Novel Pharmacological Treatment Options of Steroid-Refractory Graft-versus-Host Disease.

Background: Graft-versus-host disease (GVHD) is a potentially fatal complication of allogeneic hematopoietic stem cell transplant. The mainstay of treatment is corticosteroids, which are ineffective in 30-50% of cases. Steroid-refractory GVHD (SR-GVHD) confers a poor prognosis, with high mortality rates despite appropriate therapy. While there is no reliable treatment for SR-GVHD, a variety of novel therapeutic options are slowly emerging and have yet to be examined simultaneously. Objectives: This review evaluates the potential of novel therapeutic options, as well as their efficacy and safety, for the treatment of SR-GVHD. Study Design. The literature search was conducted in PubMed, Cochrane, and Embase, employing MeSH terms and keywords. The studies had to be prospective phases 1, 2, or 3. We excluded retrospective and nonoriginal studies. Results: While the only approved drug for acute GVHD is ruxolitinib with an impressive overall response rate of 73.2% and a complete response of 56.3%, several monoclonal antibodies and other agents are currently under investigation, offering promising results. These include anti-CD2, anti-CD147, IL-2 antagonist, a mixture of anti-CD3 and anti-CD7 antibodies, anti-CD25, monoclonal antibody to a4b7 on T-cells, anti-CD26, pentostatin, sirolimus, denileukin diftitox, infliximab, itacitinib, and alpha-1 antitripsin. However, the toxicities associated with these novel drugs need further investigation. For chronic GVHD, approved options include ruxolitinib with an ORR of up to 62%, ibrutinib with an ORR of up to 77%, and belumosudil with an ORR of up to 77%. Meanwhile, emerging treatments include tyrosine kinase inhibitors such as nilotinib, rituximab, and low-dose IL-2, as well as axatilimab and pomalidomide. Conclusion: While their efficacy needs to be better evaluated through large-scale, multicenter, randomized clinical trials, these novel agents show potential and could provide a better alternative for SR-GVHD treatment in the future.

Copper deficiency, a rare but correctable cause of pancytopenia: a review of literature.

INTRODUCTION: Copper is increasingly being recognized as a vital mineral required by both animals and humans. It plays a vital role in many metabolic processes such as cellular respiration, iron oxidation, and hemoglobin synthesis. Copper deficiency, which can be hereditary or acquired, can lead to a wide spectrum of disease processes such as ringed sideroblastic anemia, myelodysplasia, and pancytopenia. Timely identification and management of copper deficiency is necessary to prevent irreversible complications. AREAS COVERED: Our study focuses on prevalence, etiology, pathophysiology, complications, and treatment of copper deficiency. EXPERT OPINION: Copper deficiency is frequently underrecognized as the cause of anemia, neutropenia, and bone marrow dysplasia. As it is potentially treatable, it should always be kept in the differentials when patients present with neurological and hematological abnormalities.

Finite Element Analysis of the Ballistic Impact on Auxetic Sandwich Composite Human Body Armor.

In this study, the ballistic impact behavior of auxetic sandwich composite human body armor was analyzed using finite element analysis. The auxetic core of the armor was composed of discrete re-entrant unit cells. The sandwich armor structure consisted of a front panel of aluminum alloy (Al 7075-T6), UHMWPE (sandwich core), and a back facet of silicon carbide (SiC) bonded together with epoxy resin. Numerical simulations were run on Explicit Dynamics/Autodyne 3-D code. Various projectile velocities with the same boundary conditions were used to predict the auxetic armor response. These results were compared with those of conventional monolithic body armor. The results showed improved indentation resistance with the auxetic armor. Deformation in auxetic armor was observed greater for each of the cases when compared to the monolithic armor, due to higher energy absorption. The elastic energy dissipation results in the lower indentation in an auxetic armor. The armor can be used safely up to 400 m/s; being used at higher velocities significantly reduced the threat level. Conversely, the conventional monolithic modal does not allow the projectile to pass through at a velocity below 300 m/s; however, the back face becomes severely damaged at 200 m/s. At a velocity of 400 m/s, the front facet of auxetic armor was destroyed; however, the back facet was completely safe, while the monolithic panel did not withstand this velocity and was completely damaged. The results are encouraging in terms of resistance offered by the newly adopted auxetic armor compared to conventional monolithic armor.

Experimental evaluation of fracture properties of bovine hip cortical bone using elastic-plastic fracture mechanics.

