Jeffrey C. Flynn

Opportunistic Autoimmune Disorders Potentiated by Immune-Checkpoint Inhibitors Anti-CTLA-4 and Anti-PD-1

To improve the efficacy of immunotherapy for cancer and autoimmune diseases, recent ongoing and completed clinical trials have focused on specific targets to redirect the immune network toward eradicating a variety of tumors and ameliorating the self-destructive process. In a previous review, both systemic immunomodulators and monoclonal antibodies (mAbs), anti-CTLA-4, and anti-CD52, were discussed regarding therapeutics and autoimmune sequelae, as well as predisposing factors known to exacerbate immune-related adverse events (irAEs). This review will focus on immune-checkpoint inhibitors, and the data from most clinical trials involve blockade with anti-CTLA-4 such as ipilimumab. However, despite the mild to severe irAEs observed with ipilimumab in ~60% of patients, overall survival (OS) averaged ~22–25% at 3–5 years. To boost OS, other mAbs targeting programed death-1 and its ligand are undergoing clinical trials as monotherapy or dual therapy with anti-CTLA-4. Therapeutic combinations may generate different spectrum of opportunistic autoimmune disorders. To simulate clinical scenarios, we have applied regulatory T cell perturbation to murine models combined to examine the balance between thyroid autoimmunity and tumor-specific immunity.

Venous thromboembolism: management by American Association of Hip and Knee Surgeons.

A 2008 survey of American Association of Hip and Knee Surgeons membership explored current venous thromboembolism (VTE) protocols for lower-extremity total joint surgery. Fifty-three percent reported a change in VTE-related practices in the last 5 years. More than 70% reported that their primary hospital now mandates VTE prophylaxis. Although 74% of their primary hospitals recognized the American College of Chest Physicians guidelines, 68% of surgeons felt the American Academy of Orthopaedic Surgeons guidelines were more relevant to their practice. Respondents believe low molecular weight heparin to be the most efficacious but aspirin to be the easiest to use and has the lowest risks of bleeding and wound drainage. Warfarin was the most used in hospital prophylaxis, and 90% of respondents targeted an international normalized ratio of 1.6 to 2.5. Practice patterns continue to evolve, and there remains no consensus on specific treatment protocols or preferences.

Changing paradigms in minimally invasive surgery training

BACKGROUND Realizing the trends toward minimally invasive procedures, the Accreditation Council for Graduate Medical Education (ACGME) increased the requirements for laparoscopic procedures effective 2007 to 2008. Our purpose was to analyze the trend of laparoscopic versus open cases. METHODS We analyzed national ACGME general surgery operative log program data for basic and advanced open and laparoscopic procedures performed by graduating surgical residents between academic years 1996 to 1997 and 2009 to 2010. RESULTS From 1997 to 2010, the average number of procedures performed by graduating residents increased for appendectomies (36.5 to 59.3), cholecystectomies (90.9 to 112), hernia repairs (58.9 to 67.4), and colectomies (40.1 to 60.2). These increases have been accompanied by decreases in the percentage of open procedures for appendectomies (84% to 30%), cholecystectomies (24% to 9%), hernia repairs (90% to 70%), and colectomies (97% to 71%), which have resulted primarily from a decrease in open procedures (basic) or an increase in laparoscopic procedures (advanced). CONCLUSIONS The rising number of laparoscopic procedures performed by surgical residents is associated with a drastic decrease in the number of basic open procedures. Although the number of open procedures is sufficient to meet ACGME requirements for now, this is an area of concern for the adequacy of training in the future.

The Effect of Comorbidities on Discharge Disposition and Readmission for Total Joint Arthroplasty Patients

BACKGROUND As the annual demand and number of total joint arthroplasty cases increase, so do concerns of outcomes of patient with specific comorbidities relative to outcomes and costs of care. METHODS The study cohort included 2009 primary total knee arthroplasty (TKA) patients and 905 total hip arthroplasty patients. Discharge disposition was classified as discharge to any facility or home. The comorbidities of the patients who were readmitted and those without a 90-day event were also evaluated. RESULTS In the TKA population, age, female gender, nonsmoking status, venous thromboembolism (VTE) history, and diabetes were significantly associated with discharge to extended care facility (ECF) on univariate analysis, unlike body mass index. With multivariate analyses, female gender, age, VTE history, and diabetes were associated with ECF placement, but smoking was not. In the total hip arthroplasty population, age, female gender, and nonsmoking status were significantly associated with discharge to ECF on univariate analysis, whereas body mass index, diabetes, and VTE history were not. On multivariate analyses, female gender and age were associated with ECF, but smoking was not. The only significant finding for the readmission data was an increased rate of readmission for TKA patients of older age. CONCLUSION The potential of projecting patient discharge and readmission allows physicians to counsel patients and improve patient expectations.

