Citations

AbstractBackgroundSeveral organizations have proposed guidelines or clinical decision tools for the management of patients with disorders of gut‐brain interactions (DGBI) affecting the lower digestive tract including irritable bowel syndrome and chronic idiopathic constipation. Such algorithms are based on sequential therapeutic trials and modifying the treatment strategy based on efficacy and adverse events.PurposeThe aims of this review are to evaluate the evidence for efficacy of second‐ and third‐line pharmacotherapies and to assess the evidence for the alternative option to manage subgroups of patients with symptoms suggestive of lower DGBI based on diagnostic tests or documented dysfunctions. The preeminent tests to identify such subgroups that present with symptoms that overlap with lower DGBI are detailed: digital rectal examination as well as anorectal manometry and balloon expulsion for evacuation disorders, detailed measurements of colonic transit, and diagnosis of bile acid diarrhea or carbohydrate malabsorption based on biochemical measurements. The review also addresses the cost implications of screening to exclude alternative diagnoses and the costs of therapy associated with the therapeutic options following an algorithmic approach to treatment from the perspective of society, insurer, or patient. Finally, the costs of the diagnostic tests to identify actionable biomarkers and the evidence of efficacy of individualized therapy based on formal diagnosis or documentation of abnormal functions are detailed in the review.

AbstractBackgroundGastroparesis is a motility disorder of the stomach characterized by cardinal symptoms and delayed gastric emptying of solid food in the absence of mechanical obstruction. There is significant unmet need in its management, and essentially there are no medications approved for its treatment over four decades.PurposeThe objectives of this review are to develop an understanding of the goals of treatment, the evidence‐based criteria for treatment success based on the current scientific understanding of gastroparesis as well as patient response outcomes, and to propose evidence‐based principles for the successful development of treatments for gastroparesis. Specifically, we discuss the pathophysiologic targets in gastroparesis, eligibility criteria for clinical trial participation based on validated gastric emptying studies, and the patient response outcome measures that have been validated to appraise effects of treatment on clinically relevant outcomes. These considerations lead to recommendations regarding eligibility, design, and duration of proof‐of‐efficacy studies, and to endorsing the American Neurogastroenterology and Motility Society Gastroparesis Cardinal Symptom Index Daily Diary as a validated patient response outcome and to justification of the shortening of proof‐of‐efficacy, placebo‐controlled clinical trials to 4 weeks treatment duration after a baseline period. We believe that such approaches will increase the likelihood of successful assessment of efficacy of novel approaches to treating patients with gastroparesis.

Abstract Although initial therapy of mantle cell lymphoma (MCL) is not standardized, bendamustine plus rituximab (BR) is commonly used in older patients. Rituximab (R) maintenance after induction is often used. Thus, the open-label, randomized phase 2 ECOG-ACRIN Cancer Research Group E1411 trial was designed to test 2 questions: (1) does addition of bortezomib to BR induction (BVR) and/or (2) addition of lenalidomide to rituximab (LR) maintenance improve progression-free survival (PFS) in patients with treatment-naïve MCL? From 2012 to 2016, 373 previously untreated patients, 87% aged ≥60 years, were enrolled in this trial. At a median follow-up of 7.5 years, there is no difference in the median PFS of BR compared with BVR (5.5 vs 6.4 years; hazard ratio [HR], 0.90; 90% confidence interval [CI], 0.70-1.16). There were no unexpected additional toxicities with BVR treatment compared with BR, with no impact on total dose/duration of treatment received. Independent of the induction treatment, addition of lenalidomide did not significantly improve PFS, with median PFS in R vs LR (5.9 vs 7.2 years; HR, 0.84; 90% CI, 0.62-1.15). Most patients completed the planned 24 cycles of LR at the scheduled dose. In summary, adding bortezomib to BR induction does not prolong PFS in treatment-naïve MCL, and LR maintenance was not associated with longer PFS compared with R alone after BR. Nonetheless, the >5-year median PFS outcomes in this prospective cooperative group trial indicate the efficacy of BR followed by R maintenance as highly effective initial therapy for older patients with MCL. This trial was registered at www.clinicaltrials.gov as #NCT01415752.

The transplantation of engineered cells that secrete therapeutic proteins presents a promising method for addressing a range of chronic diseases. However, hydrogels used to encase and protect non-autologous cells from immune rejection often suffer from poor mechanical properties, insufficient oxygenation, and fibrotic encapsulation. Here, we introduce a composite encapsulation system comprising an oxygen-permeable silicone cryogel skeleton, a hydrogel matrix, and a fibrosis-resistant polymer coating. Cryogel skeletons enhance the fracture toughness of conventional alginate hydrogels by 23-fold and oxygen diffusion by 2.8-fold, effectively mitigating both implant fracture and hypoxia of encapsulated cells. Composite implants containing xenogeneic cells engineered to secrete erythropoietin significantly outperform unsupported alginate implants in therapeutic delivery over 8 weeks in immunocompetent mice. By improving mechanical resiliency and sustaining denser cell populations, silicone cryogel skeletons enable more durable and miniaturized therapeutic implants.