BACKGROUND: Understanding the fracture mechanics of bone is very important in both the medical and bioengineering field. Bone is a hierarchical natural composite material of nanoscale collagen fibers and inorganic material. OBJECTIVE: This study investigates and presents the fracture toughness of bovine cortical bone by using elastic plastic fracture mechanics. METHODS: The J-integral was used as a parameter to calculate the energies utilized in both elastic deformation (Jel) and plastic deformation (Jpl) of the hipbone fracture. Twenty four different types of specimens, i.e. longitudinal compact tension (CT) specimens, transverse CT specimens, and also rectangular unnotched specimens for tension in longitudinal and transverse orientation, were cut from the bovine hip bone of the middle diaphysis. All CT specimens were prepared according to the American Society for Testing and Materials (ASTM) E1820 standard and were tested at room temperature. RESULTS: The results showed that the average total J-integral in transverse CT fracture specimens is 26% greater than that of longitudinal CT fracture specimens. For longitudinal-fractured and transverse-fractured cortical specimens, the energy used in the elastic deformation was found to be 2.8-3 times less than the energy used in the plastic deformation. CONCLUSION: The findings indicate that the overall fracture toughness measured using the J-integral is significantly higher than the toughness calculated by the stress intensity factor. Therefore, J-integral should be employ to compute the fracture toughness of cortical bone.

The Use of Vancomycin Versus Teicoplanin in Treating Febrile Neutropenia: A Meta-Analysis and Systematic Review.

Background and objective The efficacy of vancomycin vs. teicoplanin for the successful treatment of febrile neutropenia (FN) has been a subject of debate in the medical community. In light of this, we performed a systematic review and meta-analysis to compare these two medications in the treatment of patients with FN in terms of treatment success and adverse events. Data source and study design We conducted a search of major electronic databases [MEDLINE (PubMed, Ovid), Google Scholar, clinicaltrial.org], which returned 10 studies with 1,630 patients (vancomycin: 788; teicoplanin: 842) for analysis. An unadjusted odds ratio (OR) with a 95% confidence interval (CI) was calculated for all studies, as well as separate sub-analyses of randomized controlled trials (RCTs) and retrospective studies. Results The average age of patients ranged from 37 to 57 years in the vancomycin group and 31 to 57 years in the teicoplanin group (n=9 studies). Over half of the patients in both groups were male (vancomycin: 55.6%; teicoplanin: 57.7%; n=9 studies). Both overall evaluation and sub-analyses revealed that both treatments were comparable in terms of treatment success, nephrotoxicity, and red man syndrome. The vancomycin group was more likely to develop skin rashes (OR: 2.49; 95% CI: 1.28-4.83). The heterogeneity for all analyses ranged from 0-47.4%. Conclusion Our analysis showed that vancomycin and teicoplanin showed comparable results in terms of successful treatment of FN. Adverse effects such as nephrotoxicity and red man syndrome were also comparable between the two treatment groups.

Relative Risk of Peripheral Neuropathy With Ado-Trastuzumab Emtansine (T-DM1) Compared to Taxane-Based Regimens in Human Epidermal Growth Factor Receptor 2 (HER2)-Positive Cancers: A Systematic Review and Meta-Analysis.

Background Peripheral neuropathy (PN), especially peripheral sensory neuropathy (PSN), is significant toxicity of taxanes, the most used class of microtubule inhibitors for human epidermal growth factor receptor 2 (HER2)-positive breast cancer patients. Ado-trastuzumab emtansine (T-DM1) is a HER2-targeted antibody-drug conjugate, consisting of trastuzumab and a microtubule inhibitor DM1, which has been approved for HER2-positive breast cancer. T-DM1 has also been found to cause significant PN, including PSN. Methods We conducted a systematic review and meta-analysis of phase 3 randomized controlled trials using T-DM1 in the experimental arm and a taxane-based regimen in the control arm to determine the relative risk of PN and PSN associated with T-DM1 as compared to taxanes. A total of 1,857 patients were included in the analysis. The Cochran-Mantel-Haenszel method and the random-effects model were used to calculate the pooled risk ratio (RR) with a 95% confidence interval (CI) for all-grade and grade ≥3 PN and PSN.  Results The relative risks of all-grade PN and all-grade PSN were lower with T-DM1 compared to taxanes. The pooled RR of all-grade PN was 0.59, 95% CI: 0.39-0.89, P = 0.01, and the pooled RR of all-grade PSN was 0.58, 95% CI: 0.46-0.74, P < 0.0001. Conclusions Our meta-analysis demonstrated that T-DM1 is associated with a relatively lower risk of all-grade PN and PSN than the taxane-based regimens for HER2-positive cancers. It could be an area of consideration in selecting therapy for HER2-positive breast cancer patients at high risk of developing or having pre-existing PN and PSN.

