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In recent years, there has been a prodigious expansion of knowledge about cyclic nucleotide phosphodiesterases (PDEs). This isozyme superfamily has now become a major focus of drug discovery efforts owing to its diversity, molecular nature, differential regulation and expression in different cell types, and the range of biological functions. Inhibition of these isozymes can lead to an increase in cAMP and cGMP levels, which can affect a variety of physiological responses. Selective inhibitors for each of the multiple forms of PDE can offer an opportunity for desired therapeutic intervention and would be an extremely useful tool in drug discovery efforts for a medicinal chemist. This review details many key aspects of multiple forms of PDEs and their inhibitors with diversified chemical structures, which can act as leads for synthesis of novel drugs.

Plasmablastic lymphoma (PBL) is a rare and aggressive variant of diffuse large B cell lymphoma. The prognosis of PBL patients is poor. The majority of patients succumb to a fulminant disease course, with most dying in the first year after diagnosis. The small number of HIV-negative PBL cases reported in the literature to date is composed of single case reports and small case series. Consequently, the natural history of the disease in HIV-negative individuals and the optimum treatment are not well characterized. Intensive induction chemotherapy has been associated with marked improved overall survival. However the optimal regimen has not been defined. We describe the third case of PBL of the maxillary sinus which occurred in a 24-year old HIV-negative man. We outline the clinicopathological features and report success using a hyper-CVAD regimen with 6 cycles and consolidation radiation therapy yielding a complete remission of four years.

132 Background: TAPUR is a phase II basket trial evaluating anti-tumor activity of commercially available targeted agents in pts with advanced cancers with genomic alterations. Results in a cohort of CRC pts with ERBB2 overexpression or amplification treated with P+T are reported. Methods: Eligible pts had advanced CRC, no standard treatment (tx) options, measurable disease, ECOG PS 0-2, and adequate organ function. Genomic testing was performed in CLIA-certified, CAP-accredited site selected labs. Pts had ERBB2 overexpression or amplification, or certain ERBB2 mutations. Recommended dosing after initial dosing was P, 420 mg IV over 30-60 mins every 3 weeks (wks) and T, 6 mg/kg over 30-60 mins every 3 wks. Simon two-stage design was used to test a null rate of 15% vs. 35% (power = 0.85; α = 0.10). If ≥2 of 10 pts in stage 1 have disease control (DC) (objective response (OR) or stable disease at 16+ wks per RECIST (SD16+)), 18 more pts enrolled. If ≥7 of 28 pts have DC, the tx is worthy of further study. Secondary endpoints are progression-free survival (PFS), overall survival (OS) and safety. Results: Twenty-eight pts enrolled from November 2016 to September 2018 were evaluable for efficacy and safety. Demographics and outcomes are summarized in Table. All pts had ERBB2 amplification; 1 also had an ERBB2 mutation. 79% of pts had at least 3 prior txs. Four PR and 10 SD16+ were observed for DC and OR rates of 50% (90% CI, 36% to 60%) and 14% (95% CI, 4% to 33%), respectively. Two pts had at least one grade 3 AE or SAE at least possibly related to P+T including anemia, infusion reaction, and left ventricular dysfunction. Conclusions: The combination of P+T showed anti-tumor activity in heavily pre-treated CRC pts with ERBB2 amplification . Additional analyses by RAS mutation status are pending. Further study is warranted to confirm efficacy of P+T in this population. Clinical trial information: NCT02693535. [Table: see text]

