Dose-escalated SBRT for borderline and locally advanced pancreatic cancer. Feasibility, safety and preliminary clinical results of a multicenter study.

Background: Pancreatic Stereotactic Body Radiotherapy (SBRT) allows for the administration of a higher biologically effective doses (BED), that would be essential to achieve durable tumor control. Escalating treatment doses need a very accurate tumor positioning and motion control during radiotherapy.The aim of this study to assess the feasibility and safety of a Simultaneous Integrated Boost (SIB) dose-escalated protocol at 45 Gy, 50 Gy and 55 Gy in 5 consecutive daily fractions, in Border Line Resectable Pancreatic Cancer (BRCP) /Locally Advanced Pancreatic Cancer (LAPC) by means of a standard LINAC platform. Methods: Patients diagnosed of BRPC/LAPC, candidates for neoadjuvant chemotherapy and SBRT, in four university hospitals of the province of Las Palmas (Canary Islands, Spain) were included in this prospective study. Radiotherapy was administered using standard technology (LINACS) with advanced positioning (Lipiodol® and metallic stent used as fiducial markers) and tumor motion control (4D, DBH, Calypso®). There were 3 planned dose-escalated SIB groups, 45 Gy/5f (9 patients) 50 Gy/5f (9 + 9 patients) and 55 Gy/5f (9 patients). The defined primary end points of the study were the safety and feasibility of the proposed treatment protocol. Secondary endpoints included radiological tumor response after SBRT, local control and survival. Results: From June 2017 to December 2022, sixty-two patients were initially assessed for eligibility in the study in the four participating centers, and 49 were candidates for chemotherapy (CHT). Forty-one were referred to radiotherapy after CHT and 33 finally were treated by escalated-dose SIB, 45 Gy (9 patients) 50 Gy (16 patients), 55 Gy(8 patients). All patients completed the scheduled treatment and no acute or late severe (≥grade3) gastrointestinal toxicity was observed.Local response was analyzed by CT/MRI two months after the end of SBRT. Ten patients (31,25 %) achieved objective response (2/9:45 Gy, 5/15:50 Gy, 3/8:55 Gy). Follow-up was closed as July 2023. Freedom from local progression at 1-2y were 89,3% (95 %CI:83,4-95,2%) and 66 % (95 %CI:54,6-77,4%) respectively. The 1-2y survival rates were 95,7% (95 %CI:91,4-100 % and 48,6% (95 %CI:37,7-59,5%) respectively. Conclusion: These promising results should be confirmed by further studies with larger sample size and extended follow-up period.

Prospective Pilot study of Quality of Life in patients with severe late-radiation-toxicity treated by Low hyperbaric-oxigen-therapy.

Background/purpose: The aim of this study is to assess for the first time the immediate and long term impact on quality-of-life of HBO treatments(HBOT) at 1.45 ATA (Absolute Atmospheric Pressure) Medical Hyperbaric chamber. Methods: Patients over 18 years-old, suffering of grade 3 Common Terminology Criteria for Adverse Events (CTCAE) 4.0 radiation induced late toxicity and progressing to standard support therapy were included in this prospective study. HBOT was given daily, sixty minutes per session by a Medical Hyperbaric Chamber Biobarica System at 1.45 ATA at 100% O2. Forty sessions were prescribed for all patients given in 8 weeks. Patients reported outcomes (PROs) was assessed by the QLQ-C30 questionnaire, before starting, in the last week of the treatment, as well as during follow up. Results: Between February-2018/June-2021, 48 patients fulfilled the inclusion criteria. A total of 37 patients (77%) completed the treatment prescribed HBOT sessions. Patients with anal fibrosis (9/37) and brain necrosis (7/37) were the most frequently treated. The most common symptoms were pain (65%) and bleeding (54%). In addition, thirty out of the 37 patients who completed the pre- and post-treatment Patients Reported Outcomes (PROs) assessment also completed the follow up European Organization for Research and Treatment of Cancer, Quality of Life Questionnaire C30 (EORTC-QLQ-C30), and were evaluated in the present study. Mean follow up was 22,10 (6-39) months.The Median score of the EORTC-QLQ-C30, at the end of HBOT and during follow-up, was improved in all assessed domains, except in the cognitive aspect (p = 0.106). Conclusions: HBOT at 1.45 ATA is a feasible and well tolerated treatment, improving long term quality of life in terms of physical function, daily activities and general health subjective state of patients suffering severe late radiation-induced toxicity.

A case report of recurrent adult-onset xanthogranuloma: is the radiotherapy a treatment option?

Adult-onset xanthogranuloma (AOX) is one of the four uncommon syndromes called adult xanthogranulomatous disease (AXD), which is diagnosed by characteristic histopathology. AXD is rare and heterogeneous group of entities that can affect multiple organ systems. Orbital involvement is included in the xanthogranulomatous disease although less prevalent. This work focuses on the use of external beam radiotherapy in the control of local symptoms of periocular manifestation of AOX as case report and literature review.

Macrophage-directed delivery of doxorubicin conjugated to neoglycoprotein using leishmaniasis as the model disease.

