triple vessel disease in XRT cases in Group 2 (64 vs 80%, p=0.02). For Group 1, there was no significant difference in all-cause survival in long-term follow-up after CABG (Fig. 1, p=0.72). Meanwhile, Group 2 cases had significantly higher all-cause mortality following XRT (Fig. 2, p<0.001). Conclusions: Patients previously treated with thoracic XRT who subsequently undergo CABG for coronary artery disease have a similar overall mortality rate compared to patients without prior XRT. This suggests that CABG is an effective method of revascularization in these patients. The higher mortality rates in CABG patients who subsequently develop disease requiring thoracic XRT is likely due to oncologic rather than cardiovascular causes, but more data are necessary to evaluate this finding.

Background and aim Thoracic radiation therapy (XRT) for cancer is associated with the development of significant coronary artery disease that may require coronary artery bypass grafting surgery (CABG). Contemporary acute surgical outcomes and long-term postoperative survival of patients with prior XRT have not been well characterised. Methods This was a retrospective, single-centre study of patients with a history of thoracic XRT who required CABG and who were propensity matched against 141 controls who underwent CABG over the same time period. The objectives were to assess early CABG outcomes and long-term survival in patients with prior XRT. Results Thirty-eight patients with a history of previous thoracic XRT underwent CABG from 1994 to 2013. The median time from XRT exposure to surgery was 7.9 years (IQR: 2.5–18.4 years). Perioperative adverse events were similar in the XRT group and controls; however, there was a trends lower utilisation of internal mammary artery (IMA) grafts in the XRT group (89%vs98%, P=0.13). After a median postoperative follow-up of 5.4 years (IQR 0.9–9.4 years), no difference in long-term all-cause mortality was observed. Conclusion Patients with prior thoracic XRT who undergo CABG have similar long-term all-cause mortality compared with controls. Isolated CABG after thoracic XRT is not associated with higher perioperative complications, but IMA graft use may be limited by prior XRT.

Objectives: To retrospectively evaluate outcomes among cancer survivors previously treated with thoracic radiotherapy (RT) who later underwent percutaneous coronary intervention (PCI). Methods: From 1998 to 2012, 76 patients first received curative RT (>30 Gy, except for Hodgkin lymphoma patients) involving the heart and lungs followed by PCI. Heart and lung–specific dosimetric parameters were correlated with overall survival (OS) and cardiac-specific survival by Cox variate methods. Results: The mean interval between cancer diagnosis and PCI was 3.7 years (range, 0.1 to 12.6 y). Median follow-up since cancer diagnosis was 5.5 years. At analysis, 46 patients (61%) were alive, 5 (7%) died of cardiac causes, and 9 (12%) of cancer. Higher maximum RT heart dose was related to poorer OS since PCI (P=0.009). Angiotensin-converting enzyme inhibitors or angiotensin receptor blockers (P=0.005) and higher mean heart dose (P<0.001) were related to poorer OS since cancer diagnosis. β-Blockers, higher mean heart dose (hazard ratio [HR]=1.49, P<0.001), and percentage of targeted volume or organ receiving ≥40 Gy for heart doses (HR=1.32, P<0.001) were associated with poorer non–cancer-specific survival since cancer diagnosis. Diabetes (HR=3.84, P=0.008) and increased percentage of targeted volume or organ receiving ≥45 Gy (HR=1.01 per additional 100 cm3 irradiated, P=0.01) for the heart decreased major adverse cardiac event–free survival. Conclusions: Prior heart and lung–directed RT had volume-dependent and dose-dependent adverse effects on long-term cardiac outcomes for patients subsequently treated with PCI. RT planning that minimizes heart and lung irradiation doses should be encouraged.