Immunotherapeutic approach for advanced pancreatic adenocarcinoma.

Pancreatic adenocarcinoma (PDAC) is the third leading cause of cancer-related death in the USA and the seventh leading cause of cancer-related death worldwide. Most of the patients' presentation is in advanced stages and remains resistant to currently available standard therapies. An in-depth understanding of PDAC's pathogenesis has shown that immunotherapy could bring about a revolution in the treatment response. Immunotherapy in PDAC appears promising in preclinical studies but failed to show benefits in clinical studies. These novel agents' therapeutic failure can be attributed to multiple variables including the tumor microenvironment, early metastasis, tumor heterogeneity and resistance to therapy. There is a need to develop biomarkers for the patient's stratification and provide individualized treatment to improve treatment outcomes.

Lay abstract Pancreatic adenocarcinoma (PDAC) is the third leading cause of cancer-related death in the USA and the seventh leading cause of cancer-related death worldwide. PDAC is a lethal cancer; most patients present at advanced stages with minimal clinical response to the current standard therapies. Immunotherapy treatment in PDAC showed promising results in the preclinical studies. However, the majority of clinical studies on immunotherapy in PDAC did not show clinical benefits. There is a need for research to explore the benefits of immunotherapy in PDAC patients. The development of new treatment strategies and a patient-tailored approach might improve future outcomes.

Transient Cold Agglutinins in a Patient With COVID-19.

Coronavirus disease 2019 (COVID-19) infection has been associated with various complications such as acute respiratory distress syndrome, acute kidney failure, myocardial infection, and thromboembolism. Cold agglutinin syndrome (CAS) has been associated with other viral infections such as Epstein-Barr virus (EBV), but there have been only a few reports of cold agglutination associated with COVID-19. In this report, we describe a case of transient cold agglutinin elevation in a COVID-19-infected patient. A 61-year-old man with hypertension, diabetes mellitus, and end-stage renal disease (ESRD) presented with shortness of breath, cough, and lethargy for five days. A clinical diagnosis of COVID-19 infection was made. The COVID-19 RNA qualitative real-time polymerase-chain-reaction (PCR) assay tested positive. During the hospital stay, he had progressive dyspnea requiring intubation and mechanical ventilation. During the third week of hospital stay, an acute drop in the hemoglobin (Hb) level to 4.5 g/dl (baseline Hb: 9 g/dl) was observed. The workup for acute anemia revealed a positive result for cold agglutinins, direct antibody test (C3d), and agglutination of the red blood cells were apparent on the peripheral blood smear. Further, cold agglutinin titers peaked during the third week of the onset of illness and significantly declined during the fifth week. These observational findings indicate that cold agglutinin titers might correlate with the disease activity.

Clinical Factors Affecting Bevacizumab Efficacy With and Without Conventional Chemotherapy in Metastatic Colon Cancer.

PURPOSE: Bevacizumab (BZ) combined with first line chemotherapy (CC) has shown good clinical outcomes in metastatic colorectal cancer (mCRC). Overall survival (OS) and/or progression free survival in mCRC patients receiving BZ with or without 5FU-based CC is thought to be affected by clinical and morphological factor(s). PATIENTS AND METHODS: We reviewed retrospective medical records of all consecutive mCRC patients treated with BZ with or without CC at tertiary care center between 2003 and 2009 out of which149 patients (m = 77, f = 72) were eligible. RESULTS: Our study population had a mean age at diagnosis of 63.5 years (SD = 11) with median follow-up period of 19.4 months. On initial radiological evaluation following BZ therapy, 56 patients (m = 31, f = 25) had complete or partial response categorized as "early responders." Remaining patients (m = 46, f = 47) who were either stable or showed progressive disease were categorized as "non-responders." Fifty percent among early responders and 60% among non-responders [relative risk (RR) 0.67 (95% confidence interval (CI), 0.43-1.06)] demonstrated disease progression on follow up. There was a slightly better OS among early responders compared to non-responders (median 21.5 months days versus 16.8 months, P = 0.07). Cox regression analysis suggested male sex (RR 0.65, 95% CI, 0.43-0.98), hematochezia (RR 0.63, 95% CI, 0.4-0.98), resectable primary tumor (RR 0.42, 95% CI, 0.24-0.72) and resectable metastatic mass (RR 0.32, 95% CI, 0.14-0.74) were found to be associated with longer OS. Abdominal pain (RR 1.76, 95% CI, 1.1-2.8), accompanying diabetes (RR 1.76, 95% CI, 1.09-2.85), and unexplained weight loss (RR 2.73, 95% CI, 1.73-4.29) were associated with poor OS. CONCLUSIONS: Better OS among mCRC patients with resectable primary and metastatic tumors was seen. This is the first study to demonstrate slightly better outcome in males and negative influence of diabetes on outcome in mCRC treated with BZ.

