Multiple Chemotherapeutic Regimens Research Articles

Genome-Wide CRISPR-Cas9 Screen Identifies Rationally Designed Combination Therapies Relevant for CRLF2-Rearranged Ph-like ALL

Philadelphia chromosome-like acute lymphoblastic leukemia (Ph-like ALL, also known as BCR-ABL1-like ALL) is a disease entity of B-cell ALL that exhibits a gene expression profile, similar to that of Philadelphia chromosome-positive ALL. Ph-like ALL is categorized into two disease subtypes: “ABL-class”- and “CRLF2/JAK pathway”-types, both of which harbor gene alterations that constitutively activate cytokine/growth factor-related signals. Ph-like ALL with the CRLF2 rearrangement exhibits poor clinical outcomes and is the most common subtype of Ph-like ALL. Tyrosine kinase inhibitor (TKI)-based treatment regimens are effective in treating ABL-class type Ph-like ALL; however, no standard regimen has been established for the CRLF2/JAK pathway type. While multiple chemotherapeutic regimens, including Ruxolitinib monotherapy and/or its combination with chemotherapy, are being tested, their efficacy is reportedly limited. Thus, novel approaches are needed to treat CRLF2/JAK pathway type Ph-like ALL, in particular for CRLF2-rearranged (CRLF2-r) ALL.To identify molecules/pathways relevant for CRLF2-r ALL pathogenesis, we performed genome-wide CRISPR-Cas9 dropout screens in the presence or absence of Ruxolitinib using two IgH-CRLF2-r ALL lines (MUTZ5 and KOPN49) that differ in RAS mutational status. To do so, we employed a baboon envelope pseudotyped lentiviral vector system, which, for the first time, enabled highly efficient transduction of human B cell amenable for genome-wide CRSPR/Cas9 screens.While sgRNAs targeting CRLF2, IL7RA or JAK1/2 significantly affected cell fitness in both lines, those targeting STAT5A, STAT5B or STAT3 did not, suggesting that the JAK-STAT axis is largely dispensable for IgH-CRLF2-r ALL cell survival. We show that regulators of RAS signaling are critical for cell fitness and Ruxolitinib sensitivity and that CRKL and FLT3 depletion enhances Ruxolitinib sensitivity in RAS wild-type (WT) cells. Gilteritinib, a pan-tyrosine kinase inhibitor that reduces CRKL activity, effectively killed RAS WT IgH-CRLF2-r ALL cells in vitro and in vivo, either alone or combined with Ruxolitinib. We further show that combining Gilteritinib with Trametinib, a MEK1/2 inhibitor, is an effective means to target IgH-CRLF2-r ALL cells regardless of RAS mutational status.Our study delineates molecules/pathways relevant for CRLF2-r ALL pathogenesis and could suggest rationally designed combination therapies appropriate for disease subtypes. DisclosuresNo relevant conflicts of interest to declare.

Genome-wide CRISPR-Cas9 screen identifies rationally designed combination therapies for CRLF2-rearranged Ph-like ALL

AbstractAcute lymphoblastic leukemia (ALL) harboring the IgH-CRLF2 rearrangement (IgH-CRLF2-r) exhibits poor clinical outcomes and is the most common subtype of Philadelphia chromosome-like acute lymphoblastic leukemia (Ph-like ALL). While multiple chemotherapeutic regimens, including ruxolitinib monotherapy and/or its combination with chemotherapy, are being tested, their efficacy is reportedly limited. To identify molecules/pathways relevant for IgH-CRLF2-r ALL pathogenesis, we performed genome-wide CRISPR-Cas9 dropout screens in the presence or absence of ruxolitinib using 2 IgH-CRLF2-r ALL lines that differ in RAS mutational status. To do so, we employed a baboon envelope pseudotyped lentiviral vector system, which enabled, for the first time, highly efficient transduction of human B cells. While single-guide RNAs (sgRNAs) targeting CRLF2, IL7RA, or JAK1/2 significantly affected cell fitness in both lines, those targeting STAT5A, STAT5B, or STAT3 did not, suggesting that STAT signaling is largely dispensable for IgH-CRLF2-r ALL cell survival. We show that regulators of RAS signaling are critical for cell fitness and ruxolitinib sensitivity and that CRKL depletion enhances ruxolitinib sensitivity in RAS wild-type (WT) cells. Gilteritinib, a pan-tyrosine kinase inhibitor that blocks CRKL phosphorylation, effectively killed RAS WT IgH-CRLF2-r ALL cells in vitro and in vivo, either alone or combined with ruxolitinib. We further show that combining gilteritinib with trametinib, a MEK1/2 inhibitor, is an effective means to target IgH-CRLF2-r ALL cells regardless of RAS mutational status. Our study delineates molecules/pathways relevant for CRLF2-r ALL pathogenesis and could suggest rationally designed combination therapies appropriate for disease subtypes.