Differentiation of septic and aseptic loosening by PET with both 11C-PK11195 and 18F-FDG in rat models

PurposeThis study aims to determine the value of PET with 11C-isoquinoline carboxamide (11C-PK11195) and 18F-fluorodeoxyglucose (18F-FDG) in assisting the differentiation of aseptic loosening (AL) from septic loosening (SL) in rat models. ProceduresInitially, the histological profiles of SL and AL (cellular infiltration and the number of CD68+ macrophage and PBR+ cells) were compared. Subsequently, we investigated whether 11C-PK11195 alone and also in combination with 18F-FDG increases the sensitivity and specificity of PET imaging for distinguishing SL from AL. ResultsThere were distinguishable features between the histological profiles of the SL and AL rat groups. The number of CD68+/PBR+ cells in AL rats was significantly higher than that seen in SL rats (P<0.05). The uptake of 11C-PK1195 was higher in AL and lower in SL rats. The uptake of 18F-FDG was higher in SL and lower in AL rats. ConclusionPET with a 11C-PK11195 and 18F-FDG imaging protocol is helpful in the clinical differential diagnosis of AL from SL.

Analysis and implications of changing hepatopancreatobiliary (HPB) case loads in general surgery residency training for HPB surgery accreditation

OBJECTIVE This study was conducted to determine whether residents are receiving enough hepatopancreatobiliary (HPB) training during general surgery residencies to exclude the necessity of pursuing formal fellowships in HPB surgery. METHODS Trends in HPB surgery training were examined using Accreditation Council for Graduate Medical Education (ACGME) operative log data for the academic years 1999/2000 to 2009/2010. RESULTS Of 800,000 HPB operations performed annually in the USA, the proportion of HPB procedures performed by general surgery residents increased from 15% (122,007) to 18% (143,000) between the periods under study. Numbers of pancreatic, liver and biliary procedures performed by graduating general surgery residents increased by 47% (from 8185 to 12,006), 31% (from 7468 to 9765), and 14% (from 106,354 to 121,239), respectively. The mean number of operations undertaken by a graduating resident increased from 8.3 to 11.5 (38% increase) for pancreatic surgeries, from 7.6 to 9.4 (24% increase) for liver surgeries, and from 107.5 to 116.6 (8% increase) for biliary surgeries. Total numbers of complex pancreatic, liver and biliary procedures increased by 91% (from 4768 to 9129) and 24% (from 6649 to 8233), and decreased by 29% (from 6581 to 4648), respectively. CONCLUSIONS The overall trend shows an increase in the number of HPB procedures undertaken by graduating general surgery residents. The mean number of procedures exceeds ACGME requirements, but falls short of association guidelines. However, certain residents exceed International Hepato-Pancreato-Biliary Association (IHPBA) fellowship requirements for total and complex procedures during residency. Consideration should be given to those residents to allow them to bypass fellowship training provided that they meet other IHPBA standards.

Enhanced Autoimmunity Associated with Induction of Tumor Immunity in Thyroiditis-Susceptible Mice

BACKGROUND Immunotherapeutic modalities to bolster tumor immunity by targeting specific sites of the immune network often result in immune dysregulation with adverse autoimmune sequelae. To understand the relative risk for opportunistic autoimmune disorders, we studied established breast cancer models in mice resistant to experimental autoimmune thyroiditis (EAT). EAT is a murine model of Hashimotos thyroiditis, an autoimmune syndrome with established MHC class II control of susceptibility. The highly prevalent Hashimotos thyroiditis is a prominent autoimmune sequela in immunotherapy, and its relative ease of diagnosis and treatment could serve as an early indicator of immune dysfunction. Here, we examined EAT-susceptible mice as a combined model for induction of tumor immunity and EAT under the umbrella of disrupted regulatory T cell (Treg) function. METHODS Tumor immunity was evaluated in female CBA/J mice after depleting Tregs by intravenous administration of CD25 monoclonal antibody and/or immunizing with irradiated mammary adenocarcinoma cell line A22E-j before challenge; the role of T cell subsets was determined by injecting CD4 and/or CD8 antibodies after tumor immunity induction. Tumor growth was monitored 3×/week by palpation. Subsequent EAT was induced by mouse thyroglobulin (mTg) injections (4 daily doses/week over 4 weeks). For some experiments, EAT was induced before establishing tumor immunity by injecting mTg+interleukin-1, 7 days apart. EAT was evaluated by mTg antibodies and thyroid infiltration. RESULTS Strong resistance to tumor challenge after Treg depletion and immunization with irradiated tumor cells required participation of both CD4(+) and CD8(+) T cells. This immunity was not altered by induction of mild thyroiditis with our protocol of Treg depletion and adjuvant-free, soluble mTg injections. However, the increased incidence of mild thyroiditis can be directly related to Treg depletion needed to achieve strong tumor immunity. Moreover, when a subclinical, mild thyroiditis was induced with soluble mTg and low doses of interleukin-1, to simulate pre-existing autoimmunity in patients subjected to cancer immunotherapy, mononuclear infiltration into the thyroid was enhanced. CONCLUSIONS Our current findings indicate that genetic predisposition to autoimmune disease could enhance autoimmunity during induction of tumor immunity in thyroiditis-susceptible mice. Thus, HLA genotyping of cancer patients should be part of any risk assessment.

