Aggressive Pituitary Macroadenoma Treated With Capecitabine and Temozolomide Chemotherapy Combination in a Patient With Nelson’s Syndrome: A Case Report

Nelson’s syndrome is considered a severe side effect that can occur after a total bilateral adrenalectomy in patients with Cushing’s disease. It usually presents with clinical manifestations of an enlarging pituitary tumor including visual and cranial nerve alterations, and if not treated, can cause death through local brain compression or invasion. The first therapeutic option is surgery but in extreme cases of inaccessible or resistant aggressive pituitary tumors; the off-label use of chemotherapy with capecitabine and temozolomide can be considered. However, the use of this treatment is controversial due to adverse events, lack of complete response, and inability to predict results. We present the case of a 48-year-old man diagnosed with Nelson’s syndrome with prolonged partial response and significant clinical benefit to treatment with capecitabine and temozolomide.

Evaluation of Antibody Response to Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Immunizations in Patients with B-Cell Malignancies

Background Multiple vaccines have been granted emergency use authorization by the Food and Drug Administration against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Of the currently available vaccines, none have been systematically studied for efficacy or toxicity in patients with immunodeficiency or with immunosuppressed states, such as B cell malignancy. The purpose of the study was to evaluate the immune response to currently available vaccines against COVID-19 in patients with hematologic and solid organ malignancies. Methods This prospective study enrolled 53 patients; 12 with CLL, 10 with multiple myeloma (MM), 11 with non-Hodgkin's lymphoma (NHL) and 21 with a solid organ malignancy. Using a quantitative assay, IgG antibodies to SARS-CoV-2 Spike (S) protein, and nucleocapsid (N) protein by enzyme immunoassay were measured at baseline prior to vaccination and at 2 weeks after completion of vaccination. A fourfold increase in IgG was considered a positive response to vaccination. Through a predesigned survey, patients also self-reported side effects from each dose of vaccination. Results Seroconversion with vaccination was seen in 9/10 (90%) patients with MM, 5/12 (41.7%) patients with CLL, 6/11 (54.1%) patients with NHL, and 17/21 (80.9%) patients with solid organ malignancy. Per univariate analysis, CLL (OR 0.23, 95% CI 0.05-0.88; p= 0.033) was associated with lower odds of seroconversion while NHL (OR 0.48, 95% CI 0.12-1.8; p =0.291), MM (OR 5.33, 95% CI 0.61-46.08; p= 0.128) and solid organ malignancy (OR 2.90, 95% CI 0.79-10.64; p= 0.107) were not. Among patients with hematological malignancies, 5/13 (38.3%) patients treated with rituximab and 2/7 (28.5%) patients on immunoglobulin replacement (IgR) therapy responded to vaccination. This corresponded to reduced odds of seroconversion, 0.18 (95% CI 0.047-0.69; p = 0.013) in patients treated with rituximab and 0.14 (95% CI 0.024-0.826; p=0.030) in patients on IgR. Among patients with solid organ malignancies, treatment with chemotherapy (OR 2.05, 95% CI 0.48-8.61; p=0.320), immunotherapy (OR 4.57, 95% CI 0.52-39.9; p=0.169) or endocrine therapy (OR 1.0) did not lower odds of seroconversion with vaccination. Multivariate analysis revealed patients who received rituximab were less likely to respond to vaccination as compared to patients not previously treated with rituximab (OR 0.22, 95% CI 0.05-0.955; p=0.044). Injection site soreness was the most commonly reported side effect. The only severe side effect occurred in a patient with solid organ malignancy who developed Parsonage Turner syndrome. Conclusion Our study, to the best of our knowledge, is the first study comparing pre and post vaccination IgG titers against the SARS-CoV-2 S protein. Majority of patients with MM and solid organ malignancies, including those receiving active treatment, responded adequately to immunization. Patients with CLL appear less likely to respond to vaccination against COVID-19 as compared to patients with NHL, MM or solid organ malignancies. Previous treatment with rituximab was the most significant risk factor for suboptimal response to vaccination, regardless of underlying hematologic malignancy. These data highlight the importance of continuing risk mitigation strategies against COVID-19 in individuals with hematologic malignancy, particularly those with CLL or on treatment with rituximab. Future research is needed to investigate approaches to provide protective IgG against SARS-CoV-2 in this at-risk population. Figure 1 Figure 1. Disclosures Mustafa: Genentech: Speakers Bureau; GalaxoSmithKline: Speakers Bureau; CSL Behring: Speakers Bureau; Regeneron: Speakers Bureau; AstraZeneca: Speakers Bureau. Walsh: Janssen: Research Funding; Merck: Research Funding; Pfizer: Research Funding. Jamshed: Takeda: Honoraria.

