Interim PET-CT-guided therapy in elderly patients with Hodgkin lymphoma-a retrospective national multi-center study.

Hodgkin lymphoma (HL), a disease of mostly young patients, also peaks in the elderly. Despite the profound improvement in the outcome of young patients, in the elderly, 5-year progression-free survival (PFS) rates are under 70%. Interim PET-CT (iPET) is known to be highly predictive for PFS in young HL patients, but it has not been sufficiently validated in the elderly patient population. In this multi-center collaboration, all consecutive elderly patients (age ≥ 60) diagnosed with HL between 1998 and 2016 were retrospectively reviewed. Baseline characteristics, outcome measures, and iPET results, classified according to the Deauville score, were recorded and analyzed. We identified 78 elderly HL patients (median age 69) who underwent iPET. ABVD was the treatment regimen in 52 (67%) patients. Eighty-three percent of patients had iPET scores of 1-3 while 17% had scores of 4-5. Patients with iPET scores of 1-3 had 5-year PFS and OS rates of 72% and 82% compared with 25% and 45%, respectively, in patients with scores of 4-5 (p < 0.001). Our findings show that iPET is highly predictive of outcome in elderly HL patients and provide evidence that iPET-guided therapy in this patient population may be key to achieving superior treatment outcome.

Factors related to the development of acquired von Willebrand syndrome in patients with essential thrombocythemia and polycythemia vera.

OBJECTIVE: We characterized acquired von Willebrand syndrome (AVWS) among essential thrombocythemia (ET) and polycythemia vera (PV) patients. METHODS: A review of patients with ET or PV evaluated for AVWS. RESULTS: Of 116 patients with ET, 64 (55%) developed AVWS; of 57 with PV, 28 (49%) developed AVWS. Median platelet counts of ET and PV patients who developed AVWS were 920×109/L and 679×109/L, respectively (P=0.01). Of patients who developed AVWS, 69.5% had platelet counts below 1000×109/L. Bleeding was more common in patients with AVWS, among both ET and PV patients (P<0.001). VWF:RCo levels and VWF:RCo/VWF:Ag ratio were lower among JAK2 V617F positive- vs. JAK2 V617F negative- ET patients (P=0.02 and P=0.002, respectively); whereas VWF:Ag levels were comparable (P=0.96). ET patients harboring the JAK2 V617F mutation were more likely to develop AVWS than were calreticulin-positive patients (70.3% vs. 45.7%, P=0.02), despite lower platelet counts (median 773 vs. 920×109/L, P=0.05). In multivariable analysis, younger age (P=0.002), platelet count (P<0.001), hemoglobin level (P=0.01) and JAK2 V617F mutation (P=0.01) independently predicted the development of AVWS among ET patients; whereas only platelet count predicted its development among PV patients (P<0.001). CONCLUSION: Among ET and PV patients, AVWS was common and associated with higher bleeding rates and higher platelet count; nonetheless, most AVWS patients had platelet counts under 1000×109/L. Thus, AVWS screening should be included in routine assessment of ET and PV patients. Among ET patients, JAK2 V617F was a main driver for the development of AVWS.

Trends and distribution of oral and pharyngeal lymphoma in Israel.

OBJECTIVES: To describe the distribution and trends of oral and pharyngeal lymphoma cases in Israel. METHODS: Incidence rates were derived from the Israel National Cancer Registry and included all registered data from 1970 to 2006. Oral lymphoma included the tongue, mouth, salivary glands, tonsils, and pharynx. Morphological description was according to WHO classification of lymphoid neoplasms. RESULTS: A total of 670 cases were diagnosed, mean age 59.5 years, half were over 65 years old. Tonsils were the most prevalent site of involvement (36.0%), followed by the pharyngeal region and salivary glands. Over the years, the prevalence of lymphoma in salivary glands increased by 49%, whereas in tonsils lymphoma decreased by 28.6%. The overall 5-year survival rate was 57% with best rates among young people. CONCLUSION: The correlation of survival, type of lymphoma and age, was similar to extra-oral lymphoma. A trend of increased cases in the parotid region, dissimilar to other oral sites, raises a question of possible external factors or an increase in autoimmune diseases. Head and neck clinicians should be aware of different sites, types, and prognoses for the different age groups.

Hypericin as an inactivator of infectious viruses in blood components.

