Bortezomib is the first proteasome inhibitor drug tested in human patients. Bortezomib demonstrates a particular clinical utility in the treatment of multiple myeloma (MM), where it is the only one of the new drugs administered as mono-therapy that prolongs survival. The significant problem for the consistent pursuit of bortezomib was neurotoxicity, which has been significantly reduced by registering subcutaneous administration or being administered once per week. Bortezomib is currently approved for the treatment of patients with progressive MM in mono-therapy and in combination with prednisone and melphalan in cases of untreated patients who are not candidates for autologous hematopoietic stem cell transplantation (AHSCT) and in combination with dexamethasone or dexamethasone and thalidomide in untreated MM patients, who are candidates for treatment AHSCT. Clinical research is focused on the combination of bortezomib with other new drugs with the hope of further optimizing the treatment of patients with multiple myeloma.

Bortezomib for the treatment of multiple myeloma.

Objective A current assessment of case reports of possible drug-induced pancreatitis is needed. We systematically reviewed the case report literature to identify drugs with potential associations with acute pancreatitis and the burden of evidence supporting these associations. Methods A protocol was developed a priori (PROSPERO CRD42017060473). We searched MEDLINE, Embase, the Cochrane Library, and additional sources to identify cases of drug-induced pancreatitis that met accepted diagnostic criteria of acute pancreatitis. Cases caused by multiple drugs or combination therapy were excluded. Established systematic review methods were used for screening and data extraction. A classification system for associated drugs was developed a priori based upon the number of cases, re-challenge, exclusion of non-drug causes of acute pancreatitis, and consistency of latency. Results Seven-hundred and thirteen cases of potential drug-induced pancreatitis were identified, implicating 213 unique drugs. The evidence base was poor: exclusion of non-drug causes of acute pancreatitis was incomplete or poorly reported in all cases, 47% had at least one underlying condition predisposing to acute pancreatitis, and causality assessment was not conducted in 81%. Forty-five drugs (21%) were classified as having the highest level of evidence regarding their association with acute pancreatitis; causality was deemed to be probable or definite for 19 of these drugs (42%). Fifty-seven drugs (27%) had the lowest level of evidence regarding an association with acute pancreatitis, being implicated in single case reports, without exclusion of other causes of acute pancreatitis. Discussion Much of the case report evidence upon which drug-induced pancreatitis associations are based is tenuous. A greater emphasis on exclusion of all non-drug causes of acute pancreatitis and on quality reporting would improve the evidence base. It should be recognized that reviews of case reports, are valuable scoping tools but have limited strength to establish drug-induced pancreatitis associations. Registration CRD42017060473.

Drug Induced Pancreatitis: A Systematic Review of Case Reports to Determine Potential Drug Associations

Acute pancreatitis is a rare complication of chemotherapy agents. We describe the case of a patient with multiple myeloma who developed acute pancreatitis after treatment with bortezomib, a proteasome inhibitor commonly used in the treatment of this disease. We reviewed the available medical literature on this topic, and found other seven similar cases, all after intravenous bortezomib. Our case is the first one occurring with the subcutaneous route of administration.

Bortezomib-induced acute pancreatitis: Case report and review of the literature:

Patients with advanced malignancies may develop pancreatitis during therapy for their cancer. Acute pancreatitis is inflammation of the pancreas. Common symptoms include abdominal pain, nausea, vomiting, shortness of breath, dehydration. Laboratory evidence of acute pancreatitis includes elevations of the amylase and lipase. Mild pancreatitis occurs when there is no organ dysfunction, moderate pancreatitis is associated with one organ dysfunction, and severe pancreatitis is complicated by multiple organ dysfunction. Hypotension, hypocalcemia, or anemia suggest a more severe course of the pancreatitis. In some instances, the pancreatitis may be an adverse reaction to the therapy being given. However, other causes such as hypercalcemia, hypertriglyceridemia, cholelithiasis, and underlying malignancy must be ruled out before ascribing pancreatitis to a specific drug. To date, two classifications systems have been proposed by Trivedi1 and Badalov2 to evaluate the degree to which a drug is responsible for pancreatitis (Table 1). Furthermore, Naranjo and colleagues have proposed a more general method of assessing the causal relationship between drugs and adverse events.3 The Naranjo algorithm is not specific for pancreatitis. Jones and colleagues4 reported that 0.1%-2% of acute pancreatitis cases were owing to drugs. In 2015, they listed the older chemotherapy agents associated with pancreatitis. However, more recently, many new agents have been approved for the management of cancers. The newer classes of antineoplastic agents including proteasome inhibitors, immune-modulating agents, tyrosine kinase inhibitors, monoclonal antibodies against programmed cell death-1 (PD-1) and its ligand PD-L1 and antibody-toxin conjugates are now associated with acute pancreatitis.