Abstract Background: Pseudomyxoma peritonei (PMP) is a rare abdominal malignancy. We hypothesized that next generation exomic sequencing would identify recurrent mutations that may have prognostic or therapeutic implications. Methods and Materials: Ten patients were selected based on availability of tissue and adequate follow-up. Mutations were tested for in 236 cancer-related genes in formalin-fixed paraffin-embedded (FFPE) slides using next-generation exomic sequencing (Foundation Medicine, Cambridge, MA). Immunohistochemistry (IHC) was used to detect MCL1 expression. Results: Detectable mutations were found in 80% of patients. Seventy percent harbored a KRAS mutation, most commonly involving codon 12 (G12D in four cases, and one case each of G12V, G12A and A59T). Four GNAS mutations (R201H/R201C substitutions) were also detected. MCL1 and JUN were concurrently amplified in three patients. One patient with MCL1 and JUN amplification had concurrent amplification of MYC and NFKBIA. ZNF703 was amplified in one patient. Patients with MCL1 amplification were also found to express MCL1 by IHC, but MCL1 expression was also detected in some patients without amplification. Conclusions: We are first to report MCL1 and JUN co-amplification in PMP. Expression of MCL1 may not be completely dependent upon amplification. The prognostic and therapeutic implications of these recurrent mutational events are the subject of ongoing investigation. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):A135. Citation Format: Aaron S. Mansfield, Terence Sio, Travis E. Grotz, Rondell P. Graham, Julian R. Molina, Florencia G. Que, Robert C. Miller. Concurrent MCL1 and JUN amplification in pseudomyxoma peritonei. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr A135.

Objectives: To evaluate outcomes among cancer patients with preexisting coronary artery disease and cardiac stenting who subsequently underwent thoracic radiotherapy (RT). Methods: From 1998 to 2012, 147 patients received percutaneous coronary intervention (PCI) and then curative external beam RT (>30 Gy, except for Hodgkin lymphoma patients) involving the heart and the lungs. Heart-specific and lung-specific dosimetric parameters were correlated to overall survival (OS) and cardiac-specific survival by Cox variate methods. Results: The mean interval between PCI and cancer diagnosis was 1.8 years (range, 0.1 to 14.2 y). Hypertension was present in 105 patients (71%), and hyperlipidemia in 82 (56%). At the time of analysis, 69 patients (47%) were alive, 3 (2%) died of cardiac causes, and 53 (36%) died of cancer. In multivariate analyses, OS since PCI was related to cancer type (P=0.004). Decreased OS since cancer diagnosis was related to older age (P<0.001) and increased percentage of targeted volume or organ receiving 20 Gy or more for lung (P<0.001), even after controlling for sex, cancer type, and stage. However, for non–cancer-specific survival and major adverse cardiac event-free survival, older age and underlying cardiopulmonary comorbidities dominated (rather than heart and lung dosimetric parameters) in predicting worse outcome for these patients with preexisting coronary artery disease who later underwent RT. Conclusions: Cancer type, older age, and preexisting cardiopulmonary comorbidities and risk factors most significantly predicted clinical outcome and survival for these patients with existing coronary stents who subsequently received thoracic RT. Dosimetric detrimental effects were not significant in our study.

Angiosarcoma of the seminal vesicle is an extremely rare malignancy, with few published case reports in the literature. We present a case of primary angiosarcoma of the seminal vesicle in a 45-year-old male who was treated with multimodality therapy, consisting of neoadjuvant chemotherapy and chemoradiation followed by surgical resection and intraoperative radiation therapy. He has been free of cancer recurrence for more than six years after completion of therapy. To our knowledge, this represents the longest reported survival of a patient with this rare tumor, and one of the few cases reported using a multimodality therapy approach.

AbstractThe American Cancer Society estimates that 73 510 new cases of bladder cancer will be diagnosed and 15 000 deaths will result this year. The paper summarizes the clinical evidence for the use of platinum‐based, non‐platinum‐based and new targeted biological agents, while reporting the future directions in the treatment of metastatic bladder cancer. For cisplatin‐base regimens, the combination of methotrexate, vinblastine, doxorubicin and cisplatin (M‐VAC) has been the mainstream treatment for both advanced and metastatic bladder cancers. It showed significant improvement in the complete response rate and overall survival time in comparison with single‐agent cisplatin. For cisplatin‐ineligible patients, namely patients with renal impairment, symptomatic cardiac disease and poor performance status, alternative therapies consisting of paclitaxel, gemcitabine and carboplatin were shown to be of benefit. Pemetrexed and vinflunine have also shown effectiveness, with small but demonstrable overall survival benefits. Gemcitabine‐based doublet therapies (combined with paclitaxel, docetaxel, irinotecan, oxaliplatin or epirubicin) have all been shown to be effective and well‐tolerated. Several new targeted therapies, such as gefetinib, sorafenib and lapatinib, have received attention in recent years; however, their effectiveness as single agents in a relapse setting have not been optimal and more studies are warranted.