BACKGROUND: Hypericin is a potent virucidal agent with activity against a broad range of enveloped viruses and retroviruses. The effective virucidal activity emanates from a combination of photodynamic and lipophilic properties. Hypericin binds cell membranes (and, by inference, virus membranes) and crosslinks virus capsid proteins. This action results in a loss of infectivity and an inability to retrieve the reverse transcriptase enzymatic activity from the virion. STUDY DESIGN AND METHODS: Since hypericin is devoid of adverse action in most blood components and blood analyses, it is investigated as an additive with potential to inactivate infective viruses in blood components intended for transfusion. RESULTS: Complete inactivation of 10(6) tissue culture-infective doses of human immunodeficiency virus was obtained in whole blood and in diluted packed red cells after illumination with fluorescent light for 1 hour. Loss of viral infectivity to cultured CEM cells has been monitored by use of a detection assay for human immunodeficiency virus p55 in enzyme-linked immunosorbent assay and cytopathic assays. In physiologic media, hypericin interacts with albumin and lipoproteins, retaining the virucidal activity in bound form. The molecule is negatively charged and forms organic and inorganic monobasic salts (ion pairs) in physiologic pH. Various ion pairs differ in virucidal efficacy. CONCLUSION: The apparent transfusibility of hypericin, taken together with the efficacy of the virucidal activity, the broad range of enveloped viruses affected, and the absence of adverse effects on stored red cells, may render hypericin useful for inactivation of infectious viruses in red cells.

Inactivation of the human immunodeficiency virus by hypericin: evidence for photochemical alterations of p24 and a block in uncoating.

Following attachment and entry of human immunodeficiency virus (HIV) into a host cell, the HIV genomic RNA is reverse transcribed to cDNA. This step may be inhibited by hypericin, a compound that induces alterations of the retroviral capsid. Incubation of HIV with hypericin rendered the virus noninfectious. The replication of HIV was blocked early; HIV cDNA could not be detected in cells challenged with hypericin-treated HIV. Hypericin did not inhibit the binding of recombinant gp120 to CD4+ cells, nor did hypericin inhibit syncytium formation. However, reverse transcriptase activity could not be released from hypericin-treated virions. Western blot analysis revealed altered mobility of the HIV major capsid protein (p24) following hypericin treatment. Hypericin-treated recombinant HIV p24 exhibited similar altered mobility. The inactivation of HIV infectivity and the alterations in p24 mobility required hypericin incubations in the presence of visible light. Collectively, these data suggest that photochemical alterations of the HIV capsid may contribute to the hypericin-mediated inactivation of HIV. Such alterations may inhibit the release of RT activity from treated HIV, and prevent uncoating and subsequent reverse transcription of the HIV genome within a target cell.

A method for the quantitation of hypericin, an antiviral agent, in biological fluids by high-performance liquid chromatography.

Hypericin, a polycyclic aromatic dianthroquinone, is a natural plant product with antiviral properties. We report here the development of a methodology for the extraction and quantitation of hypericin from plasma and biological fluids and the adaptation of a sensitive and selective method for detection of the compound by high-performance liquid chromatography. The methodology offers a rapid and specific means of monitoring drug blood levels in clinical and pharmacokinetic studies. The chromatographic procedure utilizes the substantial retentive properties of hypericin on reverse-phase media and detection by the strong visible absorbance maximum at 590 nm. Verification by the fluorescence spectral properties of hypericin in organic media can also be utilized. The assay is linear over a 3 log concentration range and hypericin is consistently recovered from murine, simian, and human plasma. The methodology was applied to assess the pharmacokinetic properties of hypericin in mice receiving a single bolus injection of 350 micrograms. A distribution half-life of 2.0 h and an elimination half-life of 38.5 h were calculated. We also discuss the limitations of direct analysis of hypericin by absorbance or fluorescence measurements.

Studies of the mechanisms of action of the antiretroviral agents hypericin and pseudohypericin.