/pdf/pancreatitis-associated-with-newer-classes-of-antineoplastic-1n1ns3wtj9.pdf

Pancreatitis associated with newer classes of antineoplastic therapies

Background and aims Drugs are considered a relatively rare and understudied cause of acute pancreatitis (AP). The lack of convincing and conclusive data on drug-induced AP (DIAP) complicates the diagnosis as well as the identification of the causative drug. The aim of this study is to document causes of DIAP cases that occurred in the Saguenay-Lac-Saint-Jean (SLSJ) population. Methods We have conducted a retrospective and descriptive population-based study of DIAP cases that occurred between 2006 and 2014 in the six hospitals serving the entire SLSJ population. Cases were selected from the Quebec Ministry of Health hospitalizations registry (MED-ECHO) administrative public database. A medical chart review was performed in an attempt to characterize DIAP hospitalizations and to identify the imputable drugs. Results During the studied period, 75 cases (30.7% male, 69.3% female) were included totaling 90 hospitalizations for DIAP. Among them, 50 causative drugs were identified and were distributed in 17 different drug classes. Recurrent DIAPs were documented in 13 cases, and among them, 6 cases have experimented a positive rechallenge. Six drugs (5-fluorouracil, atorvastatin, bortezomib, nilotinib, rosuvastatin, and triamcinolone) were associated with the highest degree of evidence. The most common causative drugs of DIAP hospitalization were azathioprine (n = 7), followed by atorvastatin (n = 6), hydrochlorothiazide (n = 5), rosuvastatin (n = 4), and codeine (n = 4). Conclusions This study has added new evidences about potentially pancreatitis-associated drugs in literature. This is the first study to report definite 5-fluorouracil- and triamcinolone-induced AP. An updated version of the evidence-based literature review is needed to support the clinicians in the identification of the causative drugs.

/pdf/a-drug-induced-acute-pancreatitis-retrospective-study-2c8kuw25hb.pdf

A Drug-Induced Acute Pancreatitis Retrospective Study.

Bortezomib, a proteasome inhibitor, has demonstrated remarkable efficacy in multiple myeloma (MM) [1,2], and its use as frontline treatment in patients with MM is now recommended by the National Co...

Bortezomib-induced acute pancreatitis in a patient with multiple myeloma.

IgG4-related disease (IgG4-RD) is an immune-mediated disorder hallmarked with lymphoplasmacytic tissues infiltrated with abundant IgG4-positive plasma cells, which has various clinical features and easily to be misdiagnosed. Here, we described a case with symptoms of body weight loss and multiple lymph node enlargements in a patient’s groin, axilla, mediastinum, and retroperitoneum at the first admission. Both F-fluorodeoxyglucose (FDG)-position emission tomography (PET) and lymph node biopsies supported the possible diagnosis of this case as a T-cell lymphoma, but no TCR gene rearrangement observed. Further examinations showed that serum IgG4 level of the patient was elevated and large amount of IgG4+ plasmocyte infiltration was detected in the involved lymph nodes, indicating this case as a possible IgG4-RD. However, the possibility of this disease as a T-cell lymphoma still could not be excluded. Tentatively, the patient was first treated as IgG4-RD with oral prednisone combined with methotrexate to avoid the unnecessary side effect of chemotherapy and economy burden. After three weeks treatment, the serum IgG4 level of the patient is evidently decreased and the enlarged lymph nodes disappeared as well. Eventually, we characterized this case as an atypical IgG4-related lymphadenopathy with 20 months’ follow-up.

/pdf/a-case-of-igg4-related-disease-seemingly-presenting-as-a-t-d8itliavgo.pdf

A case of IgG4-related disease seemingly presenting as a T-cell lymphoma

Background The glycocalyx is a gel-like structure that covers the luminal side of vascular endothelial cells. It plays an important role in maintaining the integrity of the vascular endothelial barrier structure. However, the presence or absence of glycocalyx destruction in hemorrhagic fever with renal syndrome (HFRS) and its specific mechanism and role is still unclear. Methods In this study, we detected the levels of exfoliated glycocalyx fragments, namely, heparan sulfate (HS), hyaluronic acid (HA), and chondroitin sulfate (CS), in HFRS patients and investigated their clinical application value on the evaluation of disease severity and prognosis prediction. Results The expression of exfoliated glycocalyx fragments in plasma was significantly increased during the acute stage of HFRS. The levels of HS, HA, and CS in HFRS patients during the acute stage were significantly higher than in healthy controls and convalescent stages of the same type. HS and CS during the acute stage gradually increased with the aggravation of HFRS, and both fragments showed a significant association with disease severity. In addition, exfoliated glycocalyx fragments (especially HS and CS) showed a significant correlation with conventional laboratory parameters and hospitalization days. High levels of HS and CS during the acute phase were significantly associated with patient mortality and demonstrated an obvious predictive value for the mortality risk of HFRS. Conclusion Glycocalyx destruction and shedding may be closely associated with endothelial hyperpermeability and microvascular leakage in HFRS. The dynamic detection of the exfoliated glycocalyx fragments may be beneficial for the evaluation of disease severity and prognosis prediction in HFRS.

https://www.frontiersin.org/articles/10.3389/fmed.2023.1096353/pdf

High levels of exfoliated fragments following glycocalyx destruction in hemorrhagic fever with the renal syndrome are associated with mortality risk

Hemorrhagic fever with renal syndrome (HFRS) is an acute natural focus epidemic disease characterized by fever, shock, hemorrhage and kidney injury caused by hantavirus infection. Hantavirus mainly infects human vascular endothelial cells, and induces extensive damage to small blood vessels and capillaries. Increased vascular permeability is the pathological basis for clinical manifestations of HFRS. Although domestic and foreign scholars have carried out many studies on the hantavirus pathogenesis, such as the immune pathological response induced by hantavirus, host genetics and apoptosis, thrombocytopenia, coagulation and fibrinolysis dysfunction, and the vascular endothelial damage, the pathogenesis of HFRS has not been fully elucidated and there is no effective drug yet. In-depth discussion of the molecular mechanism of HFRS and finding effective therapeutic drugs are still the research hotspots on the field of hantavirus/HFRS. This review will elaborate the research progress on the pathogenesis of HFRS in recent years. 

Xiao-Yan Wang

Papers

Bortezomib-induced acute pancreatitis in a patient with multiple myeloma.

A case of IgG4-related disease seemingly presenting as a T-cell lymphoma

High levels of exfoliated fragments following glycocalyx destruction in hemorrhagic fever with the renal syndrome are associated with mortality risk

Research Progress on the Pathogenesis of Hemorrhagic Fever with Renal Syndrome