Investigation of the mechanism of gamma irradiation effect on bovine bone.

Radiation sterilization is an effective method of bone sterilization prior to bone graft transplantation. Gamma irradiation affects the biological and mechanical properties of bone; depending on the dose of radiation. The effect of gamma irradiation on bone mechanical properties is an unwanted phenomenon. However the mechanism of the effect of irradiation on bone mechanical properties is not properly understood. In this research paper the mechanism of the effect of gamma irradiation on bovine bone is investigated using scanning electron microscopy, energy-dispersive X-rays spectroscopy and Fourier transform infrared spectroscopy techniques. Gamma irradiation affects the mineral and fiber composition of bovine bone. The mineral content of bone especially calcium, magnesium and phosphorus decrease with increasing dose of gamma radiation. At Nano-level gamma irradiation alter amide I, amide II and amide III collagen contents. High dose gamma irradiation induces collagen cross-linking reaction in bone and degrades bone properties.

Therapeutic Advances in the Management of Smoldering Myeloma.

BACKGROUND: The International Myeloma Working Group has defined smoldering multiple myeloma (SMM) as the presence of 10%-60% plasma cells in the bone marrow and M-protein (IgG, IgA) ≥3 g/dL without end-organ damage (an increased calcium level, renal failure, anemia, and destructive bone lesions). AREAS OF UNCERTAINTY: Patients considered to have SMM should not have any myeloma-defining events or amyloidosis. Different risks factors classify SMM into low-, intermediate-, or high-risk categories. The rate of progression from SMM to symptomatic myeloma is ∼10% per year during the first 5 years of diagnosis. SMM requires frequent follow-up ∼every 3 months during the first 5 years as compared to monoclonal gammopathy of undermined significance, which usually requires follow-up every 6-12 months after the first year of diagnosis. DATA SOURCES: A literature search was performed from electronic bibliographic databases: MEDLINE (Ovid SP/PubMed), EMBASE, the Cochrane Library (Cochrane Database of Systematic Reviews), and Cochrane Central Register of Controlled Trials and from annual meeting abstracts from inception to May 2017. THERAPEUTIC ADVANCES: This review presents the literature and available data that support or do not support early treatment of high-risk SMM (HR-SMM) and provides evidence-based recommendations for management of SMM patients. Despite emerging data recommending early treatment of HR-SMM, we predict the SMM category may disappear in the near future and patients will be diagnosed with either multiple myeloma or monoclonal gammopathy of undermined significance. CONCLUSIONS: Success with early therapy trials for HR-SMM is largely due to patients meeting current criteria for multiple myeloma that may have been classified as SMM and, therefore, benefitted from therapy. Based on current practices and the literature, SMM should be managed with close follow-up. Based on available data, we suggest SMM to only be treated in clinical trial settings.

Effect of orientation and age on the crack propagation in cortical bone.

The crack propagation behavior near the initial crack were studied under the compact tension (CT) fracture toughness experiments test on bovine hip bone joint specimens. The bone specimens were prepared according to ASTM E-399 for plain fracture toughness tests. The specimens were cut from the hip joint both in the longitudinal and transverse direction to the collagen fiber orientation in the bone. The precrack or initial crack "a" were produced parallel and vertical to the lontudinal axis of bone in the longitudinal and transverse specimens respectively. The specimens were tested in the universal testing machine for finding fracture toughness and crack propagation behavior due to different orientation of bone fibers. A camera attached to the machine recorded the crack propagation process. The results show a different crack propagation behavior in longitudinal specimens and transverse specimens. The toughness of the bone consistently changes with age both in longitudinal and transverse direction. Our experimental data matched with the previous published research.

Effect of x-rays and gamma radiations on the bone mechanical properties: literature review.