Neoadjuvant and Adjuvant Chemotherapeutic Strategy of Colorectal Mixed Adeno-Neuroendocrine Carcinomas.

Mixed adeno-neuroendocrine carcinomas (MANEC) is a rare pathological diagnosis characterized by the presence of both adeno-carcinomatous and neuroendocrine differentiation with each component comprising 30% of the tumor. This literature review is aimed at the extraction of all existing clinical studies and reviews on colorectal MANEC so as to ensure that a suitable chemotherapeutic regimen is chosen to improve survival outcomes and prognosis of the disease. Parallel search strategies were employed to extract past 10 years articles from PubMed, PubMed Central and Google Scholar databases. A total of 30 records consisting of one clinical trial, five retrospective cohort studies, one case control study, one case series, 16 case reports and six review papers were shortlisted. Chemotherapeutic regimens that were administered as an adjuvant and a neoadjuvant therapy were analyzed with their survival outcomes. The overall survival rate of those administered with neoadjuvant and adjuvant therapy can be as high as 57.4% and 69%, respectively. Multiple chemotherapeutic regimens were employed in colorectal MANEC and superiority of one regimen over the other can’t be established. Any drug or combination of drugs that is responsive against either of the MANEC components is found to be effective against the tumor. However, excellent responsiveness has been found with 5-fluorouracil regimens as a neoadjuvant therapy and platinum-based combinations as an adjuvant therapy. XELOX, streptozocin and S1 regimens also prove to be drugs of choice in aggressive and metastasized disease conditions. Our analysis allows for improved chemotherapeutic management of individuals with colorectal MANEC and establishes an increased potential for use of streptozocin therapy in the clinical setting. However, newer drugs like amrubicin require further research prior to describing its efficacy in colorectal MANEC.

Resveratrol protects against cisplatin-induced ovarian and uterine toxicity in female rats by attenuating oxidative stress, inflammation and apoptosis

Cisplatin is an important antineoplastic drug used in multiple chemotherapeutic regimens but unfortunately causes serious toxic effects as ovarian and uterine toxicity. This study aimed to investigate the potential protective effect of resveratrol (RSV) against cisplatin-induced ovarian and uterine toxicity in female rats. Thirty-two female Wistar rats were divided randomly into four groups (n = 8 in each). Control group received oral normal saline for 28 days; RSV group received RSV (10 mg/kg; daily) via oral gavage; CIS group received a single dose of CIS (7 mg/kg; i.p.) on the 21st day; (CIS + RSV) group received both RSV and CIS by the same schedules and doses of RSV and CIS groups, respectively. Results demonstrated a significant decrease in MDA level and a significant increase in both glutathione content and activity of the antioxidant enzymes GPx, SOD, and CAT in the tissues of the ovary and uterus of CIS + RSV group in comparison to that of CIS group (P<0.05), also there are significantly decreased tissue levels of the proinflammatory cytokines and enzymes (NF-κB, IL-1β, IL-6, TNF-α, COX-2, and iNOS), increased estradiol, progesterone, prolactin and decreased FSH serum levels in CIS + RSV group compared to CIS group (P < 0.05). Moreover, there is downregulation of tissues Cleaved Caspase-3, NF-κB and Cox-2 proteins as shown in Western blot analysis, also apoptosis was significantly inhibited, evidenced by downregulation of Bax and upregulation of Bcl-2 proteins, and the ovarian and uterine histological architecture and integrity were maintained in CIS + RSV group compared to CIS group. In conclusion, these findings indicate that RSV has beneficial effects in ameliorating cisplatin-induced oxidative stress, inflammation, and apoptosis in the ovarian and uterine tissues of female rats.