Chronic myeloid leukemia (CML) is defined by the presence of Philadelphia chromosome resulting from a reciprocal translocation between chromosomes 9 and 22 [t9;22] that gives rise to a BCR::ABL1 fusion gene. CML occurs in 3 different phases (chronic, accelerated, and blast phase) and is usually diagnosed in the chronic phase in developed countries. Tyrosine kinase inhibitor (TKI) therapy is a highly effective treatment option for patients with chronic phase–CML. The primary goal of TKI therapy in patients with chronic phase–CML is to prevent disease progression to accelerated phase–CML or blast phase–CML. Discontinuation of TKI therapy with careful monitoring is feasible in selected patients. This manuscript discusses the recommendations outlined in the NCCN Guidelines for the diagnosis and management of patients with chronic phase–CML.

AbstractBackgroundThe advent of antibiotic-coated devices has reduced the rate of inflatable penile prosthesis (IPP) infections; however, this may have altered microbial profiles when infections do occur.AimTo describe the timing and causative organisms behind infection of infection retardant–coated IPPs in the context of our institution’s perioperative antimicrobial protocols.MethodsWe retrospectively reviewed all patients undergoing IPP placement at our institution from January 2014 to January 2022. In all patients, perioperative antibiotic administration was congruent with American Urological Association guidelines. Boston Scientific devices are impregnated with InhibiZone (rifampin and minocycline), and all Coloplast devices were soaked in rifampin and gentamicin. Intraoperative irrigation was performed with betadine 5% irrigation prior to November 2016 and with vancomycin-gentamicin solution afterward. Cases involving prosthesis infection were identified, and variables were extracted from the medical record. Descriptive and comparative statistics were tabulated to identify clinical characteristics, including patient comorbidities, prophylaxis regimen, symptom onset, and intraoperative culture result. We previously reported an increased infection risk with Betadine irrigation and stratified results accordingly.OutcomesThe primary outcome was time to infectious symptoms, while the secondary outcome was description of device cultures at the time of explantation.ResultsA total of 1071 patients underwent IPP placement over 8 years with an overall infection rate of 2.6% (28/1071). After discontinuation of Betadine, the overall infection rate was significantly lower at 0.9% (8/919) with a relative risk of 16.9 with Betadine (P < .0001). Primary procedures represented 46.4% (13/28). Of 28 patients with infection, only 1 had no identified risk factors; the remainder included Betadine at 71% (20/28), revision/salvage procedure at 53.6% (15/28), and diabetes at 50% (14/28). Median time to symptoms was 36 days (IQR, 26-52); almost 30% of patients had systemic symptoms. Organisms with high virulence, or ability to cause disease, were found in 90.5% (19/21) of positive cultures.Clinical ImplicationsOur study revealed a median time to symptoms of just over 1 month. Risk factors for infection were Betadine 5% irrigation, diabetes, and revision/salvage cases. Over 90% causative organisms were virulent, demonstrating a microbial profile trend since antibiotic coating development.Strengths and LimitationsThe large prospectively maintained database is a strength along with the ability to follow specific changes in perioperative protocols. The retrospective nature of the study is a limitation as well as the low infection rate, which limits certain subanalyses from being performed.ConclusionIPP infections present in a delayed manner despite the rising virulence of infecting organisms. These findings highlight areas for improvement in perioperative protocols in the contemporary prosthetics era.

OBJECTIVE There are few prior reports of acute pelvic instrumentation failure in spinal deformity surgery. The objective of this study was to determine if a previously identified mechanism and rate of pelvic fixation failure were present across multiple institutions, and to determine risk factors for these types of failures. METHODS Thirteen academic medical centers performed a retrospective review of 18 months of consecutive adult spinal fusions extending 3 or more levels, which included new pelvic screws at the time of surgery. Acute pelvic fixation failure was defined as occurring within 6 months of the index surgery and requiring surgical revision. RESULTS Failure occurred in 37 (5%) of 779 cases and consisted of either slippage of the rods or displacement of the set screws from the screw tulip head (17 cases), screw shaft fracture (9 cases), screw loosening (9 cases), and/or resultant kyphotic fracture of the sacrum (6 cases). Revision strategies involved new pelvic fixation and/or multiple rod constructs. Six patients (16%) who underwent revision with fewer than 4 rods to the pelvis sustained a second acute failure, but no secondary failures occurred when at least 4 rods were used. In the univariate analysis, the magnitude of surgical correction was higher in the failure cohort (higher preoperative T1-pelvic angle [T1PA], presence of a 3-column osteotomy; p < 0.05). Uncorrected postoperative deformity increased failure risk (pelvic incidence–lumbar lordosis mismatch > 10°, higher postoperative T1PA; p < 0.05). Use of pelvic screws less than 8.5 mm in diameter also increased the likelihood of failure (p < 0.05). In the multivariate analysis, a larger preoperative global deformity as measured by T1PA was associated with failure, male patients were more likely to experience failure than female patients, and there was a strong association with implant manufacturer (p < 0.05). Anterior column support with an L5–S1 interbody fusion was protective against failure (p < 0.05). CONCLUSIONS Acute catastrophic failures involved large-magnitude surgical corrections and likely resulted from high mechanical strain on the pelvic instrumentation. Patients with large corrections may benefit from anterior structural support placed at the most caudal motion segment and multiple rods connecting to more than 2 pelvic fixation points. If failure occurs, salvage with a minimum of 4 rods and 4 pelvic fixation points can be successful.