The antileishmanial potency of doxorubicin conjugated to mannose-human serum albumin (man-HSA) was tested in experimental visceral leishmaniasis. Conjugation of doxorubicin did not decrease the affinity of the neoglycoprotein for the macrophage mannose receptor. Conjugated doxorubicin eliminated intracellular amastigotes of Leishmania donovani in peritoneal macrophages almost 12.5 times more efficiently than did the free drug and greatly reduced and possibly eliminated splenic intracellular parasites in four consecutive dosages at 5 micrograms/kg/day for 45 days. Free drug at a similar dose had little effect. The leishmanicidal effect of doxorubicin conjugate can be prevented by competitive inhibitors such as man-HSA or mannan and inhibitors of receptor-mediated endocytosis such as colchicine and monensin. These results not only indicate the potential of doxorubicin as an effective chemotherapeutic agent for leishmaniasis but also establish the use of mannosylated neoglycoprotein as a drug carrier in the therapy of macrophage-associated diseases.

Pharmacokinetics and biodistribution of methotrexate conjugated to mannosyl human serum albumin.

The superior efficacy of mannosylated neoglycoprotein-conjugated methotrexate, compared with free drug, in eliminating the parasite burden in both the in-vitro macrophage model and in-vivo mouse model of visceral leishmaniasis has been demonstrated previously. In the present study it was found that: (i) methotrexate conjugated to mannosyl human serum albumin (Man-HSA) was taken up rapidly by the liver and spleen, whereas the free drug was taken up by the kidney; (ii) uptake of the conjugate was ten-fold more efficient in liver macrophages (Kupffer cells) than in hepatocytes; (iii) most of the drug conjugate reached the lysosomes of Kupffer cells; and (iv) the active drug was released in the lysosomes of macrophages to act on Leishmania parasites.

Potential of doxorubicin as an antileishmanial agent.

Doxorubicin, a well characterized anticancer drug, was tested in vitro and in vivo for activity against Leishmania donovani. Activity in vitro was very high against both the promastigote and amastigote forms of this parasite with 50% effective dose (ED50) values on the order of 0.43 microM and 0.86 microM, respectively. An in vivo inhibition of spleen parasite burden up to 95% in an infected mouse model was achieved when a dosage of 625 micrograms doxorubicin/kg body weight/day was given in 4 consecutive doses, which is far less than the toxic dose. These results suggest that doxorubicin is highly active against visceral leishmaniasis and may be considered with second-line therapeutic agents such as amphotericin B and pentamidine.

Chromosome preparation from human bone marrow--technique modified for immediate clinical investigation.

A modified method for chromosome preparation from bone marrow aspirates of normal individuals and leukaemic patients is described for immediate clinical investigation. Hanks' balanced salt solution at different concentrations was used for in vitro incubation and hypotonic treatment. The method yields quite a high mitotic index with good metaphase spreads.

Down-regulation of mannose receptors on macrophages after infection with Leishmania donovani.

Macrophages express a mannose-specific endocytosis receptor that binds and internalizes mannose-terminated glycoproteins. Infection of mouse peritoneal macrophages with Leishmania donovani resulted in a decrease in mannose-receptor activity. With 125I-labelled beta-glucuronidase as ligand, a 2-fold decrease in uptake rate was observed in infected cells, with no change in Kuptake. Cell-surface binding of 125I-mannose-BSA was diminished 2.5-fold after infection. The decrease in ligand binding appeared to be due to a decrease in the number of sites, with no change in affinity. Elimination of parasites from infected cells by treatment with neoglycoprotein-conjugated methotrexate resulted in an increase in receptor number. Cycloheximide suppressed the drug-treatment-mediated rise in receptor number in infected macrophages. A decrease in receptor activity was also observed in liver Kupffer cells isolated from parasite-infected mice. Binding of ligand by another carbohydrate receptor, the mannose 6-phosphate receptor, was not altered by infection. Phagocytosis of yeast cells was also not altered. These results suggest that mannose receptor synthesis in macrophages is specifically suppressed after infection with Leishmania parasites.

Induction of fertile male flowers in genetically female Cannabis sativa plants by silver nitrate and silver thiosulphate anionic complex.

Apical application of silver nitrate (AgNO3; 50 and 100 µg per plant) and silver thiosulphate anionic complex (Ag(S2O3) 2 (3-) ; STS; 25, 50 and 100 µg per plant) to female plants of Cannabis sativa induced the formation of reduced male, intersexual and fully altered male flowers on the newly formed primary lateral branches (PLBs); 10 µg per plant of AgNO3 was ineffective and 150 µg treatment proved inhibitory. A maximum number of fully altered male flowers were formed in response to 100 µg STS. The induced male flowers produced pollen grains that germinated on stigmas and effected seed set. Silver ion applied as STS was more effective than AgNO3 in inducing flowers of altered sex. The induction of male flowers on female plants demonstrated in this work is useful for producing seeds that give rise to only female plants. This technique is also useful for maintaining gynoecious lines.

Induction of male flowers in a pistillate line ofRicinus communis L. by silver and cobalt ions.

Aqueous solutions of silver nitrate (10-100 µg/plant) and cobalt chloride (125-500 µg/plant), injected into the main stem of plants of the pistillate cv. 240 ofRicinus communis when the vegetative shoot apex was beginning to become reproductive, induced the formation of staminate (male) flowers with viable pollen in the normally strictly pistillate (female) terminal inflorescence, their number increasing with the dose of Ag(+) and Co(2+). No formation of bisexual flowers was noted. Female flowers pollinated with pollen from the induced male ones produced fruits and viable seeds.