Onconephrology: A New Challenge for the Nephrologist.

Clinical Background: Cancer therapeutics (for both solid and hematological malignancies) have evolved over the last two decades, from traditional chemotherapies to novel treatments. A better supportive care, older patients with comorbidities who receive multiple chemotherapeutic and pharmacological regimens, multiple CT scans with contrast agents, and new therapeutic options are also increasing the number of cancer patients who can develop acute kidney injury (AKI) or chronic kidney disease (CKD). Challenges: Targeted therapies and immunotherapies, which harness the body's own immune system to fight cancer cells have led to improved survival in cancer patients, yet all are associated with many organ toxicities. Renal toxicity is mainly represented by acute tubular-interstitial damage, glomerular lesions, thrombotic microangiopathy, tumor lysis, proteinuria, arterial hypertension, AKI, CKD, and secondary fluid/electrolyte disturbances. On the other hand, it is important to consider how the presence of CKD, AKI, and other renal disorders may affect treatment options for the oncologists and patient's outcome. All these features require a specialized approach. Prevention and Treatment: A new evolving field, namely Onconephrology, has emerged during the last few years, including the broad spectrum of renal disorders that can arise in patients with cancer. Nephrologists have become an indispensable part of the multidisciplinary cancer care teams, but a clear and updated knowledge of solid and hematological malignancies, always new anticancer therapies, and their relationships with kidney function is essential to ensure the highest quality of care. In this chapter, we summarize the principal aspects of this new field of Nephrology.

Colon cancer and immunotherapy-can we go beyond microsatellite instability?

Immune checkpoint blockade (ICB) has changed the landscape of cancer therapy in multiple tumor types since the first agent, Ipilimumab, was first FDA approved for the treatment of metastatic melanoma in 2011. Its role in GI Cancers, particularly in colon cancers, has not been as robust as in other tumor types but select patients with DNA mismatch repair defects, even those who has progressed on multiple standard chemotherapeutic regimens have demonstrated significant, almost unprecedented, responses in this multidrug refractory population. Unfortunately, these cases represent only a small percentage of colon cancer patients with little efficacy in the 95% of metastatic colon cancers who have proficient DNA mismatch repair. Multiple strategies have been, and are currently being, evaluated to determine the potential benefits of this drug class to microsatellite stable (MSS) patients.

A retrospective analysis of risk factors for severity of nosocomial COVID-19 in patients with hematological malignancy

With the global spread of coronavirus disease 2019 (COVID-19), patients with cancer may be at a higher risk of suffering from COVID-19. Although patients with hematological malignancy (HM) are reported to have a higher risk of severe COVID-19 compared with those with solid cancer, the effects of treatment for HM on COVID-19 severity have not been fully elucidated. We retrospectively analyzed the risk factors, including number and timing of chemotherapeutic regimens for HM, for COVID-19 severity in 17 patients with HM, who had developed nosocomial COVID-19 in our department, by dividing them into two groups; a severe group (N=7) and a non-severe group (N=10). The overall mortality rate was 47%, and mortality in the severe group was significantly higher than that in the non-severe group (odds ratio [OR], 18.44; 95% confidence interval [CI], 1.27-1223.17, P=0.02). Univariate analysis identified two or more chemotherapeutic regimens for HM (OR, 17.34; 95%CI, 1.15-1165.33, P=0.03) and a low hemoglobin level (P=0.02) as significant risk factors for COVID-19 severity. However, a history of chemotherapy for HM within 3 months prior to the onset of COVID-19 was not a significant risk factor (P=0.54). A history of multiple chemotherapeutic regimens in patients with HM may be a risk factor for COVID-19 severity, and physicians should be aware of this.