Background: Increased incidence of cardiac involvement and pulmonary hypertension (PH) has been reported in patients with chronic myeloproliferative disorders (CMPD). Most studies are small and retrospective except one where majority of the patient had essential thrombocytosis (ET). Method: We conducted a study to assess the incidence of PH in patients with CMPD. Patients were excluded if they had secondary cause of PH. Diagnosis of PH was established if right ventricular systolic pressure (RVSP) by transthoracic echocardiography (TTE) and Doppler study was ≥ 35 mmHg. 27 patients with diagnosis of CMPD established by standard criterion were included in the study. 9 patients had ET, 14 had polycythemia vera (PV) and 3 had chronic myeloid leukemia (CML). Results: Diagnosis of PH was established in 14/27 patients. 2 patients were excluded form analysis because of poor ejection fraction on TTE, 1 with PV and 1 with CML, giving final diagnosis of PH in 12/25 (48%) patients. 9 patients were males and 16 were females. Mean age at diagnosis in the entire cohort was 56.2 years and that with and without PH was 54.5 vs. 57.7 years respectively. Mean duration of follow up was 8.7 years and that with and without PH was 7.8 vs. 9.9 years respectively. 7/9 ET, 5/14 PV AND 0/2 CML patients had PH, mostly of mild to moderate severity. All patients were asymptomatic at the time of their last visit within last 2 months. The results are depicted in the table 1. There was no relation of PH to duration of disease, platelet count and hematocrit at diagnosis or during follow up period for the entire group or specific diagnosis of ET or PV. Because of erratic and variable duration of aspirin use by individual patients, we could not determine its significance. Discussion: The results of our study are similar to the study reported by Garypidou et al with regard to ET. However they had only 2 patients with PV and both of them had no evidence of PH. In our study 5/14 PV (36%) patients had PH, indicating PV patients also have significant risk of having PH. Pathogenesis of PH can be reliably related to CMPD because: Cases of secondary PH were excluded TTE excluded cardiac causes of PH Incidence of primary PH is very low (0.2cases/100,000) and usually occurs in 3rd or 4th decade. Moreover autopsy studies have demonstrated the presence of atypical megakaryocytes and thrombotic material in the lung capillaries of pulmonary hypertension patients and CMPD. Increased level of thrombopoietin also has been demonstrated in pulmonary artery of patients with PH. Thus platelets are implicated in pathogenesis of PH in patients with CMPD. Since PH seems to be common in patients with CMPD, more studies are needed to study the long-term impact of PH on survival in these patients. Impact of therapy including platelet lowering agents and ASA on development and progression of PH also needs to be studied. Table 1 CMPD Total No (%) MeanAge at Dx(yrs) Duration of Ds(yrs) Mean Plt at Dx(k/muL) Mean Plt at fu(k/muL) Mean Hct at Dx(%) Mean Hct at fu(%) Dx-diagnosis, Ds-disease, yrs-years, Plt-platelet, fu-follow up, Hct-hematocrit, PH-pulmonary hypertension, +-present, − absent ET PH + 7/9(77.8) 56.3 7.2 877.7 488.6 41.1 36.7 ET PH − 2/9(22.2) 65.0 8.0 698.0 492.0 45.3 40.0 PV PH + 5/14(35.7) 52.0 10 528.8 320.4 53.9 43.2 PV PH − 9/14(64.3) 58.7 10.6 511.9 316.8 58.9 41.9 CML PH − 2/2 46.5 4.0 620.5 387.5 36.9 36.2

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Oxime and dioxime derivatives of various 16E-arylidenosteroids in the androstene series have been prepared and evaluated at the National Cancer Institute (NCI), Bethesda (USA) for their antineoplastic activity against various tumor cell lines in order to determine the structural requirements for cytotoxic activity. Aldol condensation of dehydroepiandrosterone (DHA) and DHA acetate with various aldehydes followed by treatment with hydroxylamine hydrochloride resulted in the formation of 16E-arylidenosteroid-oxime system. Oximes 15, 16 and compound 20 with a higher degree of oxidation in ring A have been found active in a 60 cell line antitumor prescreen by virtue of their cytotoxic effect against one or more tumor cell line and were further referred for in vivo hollow fiber bioassay. These compounds showed interesting intraperitoneal and subcutaneous scores in the in vivo hollow fiber bioassay and have been referred to the Biological Evaluation Committee for Cancer Drugs for further detailed in vivo testing.