Geranylgeraniol Restores Zoledronic Acid-Induced Efferocytosis Inhibition in Bisphosphonate-Related Osteonecrosis of the Jaw

Bisphosphonate-related osteonecrosis of the jaw (BRONJ) is a severe side effect of long-term administration of bisphosphonates such as zoledronic acid (ZA), but its pathogenesis remains unclear. Impairment of the clearance of apoptotic cells (termed “efferocytosis”) by ZA may be associated with the pathogenesis of BRONJ. The aim of this study was to investigate whether ZA might inhibit macrophage efferocytosis and promote osteocytic apoptosis, and the underlying mechanisms responsible for the disturbing balance between clean and generation of osteocytic apoptosis. We found that ZA significantly promoted the apoptosis of osteocyte and pre-osteoblast via BRONJ mouse models and in vitro MC3T3-E1 but also inhibited the efferocytosis of macrophage on apoptotic cells. Moreover, supplement with geranylgeraniol (GGOH), a substrate analog for geranylgeranylation of Rac1, could restore Rac1 homeostasis and rescue macrophage efferocytosis. GGOH partially inhibits MC3T3-E1 apoptosis induced by ZA via downregulation of Rac1/JNK pathway. We also examined the Rac1 distribution and activation conditions in bone marrow-derived macrophages (BMDMs) and MC3T3-E1 under ZA treatment, and we found that ZA impaired Rac1 migration to BMDM membrane, leading to round appearance with less pseudopodia and efferocytosis inhibition. Moreover, ZA simultaneously activated Rac1, causing overexpression of P-JNK and cleaved caspase 3 in MC3T3-E1. Finally, the systemic administration of GGOH decreased the osteocytic apoptosis and improved the bone healing of the extraction sockets in BRONJ mouse models. Taken together, our findings provided a new insight and experimental basis for the application of GGOH in the treatment of BRONJ.

Different Presentation and Outcomes in the Surgical Treatment of Advanced MRONJ in Oncological and Nononcological Patients Taking or Not Corticosteroid Therapy

Medication-related osteonecrosis of the jaw (MRONJ) is a severe side effect caused by antiangiogenic antiresorptive drugs used to treat various oncological and non oncological diseases. The clinical and radiological characteristics of MRONJ depend on the type of causative drug, the time of administration, and its dosage. Proven systemic risk factors like anemia, uncontrolled diabetes, corticosteroid therapy, and chemotherapy in neoplastic diseases (e.g., high doses of methotrexate up to 30 mg daily) significantly increase the chances of acquiring MRONJ. The risk factors themselves can affect treatment outcomes. Although the main scientific societies have recently disseminated good practice rules on the patient’s prevention, diagnosis, and management, there are still no guidelines on shared therapeutic strategies. In general, if conservative treatment fails, surgical treatment is considered, including local debridement, osteoplasty, and marginal or segmental osteotomy. In literature, cohorts of heterogeneous patients with MRONJ have been analyzed for a long time, resulting in a lack of uniformity of information and difficulties interpreting the data. According to the American Association of Oral and Maxillofacial Surgeons criteria, this retrospective study evaluates the surgical treatment outcomes of 64 patients with stage II-III MRONJ, evaluated at the Department of Maxillofacial Surgery of the University of Turin (Italy). The first objective of this retrospective study is to evaluate treatment results for stages II-III in all cases; the second objective is to evaluate the same results by dividing the sample into different cohorts of patients: first, based on the underlying pathology, i.e., oncological and non oncological, and secondly, based on the drug or combination of drugs they took.