Metastatic extramammary paget disease, a remarkable clinical case and a brief review of a rare disease.

Extramammary Paget Disease (EMPD) is an often-misdiagnosed rare disorder, whose cause remains unknown. Diagnosis is confirmed by skin biopsy. Primary treatment for EMPD is surgery. Recurrence is common in the first two years and prognosis is good if the disease is localized and there is no underlying associated cancer. Patients with invasive and metastatic EMPD are uncommon and exhibit a poor prognosis, even when there is good response to a first chemotherapy line. Multiple chemotherapeutic regimens, with varying levels of success, have been attempted, but standard of care is not established. The central nervous system seems to be a common metastatic site with better survival than visceral metastasis.We report a case of metastatic EMPD that addresses the difficulties associated with the treatment of this rare disease, that has no current guidelines.

Abstract 5863: Identifying the radiosensitizing effects of PARP inhibitor in ovarian cancer

Abstract Ovarian cancer is the seventh-most common cancer with a high mortality rate among women. Radiation therapy (RT) is used in ovarian cancer for local relapse, but doses are limited due to concern for small bowel obstruction in patients who have had multiple surgeries and chemotherapeutic regimens. Therefore, it’s an ideal setting to improve the therapeutic window by combining RT and a radiosensitizer. Poly (ADP-ribose) polymerase-1 (PARP-1) is involved in the recognition of DNA damage and the facilitation of DNA repair by recognizing DNA single-strand breaks (SSB). Inhibition of PARP1, especially in tumors driven by BRCA1 or 2 mutations, has been shown to potentiate the DNA-damaging effects of radiation in vitro and in vivo and to increase tumor vasculature perfusion and oxygenation. Approximately half of ovarian cancers have germline or somatic BRCA gene mutation, epigenetic silencing or other mutations that affect homologous recombination (HR) competency resulting in DNA repair defects, making this tumor particularly susceptible to the radiation-sensitizing effects of PARP inhibitors. Here, we investigated the therapeutic effects of the PARP inhibitor olaparib in preclinical models of ovarian cancer. Basic BRCA1 and PARP1 protein and mRNA levels were characterized in a panel of ovarian cancer cell lines. The radiosensitizing effects of olaparib were tested on both HR-proficient and HR-deficient ovarian cancer cells by evaluating the colony formation, DNA damage, apoptosis, and PARP1 activity. Survival benefit of olaparib was also examined in xenograft models of ovarian cancer. Our results demonstrate that combination of olaparib with IR decreased colony formation, inhibited DNA damage (γH2AX) repair, and induced more apoptosis compared to olaparib or IR alone. In addition, HR-deficient cells were more sensitive to IR than HR-proficient cells in the presence of olaparib. Furthermore, olaparib inhibited PARP1 activity in vivo, significantly decreased tumor growth and increased overall survival when combined with IR in mice bearing subcutaneous xenografts of HR-deficient OVCAR8 cells while producing a relative modest effect on overall survival of mice bearing xenografts of HR-proficient SKOV3 cells. These results provide a preclinical rationale for improved treatment modalities using olaparib as an effective radiosensitizer in ovarian cancer, particularly in tumors with HR-deficiencies. Citation Format: Yue Bi, Ioannis Verginadis, Souvik Dey, linlang Guo, Lilie Lin, Yanfang Zheng, Constantinos Koumenis. Identifying the radiosensitizing effects of PARP inhibitor in ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5863. doi:10.1158/1538-7445.AM2017-5863