Administration of the aromatic polycyclic dione compounds hypericin or pseudohypericin to experimental animals provides protection from disease induced by retroviruses that give rise to acute, as well as slowly progressive, diseases. For example, survival from Friend virus-induced leukemia is significantly prolonged by both compounds, with hypericin showing the greater potency. Viremia induced by LP-BM5 murine immunodeficiency virus is markedly suppressed after infrequent dosage of either substance. These compounds affect the retroviral infection and replication cycle at least at two different points: (i) Assembly or processing of intact virions from infected cells was shown to be affected by hypericin. Electron microscopy of hypericin-treated, virus-producing cells revealed the production of particles containing immature or abnormally assembled cores, suggesting the compounds may interfere with processing of gag-encoded precursor polyproteins. The released virions contain no detectable activity of reverse transcriptase. (ii) Hypericin and pseudohypericin also directly inactivate mature and properly assembled retroviruses as determined by assays for reverse transcriptase and infectivity. Accumulating data from our laboratories suggest that these compounds inhibit retroviruses by unconventional mechanisms and that the potential therapeutic value of hypericin and pseudohypericin should be explored in diseases such as AIDS.

Therapeutic agents with dramatic antiretroviral activity and little toxicity at effective doses: aromatic polycyclic diones hypericin and pseudohypericin.

Two aromatic polycyclic diones hypericin and pseudohypericin have potent antiretroviral activity; these substances occur in plants of the Hypericum family. Both compounds are highly effective in preventing viral-induced manifestations that follow infections with a variety of retroviruses in vivo and in vitro. Pseudohypericin and hypericin probably interfere with viral infection and/or spread by direct inactivation of the virus or by preventing virus shedding, budding, or assembly at the cell membrane. These compounds have no apparent activity against the transcription, translation, or transport of viral proteins to the cell membrane and also no direct effect on the polymerase. This property distinguishes their mode of action from that of the major antiretro-virus group of nucleoside analogues. Hypericin and pseudohypericin have low in vitro cytotoxic activity at concentrations sufficient to produce dramatic antiviral effects in murine tissue culture model systems that use radiation leukemia and Friend viruses. Administration of these compounds to mice at the low doses sufficient to prevent retroviral-induced disease appears devoid of undesirable side effects. This lack of toxicity at therapeutic doses extends to humans, as these compounds have been tested in patients as antidepressants with apparent salutary effects. Our observations to date suggest that pseudohypericin and hypericin could become therapeutic tools against retroviral-induced diseases such as acquired immunodeficiency syndrome (AIDS).

Genetic improvement of Papaver bracteatum: heritability and selection response of thebaine and Seed Yields.

The heritability and repeatability of various characters affecting thebaine and seed yields in Papaver bracteatum were estimated from parents and progeny families during two consecutive years of growth. Thebaine and seed yields per plant showed the lowest heritability and therefore low selection response. High selection responses were obtained for thebaine content of the capsules and mean weight per capsule, and are therefore the most appropriate criteria for increasing the thebaine yield per plant or per unit area. Similarly seed yield per capsule is more advantageous as a selection criterion for increasing the yield of seeds.

Immunosuppressive activity of two plant steroidal lactones withaferin A and withanolide E.

Withaferin A and withanolide E, two steroidal lactones of plant origin were demonstrated to have specific immunosuppressive effects on human B and T lymphocytes as well as on mice thymocytes. E rosettes and EAC rosette formation by normal human T and B lymphocytes were inhibited by the two compounds at very low concentrations. The formation of mouse red blood rosettes by chronic lymphatic leukemic cells were only inhibited by withaferin A. The functional activity of normal human T lymphocytes as assessed by a local xenogeneic graft versus host reaction was also affected by these two plant steroidal lactones. These experiments demonstrate a specific action of the compound on antigen recognition as well as proliferative capacity of T lymphocytes as well as B lymphocytes.

Quaternary pilocarpine derivatives as potential acetylcholine antagonists. 2. Alterations in the lactone and imidazole moieties.

In order to investigate the chemical behavior of pilocarpine, as well as the factors which determine its pharmacological activity, systematic and specific structural changes involving the lactone and imidazole moieties have been performed. Series of model compounds with cyclic or open-chain structures and a variety of N-3 bonded chains obtained from previously prepared anticholinergic derivatives of pilocarpine have been synthesized. The changes included N-3 chains of different lengths with an acetylcholine-like structure, the introduction of nucleophilic groups such as ketoxime, hydroxamic, or both at the side chain, or following hydroxylaminolysis of the lactone, respectively. Specific structural alterations could be obtained by reacting with free hydroxylamine under carefully controlled conditions, and the existence of syn and anti isomers was disclosed in certain cases. The new groups in the pilocarpine derivatives influenced their degree of antagonism to acetylcholine. Several compounds displayed some antidotal activity.