TumorSelect® Technology Enhancing the Safety and Efficacy of Cancer Chemotherapy

Veiled Therapeutics has developed an anticancer technology, TumorSelect® Technology, which combines proprietary anticancer prodrugs and nanotechnology, which takes advantage from current knowledge of human physiology. Tumors have a voracious appetite for cholesterol which facilitates tumor growth and fuels their proliferation. We have transformed this need into a stealth delivery system to disguise and deliver anticancer drugs with the assistance of both the human body and the tumor cell. Veiled’s designer prodrugs are assembled within pseudo-LDL nanoparticulates which carry them to tumor tissues where they are taken up, internalized and transformed into active drug and kill the cancer cells. This three-prong approach delivers the anticancer drug selectively to the tumors and thereby avoids or reduces the severe side effect toxicities associated with current chemotherapy. Reduction of side effect toxicity of cancer therapy by our technology will improve patient quality of life, patient retention in treatment regimes, more rapid patient recovery post treatment, and overall patient benefit.A. BackgroundThe costs of cancer, measured in terms of mortality, morbidity, direct costs of treatment, and costs of lost productivity are high.B. MethodsART-207 was synthesized; a pseudo-LDL lipid nanodispersion was formed; and mouse xenograft studies were performed. C. ResultsPreclinical toxicity, efficacy, and distribution data clearly show significant advantages of TumorSelect® paclitaxel over conventional Cremophor® formulations of paclitaxel. These advantages include:· Increased suppression of tumor growth and regrowth· Lower toxicity· Increased survival· Higher number of tumor free animals· Significantly lower concentrations of paclitaxel in non-target tissues· Significantly higher concentrations of paclitaxel in tumor tissueThus, data obtained demonstrated targeted drug delivery and support LDL-receptor dependent mechanism of selective cellular uptake by tumor tissue of TumorSelect® formulated paclitaxel.D. ConclusionsNon-target tissue concentrations of paclitaxel are significantly lower in non-tumored and tumored mice injected with formulated TumorSelect® paclitaxel compared with the mice injected with Cremophor® EL/EtOH (ethanol) paclitaxel (<20%).Tumor concentrations of paclitaxel are significantly higher in tumors of mice injected with formulated TumorSelect® paclitaxel compared with the mice injected with Cremophor® EL/EtOH paclitaxel (194%).Plasma and heart concentrations of paclitaxel are significantly lower in tumored vs. non-tumored animals injected with formulated TumorSelect® paclitaxel (<80%).Selective cellular uptake of TumorSelect® paclitaxel by tumors actively expressing LDL-receptors has been demonstrated.Tumor suppression observed was sustained for 63 days after Q1Dx5 dosing with TumorSelect® paclitaxel.TumorSelect® technology represents a potential major improvement in the clinical treatment of cancer through enhanced efficacy due to tumor-facilitated targeted delivery and reduced patient toxicity with its associated deleterious side effects.

Continuous Intravenous Administration of Granulocyte-Colony-Stimulating Factors—A Breakthrough in the Treatment of Cancer Patients with Febrile Neutropenia

(1) Background: Febrile neutropenia (FN) remains one of the most challenging problems in medical oncology and is a very severe side effect of chemotherapy. Its late consequences, when it is recurrent or of a severe grade, are dose reduction and therapy delays. Current guidelines allow the administration of granulocyte-colony-stimulating factors (G-CSF) for profound FN (except for the case when a pegylated form of G-CSF is administrated with prophylactic intention) in addition to antibiotics and supportive care. (2) Methods: This is a prospective study that included 96 patients with confirmed malignancy, treated with chemotherapy, who developed FN during their oncological therapy, and were hospitalized. They received standard treatment plus a dose of G-CSF of 16 µg/Kg/day IV continuous infusion. (3) Results: The gender distribution was almost symmetrical: Male patients made up 48.96% and 51.04% were female patients, with no significance on recovery from FN (p = 1.00). The patients who received prophylactic G-CSF made up 20.21%, but this was not a predictive or prognostic factor for the recovery time from aplasia (p = 0.34). The median chemotherapy line where patients with FN were included was two and the number of previous chemotherapy cycles before FN was three. The median serological number of neutrophils (PMN) was 450/mm3 and leucocytes (WBC) 1875/mm3 at the time of FN. Ten patients possess PMN less than 100/mm3. The median time to recovery was 25.5 h for 96 included patients, with one failure in which the patient possessed grade 5 FN. Predictive factors for shorter recovery time were lower levels of C reactive protein (p < 0.001) and procalcitonin (p = 0.002) upon hospital admission and higher WBC (p = 0.006) and PMN (p < 0.001) at the time of the provoking cycle of chemotherapy for FN. The best chance for a shorter duration of FN was a short history of chemotherapy regarding the number of cycles) (p < 0.0001). (4) Conclusions: Continuous IV administration of G-CSF could be an alternative salvage treatment for patients with profound febrile neutropenia, with a very fast recovery time for neutrophiles.