PTPS-14THE NEED FOR MULTI-TARGETED THERAPY IN PEDIATRIC BRAIN TUMORS WITH BRAF MUTATION

Emerging evidence confirms dysregulation of BRAF gene inducing oncogenesis of pediatric brain tumors. To-date few reports show short-lived efficacy using BRAF inhibitors in these tumors. This indicates the need to target diverse pathways to have sustained clinical efficacy. We present two cases where a combination of vemurafenib (BRAF inhibitor) with everolimus (mTOR inhibitor) as a part of an IRB approved protocol was used. A 10-year-boy diagnosed with a left parietal pleomorphic xanthoastrocytoma (PXA) demonstrated tumor progression despite radiotherapy and three surgical interventions over two years. The tumor showed BRAF mutation for which he received a combinatorial therapeutic approach using the above two drugs given orally every day on a 28 day cycle. He experienced a partial response after two cycles and continued response after 13 cycles. This therapy has been well-tolerated with only minor (Grade I) skin rash. The child remains clinically stable with a Lansky score of 100. The second case is a 13-year-old female diagnosed at 1 year of age with a right-sided optic pathway glioma. The biopsy was consistent with pilocytic astrocytoma. The tumor progressed through multiple chemotherapeutic regimens, including carboplatin, vincristine, vinblastine, celexocib. Molecular analysis performed at our institution demonstrated the tumor to harbor a BRAF mutation for which she is currently receiving the above therapeutic regimen. She is tolerating the therapy well, with mild mouth sores. Her tumor after four cycles shows ongoing response and stable vision. It is now known that these tumors can induce escape mechanisms conferring therapeutic resistance and short-lived efficacy, undermining single drug BRAF targeted approach. This is the first ongoing study targeting these pathways (RAF/MAPK/ERK) and PI3K/mTOR pathway in pediatric brain tumors with BRAF mutation. Larger prospective larger studies are warranted to overcome therapeutic limitations through optimal combination therapy targeting multiple signaling pathways.

Abstract 4712: Personalized ovarian cancer surveillance and detection of a therapeutic drug target in circulating tumor DNA

Abstract Retrospective studies have demonstrated that nearly 50% of ovarian cancer patients with normal CA125 levels have persistent disease; however, prospectively distinguishing between patients is currently impossible. Here we demonstrate that for one patient, with the first reported FGFR2 fusion transcript in ovarian cancer, circulating tumor DNA (ctDNA) is a more sensitive and specific biomarker than CA125 and it can also inform on a candidate therapeutic. Over a four year period, during which the patient underwent primary debulking surgery and chemotherapy, tumor recurrences and multiple chemotherapeutic regimens, blood samples were longitudinally-collected and stored. Whereas post-surgical CA125 levels were elevated only three times over 28 measurements, the FGFR2 fusion ctDNA biomarker was readily detectable by qtRT-PCR in all of these same blood samples and in the tumor recurrences. Given the persistence of the FGFR2 fusion, we treated tumor cells derived from this patient and other with the FGFR2 inhibitor BGJ398. Only tumor cells derived from this patient were sensitive to FGFR2 inhbitor treatment. Using the same overall approach, ctDNA is demonstrated in other patients and the results compared to CA125. Taken together, we demonstrate that a relatively inexpensive, PCR-based ctDNA surveillance assay can outperform CA125 in identifying occult disease. To our knowledge, this use of a personalized biomarker represents the first example in ovarian cancer demonstrating the presence of continuous occult disease in the face of negative clinical, radiologic and biochemical examination. Moreover, the recent identification of FGFR fusions in other solid cancers suggests a broader application of this strategy beyond ovarian cancer. Citation Format: John A. Martignetti, Olga Camacho-Vanegas, Nolan Priedigkeit, Catalina Camacho-Vanegas, Elena Pereira, Li Lin, Bojan Losic, hardik Shah, Jun Liao, Jian Ma, Pratik Lahiri, Mark Chee, Eric Schadt, Peter Dottino. Personalized ovarian cancer surveillance and detection of a therapeutic drug target in circulating tumor DNA. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4712. doi:10.1158/1538-7445.AM2014-4712

44-Year-Old Man With Exertional Dyspnea, Weight Loss, and Palpitations

44-Year-Old Man With Exertional Dyspnea, Weight Loss, and Palpitations

Personalized Ovarian Cancer Disease Surveillance and Detection of Candidate Therapeutic Drug Target in Circulating Tumor DNA

