[A case of small intestinal lymphoma with ileus requiring surgery during chemotherapy].

Perforation, bleeding, and ileus are known complications of small intestinal lymphoma and can occur either at diagnosis or during the course of treatment. Surgery is an important component in the management of these gastrointestinal complications. However, there is no consensus regarding the indications for and timing of surgery in small intestinal lymphoma. We herein present our experience with a case of small intestinal lymphoma with ileus that required surgery during chemotherapy. A 69-year-old man developed abdominal pain. Computed tomography revealed lower right jaw lymphadenopathy, small intestinal wall thickening, and mesenteric lymphadenopathy. Malignant lymphoma (diffuse large B-cell type) was diagnosed on the basis of a lower jaw lymph node biopsy. The patient was initially administered chemotherapy. After the third cycle of chemotherapy, the patient developed small intestinal obstruction detected upon abdominal computed tomography. Because a stricture persisted despite medical treatment, we performed partial resection of the small intestine. The postoperative course was good, and the patient rapidly resumed chemotherapy. Currently, 6 months after the surgery, the patient is alive without any progression of the lymphoma. A multidisciplinary treatment strategy, including surgery, is desirable to achieve a safe but radical cure for small intestinal lymphoma.

Mechanism of Protein-PDMS Visible Particles Formation in Liquid Vial Monoclonal Antibody Formulation.

Visible particles (VPs) formation in liquid monoclonal antibody formulations is a critical quality issue. Formulations that include poloxamer 188 (PX188) as a surfactant are prone to the formation of VPs comprising aggregated complexes of protein and polydimethylsiloxane (PDMS; silicone oil) derived from primary containers. However, the mechanisms through which these VPs form are complicated and remain to be fully elucidated. This study demonstrates for the first time the dominant spot and pathway of protein-PDMS VP formation in a particular liquid vial formulation. Specifically, when a vial sealed with a PDMS-coated stopper is stored in an upright position under conditions whereby the antibody solution has become well-adhered to the stopper and an air phase exists in the vicinity, protein-PDMS aggregates form on the stopper and are then desorbed into the drug solution to be detected as VPs. Here, we evaluated the effects of several factors on VP formation: adhesion of the drug solution to the stopper, storage orientation, silicone coating on the stopper, vial material, and hydrophobicity of PX188. Remarkably, we found that changing any one of the factors could significantly affect VP formation. Our findings are instructive for better understanding the mechanisms of VP formation in vial products and can provide strategies for VP mitigation in biotherapeutics.

Viscosity increase/gelation of therapeutic IgG monoclonal antibodies induced by Zn2+: One possible root cause of clogging of staked-in-needle prefilled syringes.

We investigated the elution of zinc ions (Zn2+) from the elastomer of rigid needle shields (RNS) attached to staked-in-needle prefilled syringes (SIN-PFS) and the physicochemical impacts of Zn2+ on therapeutic IgG monoclonal antibody (mAb) solutions. The elution of metal ions from typical RNS elastomer under realistic buffer and storage conditions was investigated by inductively coupled plasma-mass spectrometry. Among the metal ions examined, only Zn2+ was detected. The elution of Zn2+ from RNS elastomer was found to be buffer-dependent. We investigated the influence of Zn2+ on the viscosity of seven mAb solutions at 180 mg/mL. The effect of Zn2+ clearly depended on antibody type. Drastic increases in viscosity or gelation were observed in four out of the seven mAbs. Dynamic light scattering (DLS) and small-angle X-ray scattering (SAXS) showed the effect of Zn2+ on mAb viscosity was explained by the colloidal destabilization of mAb solutions. Thus, Zn2+ leaching from RNS elastomer may possibly increase viscosity or cause gelation, and consequently cause possible needle clogging during long-term storage. DLS and SAXS can predict reactivity of mAbs to Zn2+, and require only small amounts of samples. This makes it possible to predict compatibility with RNS elastomer and evaluate needle clogging risk in SIN-PFSs in the early stages of mAb development.

Impact of Poloxamer 188 Material Attributes on Proteinaceous Visible Particle Formation in Liquid Monoclonal Antibody Formulations.

Surfactants such as Poloxamer 188 (PX188) play an important role in controlling particle formation in biotherapeutic formulations due to interfacial stresses. This study demonstrates for the first time that hydrophobicity of PX188 is a potential critical material attribute (CMA) as far as control of visible particle (VP) formation is concerned. We have found that within PX188 lots satisfying pharmacopeial specifications, there is variability in material attributes such as hydrophobicity, as determined from their reversed-phase high-performance liquid chromatography profiles. However, it currently remains unknown how such variability in hydrophobicity of PX188 affects surfactant function and VP formation. Here, we compared the effect of seven PX188 lots in two monoclonal antibody drug product formulations under various stress conditions. Notably, proteinaceous VP formation was reduced while using a PX188 lot with higher hydrophobicity. Our findings emphasize the importance of monitoring lot-to-lot variability of PX188 and provide insight into potential CMA for improving and controlling material attributes of PX188 for use in liquid biotherapeutic formulations.