A Fibrinogen Alpha Fragment Mitigates Chemotherapy-Induced MLL Rearrangements

Rearrangements in the Mixed Lineage Leukemia breakpoint cluster region (MLLbcr) are frequently involved in therapy-induced leukemia, a severe side effect of anti-cancer therapies. Previous work unraveled Endonuclease G as the critical nuclease causing initial breakage in the MLLbcr in response to different types of chemotherapeutic treatment. To identify peptides protecting against therapy-induced leukemia, we screened a hemofiltrate-derived peptide library by use of an enhanced green fluorescent protein (EGFP)-based chromosomal reporter of MLLbcr rearrangements. Chromatographic purification of one active fraction and subsequent mass spectrometry allowed to isolate a C-terminal 27-mer of fibrinogen α encompassing amino acids 603 to 629. The chemically synthesized peptide, termed Fα27, inhibited MLLbcr rearrangements in immortalized hematopoietic cells following treatment with the cytostatics etoposide or doxorubicin. We also provide evidence for protection of primary human hematopoietic stem and progenitor cells from therapy-induced MLLbcr breakage. Of note, fibrinogen has been described to activate toll-like receptor 4 (TLR4). Dissecting the Fα27 mode-of action revealed association of the peptide with TLR4 in an antagonistic fashion affecting downstream NFκB signaling and pro-inflammatory cytokine production. In conclusion, we identified a hemofiltrate-derived peptide inhibitor of the genome destabilizing events causing secondary leukemia in patients undergoing chemotherapy.

Antihyperglycemic Activity of The Ethanolic Extract of the Bark of Mitragyna Ciliata (MYCA) in Albino Induced Diabetic Rats

Background: Diabetes an epidemic that gives rise to an increased macro vascular complication mortality rate of 1.5 million annually, increasing by 2035. Treatment of diabetes is complicated and associated with a severe side effect.</p> <p>Objective: To evaluate the antihyperglycemic property of the ethanolic extract of the back of MYCA and its toxicological effect on the hematological parameters with histopathological analysis of selected organs of induced diabetic albino rats.</p> <p>Method: The ethanoic extract (1000 mg/kg bw and 500mg/kg bw) and glibenclamide (0.5mg/kg bw) were administered to diabetic induced rats. The effect of the extract on the hematological was studied in the diabetic induced rats. Histopathological changes were observed in the liver of induced diabetic rats after the administration of the MYCA extract.</p> <p>Results: The anti-hyperglycaemic effect was observed at two different levels, for two different doses (1000mg/kg and 500mg/kg). The results also showed significant suppression of blood glucose level in glucose fed hyperglycaemic albino rats but showed no significantly suppressed glucose level in overnight fasted normoglycemic rats.</p> <p>Conclusion: The findings revealed that the ethanolic extract of MITRAGYNA CILIATA (MYCA) possess antihyperglycemic property. Besides, the extract can prevent the various complication of diabetes and improve some hematological parameters.

Can Neutrophil-lymphocyte Ratio Be a Useful Criterion for Neuroleptic Malignant Syndrome in the Absence of Leukocytosis?

Objective: Neuroleptic malignant syndrome (NMS) is a rare but severe side effect of antipsychotic medication. Neutrophil-lymphocyte ratio (NLR) is a simple marker used to measure systemic inflammation. Method: In this case report we explore the relationship of inflammation in the etiology of NMS. In our case involving NMS, although there was no leukocytosis, the NLR was increased up to systemic infection levels. Conclusion: We hypothesized that systemic inflammation may take a role in developing NMS. If so, NLR could be a new marker of NMS that may be able to provide more sensitive results than leukocyte levels.