Retrospective studies have demonstrated that nearly 50% of patients with ovarian cancer with normal cancer antigen 125 (CA125) levels have persistent disease; however, prospectively distinguishing between patients is currently impossible. Here, we demonstrate that for one patient, with the first reported fibroblast growth factor receptor 2 (FGFR2) fusion transcript in ovarian cancer, circulating tumor DNA (ctDNA) is a more sensitive and specific biomarker than CA125, and it can also inform on a candidate therapeutic. For a 4-year period, during which the patient underwent primary debulking surgery and chemotherapy, tumor recurrences, and multiple chemotherapeutic regimens, blood samples were longitudinally collected and stored. Whereas postsurgical CA125 levels were elevated only three times for 28 measurements, the FGFR2 fusion ctDNA biomarker was readily detectable by quantitative real-time reverse transcription-polymerase chain reaction (PCR) in all of these same blood samples and in the tumor recurrences. Given the persistence of the FGFR2 fusion, we treated tumor cells derived from this patient and others with the FGFR2 inhibitor BGJ398. Only tumor cells derived from this patient were sensitive to FGFR2 inhibitor treatment. Using the same methodologic approach, we demonstrate in a second patient with a different fusion that PCR and agarose gel electrophoresis can also be used to identify tumor-specific DNA in the circulation. Taken together, we demonstrate that a relatively inexpensive, PCR-based ctDNA surveillance assay can outperform CA125 in identifying occult disease.

Abstract 4740: Doxorubicin eliminates tumor-induced myeloid-derived suppressor cells and enhances T-helper lymphocyte-based immunotherapy in a murine breast cancer model.

Abstract Myeloid-derived suppressor cells (MDSC) represent a heterogeneous population of cells equipped with the ability to inhibit T lymphocyte-mediated immune responses. A significant increase in the number of MDSC has been reported in the blood, secondary lymphoid organs and tumor beds in tumor-bearing animals and in patients with many types of cancers. MDSC frequency correlates with the disease stage and prognosis. These cells impair CD8+ cytotoxic T lymphocyte (CTL)-mediated anti-tumor immunity by different overlapping mechanisms such as reactive oxygen species or immunosuppressive cytokine production. Importantly, MDSC elimination or inactivation substantially enhances the efficiency of immunotherapy. Multiple studies have lent support to the concept that some anti-neoplastic molecules, besides their conventional direct cytotoxic influence on cancer cells, may also exhibit immunostimulatory effects, thereby promoting anti-tumor immunity. We present results demonstrating that doxorubicin, utilized in multiple chemotherapeutic regimens and known to trigger an immunogenic type of cancer cell death, dramatically reduces the number of tumor-induced MDSC in the murine mammary tumor model 4T1. Elimination of these suppressive cells occurs by an apoptotic process. In addition, residual MDSC isolated from doxorubicin-treated animals are significantly impaired in their immunosuppressive function. Of particular interest, the number of apoptotic CD4+ or CD8+ T lymphocytes is not augmented in mice administered with doxorubicin compared to untreated animals. We further demonstrate that doxorubicin-mediated elimination of MDSC is associated with enhanced T and NK cell activation, proliferation and expression of Perforin and Granzyme B. Lastly, we evaluated a chemoimmunotherapeutic strategy associating doxorubicin with T helper-1 or T helper-17 lymphocytes generated and activated in vitro. Our results indicate that this combination regimen hinders tumor development as evidenced by reduced number of 4T1 metastatic nodules in the lungs of treated animals. This therapeutic effect is associated with an increased cytotoxic activity of CD8+ T lymphocytes in the spleen of the treated mice. These observations thus highlight a new application of doxorubicin as a MDSC depleting agent and further advocate for the implementation of this drug in cancer immunotherapy approaches. Citation Format: Darya Alizadeh, Malika Trad, Emmanuel Katsanis, Nicolas Larmonier. Doxorubicin eliminates tumor-induced myeloid-derived suppressor cells and enhances T-helper lymphocyte-based immunotherapy in a murine breast cancer model. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4740. doi:10.1158/1538-7445.AM2013-4740

Myeloid Neoplasms Secondary to Plasma Cell Myeloma: An Intrinsic Predisposition or Therapy-Related Phenomenon?