The bone auto grafting, isografting, allografting and xenografting are used for defective bone replacement or treatment in almost all living species. The X-ray and Gamma (electromagnetic radiation) sterilization performed on the donor bone graft to prevent toxicity or migration of virus/bacterial infections from donors to reciver. Conversely, X-ray and Gamma radiation deteriorates the bone mechanical properties and bone become more susceptible to fracture. Fracture toughness as well as other mechanical properties of bone change with these radiations. In this literature review the effect of the X-rays and Gamma radiation on bone mechanical properties are discussed. All relevant literature was reviewed. After reviewing the literature only the research relating to the effect of X-rays and Gamma radiations on bone mechanical properties are included. Literature studies showed significant effect of the X-rays and Gamma radiations on the mechanical properties of the bones. In some studies the differences exists on the doses of radiations which were discussed in this study. The high energetic electromagnetic radiation (X-rays and Gamma radiations) changed/modify the collagen network of the bone, which reduced the mechanical properties of bone; however these changes depend on the radiation dose.

C-Reactive Protein Monitoring Predicts Neutropenic Fever Following Autologous Hematopoietic Stem Cell Transplantation for Multiple Myeloma.

Background Neutropenic fever (NF) is a known and common complication of autologous hematopoietic stem cell transplantation (ASCT). Early risk assessment may help direct treatment. We retrospectively analyzed the role of serial serum C-reactive protein (CRP) levels in predicting NF and assessed the clinical value of CRP within 14 days after transplantation. Methods One hundred twenty-one multiple myeloma (MM) patients received 170 first and/or second ASCT between January 2014 and March 2017. A Cox regression model was applied to assess the prognostic value of CRP as a time-dependent covariate at the onset of NF within 14 days post-transplant. Results Forty-seven of 170 patients developed NF. High CRP levels (4.0-43.2 mg/dL) were associated with a 5.45-fold increased risk of NF (P = 0.02). Patients had a nearly three-fold increased risk of NF after the second transplant (P < 0.01), but this was not associated with increased mortality. Those with NF had higher maximum values of CRP (P < 0.01) which tended to occur at or after the onset of NF. Conclusion CRP monitoring provides important information about the risk for NF immediately after first MM ASCT, and even more so after the second.

Bloodless tandem autologous transplant in Jehovah's Witness patients.

Tandem autologous transplants are generally the preferred therapy for newly diagnosed intermediate- and high-risk myeloma patients. More Jehovah's Witnesses (JW) are receiving single autologous peripheral blood stem cell transplants (PBSCTs). However, tandem autologous transplants have not been reported in JW patients. We performed a retrospective study of 54 patients, including four JW patients who received tandem autologous transplants between August 2000 and January 2017 and the last 50 consecutive tandem autologous transplants performed between August 2014 and August 2016. The bleeding complications, number, and cost of transfusions of blood products were compared. The median number of CD34 cells infused in non-JW patients was 8.16 million cells/kg versus 9.44 million cells/kg in JW patients. During the first 30 days, one JW experienced Grade III pulmonary hemorrhage, while none of the non-JW patients had a Grade III or higher bleeding problem. After tandem autologous transplants, complete remission was achieved in 88% of non-JW, compared with 75% in JW patients. In the first 30 days post-transplant, median platelet and packed red blood cell (PRBC) transfusions in non-JW patients was 2 (range: 0-40) and 1 (range: 0-11), respectively. Total cost of PRBC and platelet transfusions for the 50 non-JW was $214,664 (average $2147/transplant). Tandem autologous transplants can thus be performed safely without a single blood transfusion.

Non-traumatic splenic rupture in a patient with human granulocytic anaplasmosis and focused review of the literature.

We report a rare case of a 53-year-old man with no significant past medical history who reported multiple tick bites within a 2-month period. The patient reported not "feeling well" for the 2 ½ weeks. He complained of generalized body aches, pains, and chills. He did not report nausea, vomiting, or yellowish discoloration of the eyes or skin. He presented to the emergency room with syncope preceded by severe abdominal pain. Upon presentation, he was pale and hypotensive. He had not experienced any trauma. Computed tomography revealed a splenic rupture, hemoperitoneum, and active extravasation of contrast material. The estimated amount of hemoperitoneum was 1.5 liters of blood. Subsequently, an infectious disease work-up revealed a positive Anaplasma phagocytophilum polymerase reaction in blood. The patient was aggressively resuscitated, and a splenectomy was performed followed by doxycycline therapy. He successfully recovered.