We describe 41 cases of myeloid neoplasms (MNs) secondary to plasma cell myeloma (PCM). The types of MN included myelodysplastic syndrome (MDS) in 34 (82.9%), acute myeloid leukemia (AML) in 4 (9.8%), and myeloproliferative neoplasm (MPN) or MDS/MPN in 3 (7.3%) cases. The latency from treatment to diagnosis of MN ranged from 9 to 384 months, with a median of 60 months. Of 37 cases with cytogenetic studies, complex abnormalities were detected in 22 (59.5%), -5(q)/-7(q) in 4 (10.8%), other abnormalities in 8 (21.6%), and normal karyotype in 3 (8.1%) cases. Complex abnormalities and -5(q)/-7(q) correlated directly with multiple chemotherapeutic regimens, particularly with combined melphalan/cyclophosphamide. Moreover, the features of cytogenetic abnormalities in our series were significantly different from those with concomitant PCM/MN who had significantly lower complex abnormalities. The latency, skewed proportion of MDS, and bias toward complex cytogenetic abnormalities/unbalanced aberrations of chromosomes 5/7 suggested an alkylating mutagenic effect on pathogenesis of secondary MN. Kaplan-Meier survival analysis demonstrated a median survival of 19 months, which was better than that for therapy-related (t)-MDS/AML. In contrast to t-MDS, the survival in our patients appeared to depend on subtypes of MDS as seen in de novo diseases.

Germ Cell Tumor Metastasis to Esophageal Mucosa

Purpose: The patient is a 43 yo male with a history of aggressive nonseminomatous germ cell tumor s/p multiple chemotherapeutic regimens as well as 5 episodes of retroperitoneal lymph node dissection for recurrent disease presented to his oncologist's office with a feeling of a mass in his throat. He reported no dyphagia, odynophagia, nausea, or vomiting. On further evaluation, he was found to have a rising alpha-fetoprotein (AFP) from 2 to 16. A PET/CT showed aortocaval and retrocrural FDG avid lymphadenopathy. Therefore, the patient was referred to a cardiothoracic surgeon for further management. However, given concern for esophageal wall invasion, an endoscopic ultrasound was recommended. Endoscopic evaluation showed a medium-sized nodule in the lower third of the esophagus. Ultrasonography revealed a 40x22 mm mass at the GE junction. It was hypoechoic, cystic, but associated with some shadowing as well as through-enhancement. However, no invasion into the gastric or esophageal wall was visualized. In addition, a malignant appearing lymph node was visualized in the pericardial region (level 16) consistent with the CT findings. The nodule did not appear invasive sonographically. Biopsies at that time were suspicious for a poorly differentiated adenocarcinoma that was not clearly consistent with patient's known germ cell tumor. Subsequently, patient underwent repeat endoscopy for band ligator-assisted mucosal resection. Final pathology was consistent with metastatic germ cell tumor using tumor markers AFP, SALL, and OCT 3/4. Germ cell tumors have a high incidence of metastases, especially to retroperitoneal lymph nodes. Infrequently, these tumors are also known to metastasize to the thorax and even mediastinum. However, to the best of our knowledge, this is the first reported case of a mucosal metastasis of a germ cell tumor in the esophagus.

Phase I study of BPM 31510 in advanced solid tumors: Updated analysis of a novel treatment with promising activity.

3015 Background: BPM 31510 is a novel small molecule that targets the metabolic machinery of the cancer microenvironment to reverse the aerobic glycolytic phenotype of cancer cells. Effector downstream signaling results in re-capitulation of BCL-2 mediated apoptosis and disruption in tumor vasculature by modulation of VEGF. (NR Narain et al., Proceedings of AACR Meeting Abstracts 2011). Methods: A standard 3+3 phase I, dose-escalation study design was used in patients with advanced solid tumors refractory to standard treatment. Primary objectives were establishment of the maximum tolerated dose (MTD) and safety/pharmacokinetic (PK) correlates. Secondary objectives included exploratory pharmacodynamics (PD) and preliminary efficacy (RECIST-1.1) of BPM 31510 in sequential cohorts of 3 to 6 pts. Results: At time of submission, 34 patients with advanced cancer who had failed multiple chemotherapeutic regimens had been enrolled in 7 dose cohorts (ranging from 5.6 mg/kg to 78.2 mg/kg). Patients received a median of 2 cycles (1-7). 2 patients have had grade 3 elevation in PT/INR, otherwise there have been no grade 3/4 treatment related toxicities to date. The pharmacokinetics of BPM 31510 are linear and there were no sex differences in the parameters normalized by dose and body surface area. Tmax and Cmax are associated with the end of the infusion. The values for t1/2 ranged from 2.18 to 13.3 hr, with little or no dependence of t1/2 on dose. Objective tumor responses have been noted at the dose of 58.6mg/kg with 1 partial response (myxoid liposarcoma) and 1 minor response (pleomorphic sarcoma). Six patients (19%) have had disease stabilization (&gt; 4 months). Conclusions: Interim data from this phase I study indicate that BPM 31510 is well tolerated with no dose limiting toxicities to date. A partial response and minor response were observed and correlates with dose escalation. Taken together, there is strong rationale for further clinical development of this compound as an anti-cancer agent.

Sorafenib and bevacizumab for recurrent metastatic hepatoblastoma: Stable radiographic disease with decreased AFP

We report the use of sorafenib and bevacizumab in combination for a patient with recurrent metastatic hepatoblastoma (HB). This combination demonstrated activity against our patient's refractory HB that had been extensively treated with multiple prior chemotherapeutic regimens. The patient had stabilization of radiographic disease coupled with an 83% decrease in his alpha-fetoprotein level. Given the response in this setting and the paucity of other available options, consideration could be given to using this combination as therapy in patients with recurrent HB who have failed more traditional agents.

Retreatment with bevacizumab in patients with recurrent ovarian cancer does not increase morbidity and has a favorable disease response

Objective: The Gynecologic Oncology Group (GOG) 218 study showed the use of Bevacizumab (BEV) with front line chemotherapy followed by maintenance BEV increased PFS in women with advanced epithelial ovarian (EOC). Additionally, BEV has demonstrated a significant clinical impact when used for the treatment of recurrent EOC. Although the use of BEV in front line and/or recurrent EOC treatment has been increasing, little data exists regarding the cumulative treatment-related toxicity and response in patients exposed to multiple chemotherapeutic regimens containing BEV.

Long-term remission of an advanced recurrent endometrial cancer in a heavily pretreated patient using a combined regimen with bevacizumab and metronomic cyclophosphamide

The treatment of advanced endometrial cancer remains a challenge and the range of valuable treatments remains limited. Recently, the monoclonal vascular endothelial growth factor--antibody bevacizumab as a single-agent regimen or in combination with different chemotherapeutic approaches has been approved as a therapeutic option for several solid tumors. First, clinical trials evaluating the use of bevacizumab in endometrial cancers have been completed, but the results have not been published yet. A 59-year-old patient with advanced recurrent endometrial cancer presented at our institution suffering from increasing abdominal discomfort. She had been extensively pretreated using radiotherapeutic approaches and multiple chemotherapeutic regimens. The level of cancer antigen 125 (CA 125) was rising and a cystic pelvic mass was detected, consistent with a persistent local tumor relapse. As several cytotoxic treatment attempts had failed, we decided to induce a combined therapy with bevacizumab (intravenously) and metronomic cyclophosphamide (orally) as an individual treatment option. After 6 weeks of treatment, the patient's abdominal complaints had completely disappeared, CA 125 had decreased significantly to nearly baseline levels, and the previously detected cystic pelvic mass could no longer be seen. No significant side effects could be observed besides a mild fatigue. During the following weeks, CA 125 levels continued to decrease, and the patient experienced a long-time remission in fine condition for 10 months before PD. Bevacizumab in combination with metronomic cyclophophamide can be a well-tolerated salvage treatment option for patients with advanced, heavily pretreated recurrent endometrial cancer that exacts further evaluation within clinical trials.