Implant Wear Induced Inflammation Is Mitigated in CX3CR1 / Mice

Wear debris‐induced monocyte recruitment plays a key role in the formation of chronic periprosthetic tissue inflammation associated with aseptic loosening. The purpose of this study was to investigate the role(s) of chemokine receptor CX3CR1 in ultra high molecular weight polyethylene (UHMWPE) particle‐induced tissue inflammation using a murine air pouch model developed in CX3CR1 knockout (CX3CR1−/−) mice. UHMWPE debris or saline were introduced into established air pouches on CX3CR1−/− and CX3CR1+/+ mice. Pouch tissues were collected 7 days after UHMWPE inoculation. Results showed that UHMWPE stimulation induced strong pouch tissue inflammation in CX3CR1+/+ mice, as manifested by inflammatory cellular infiltration (mainly macrophages), pouch tissue proliferation, and increased gene expression of IL‐1ß and TNFα. UHMWPE‐induced inflammation was significantly mitigated in CX3CR1−/− mice, as manifested by reduction of tissue inflammation (pouch thickness and cell density), inflammatory cytokine production (IL‐1ß and TNFα) and macrophage accumulation. The observations support the hypothesis that the activation of the CX3CR1 chemokine pathway contributes to the severity of UHMWPE particle‐induced tissue inflammation, and suggests that CX3CR1 signaling is involved in the recruitment of monocytes to the wear debris‐containing inflammatory tissues. Blocking of CX3CR1 pathway may represent a viable therapeutic approach to the prevention and treatment of patients with aseptic loosening.

Relationship of Blood Metal Ion Levels and Leukocyte Profiles in Patients With Articular Surface Replacement Metal-on-Metal Hip Replacement

The purpose of this study was to compare blood leukocyte profiles and metal ion concentrations between hip resurfacing arthroplasty (articular surface replacement) patients with and without revision. A total of 25 articular surface replacement patients were recruited (10 with stable implants and 15 undergoing revision). Blood concentrations of chromium (Cr) and cobalt (Co) were measured. Flow cytometry was used to quantify the subpopulations of leukocytes, including CD14+ monocytes, CD16+ monocytes, CD3+ T-lymphocytes, CD19+ B-lymphocytes, CD4+ helper T-cells, and CD45+RA memory vs naïve T-cells. Patients undergoing revision had higher blood Co (mean, 10.85 µg/L) and Cr (mean, 3.19 µg/L) levels than patients with stable implants (mean Co, 3.06 µg/L; mean Cr, 1.07 µg/L) (P<.05). The number of CD4+ helper T-cells was higher in patients with stable implants (mean, 842±311 cells/µL) than in patients undergoing revision (mean, 591±208 cells/µL) (P<.05). There was a significant association between total metal ion levels (Co+Cr) and the number of CD14+ monocytes (P=.045) and inflammatory CD16+ monocytes (P=.046). The authors observed that the increase in blood metal ions was associated with an increase in CD16+ monocytes. They believe that continued analysis of blood leukocyte profiles may be helpful in defining differences among failed articular surface replacement, stable articular surface replacement, and failed metal-on-polyethylene implants. [Orthopedics. 2018; 41(3):e424-e431.].

Elution Profiles of Two Methods of Antibiotic Tibial Nail Preparations

Interlocking nails coated with antibiotic-supplemented cement provide effective treatment of infected long bone nonunion, but the thicker coating on guidewires may provide greater antibacterial activity. This study compared the properties of cement cured on each construct by evaluating 2-cm segments of 8-mm interlocking nails and 3.5-mm guidewires coated with antibiotic-supplemented cement. Each construct (n=7 for each group) was coated with polymethylmethacrylate cement (Simplex; Stryker Orthopaedics, Mahwah, New Jersey) containing either 1 g tobramycin or 1 g vancomycin powder plus 2.2 g tobramycin powder. A No. 40 French polyvinyl chloride chest tube was used as a mold for all constructs. Segments were soaked in sterile phosphate-buffered saline, and entire aliquots were exchanged at various intervals over a 6-week period. Antibiotic concentration, antibacterial activity, cement curing temperature, and porosity were measured. At least half of the total elution of antibiotics occurred within the first 24 hours for all constructs. For the tobramycin-only cement, no differences between constructs were observed. For constructs containing both antibiotics, interlocking nails showed more antibiotic release than guidewires at most time points (P<.05-P<.001). Antibiotics were released for 6 weeks and continued to inhibit Staphylococcus aureus growth. Cement curing temperatures for interlocking nails were lower than those for guidewires (P<.05). Guidewires coated with cement containing tobramycin and vancomycin showed significantly greater porosity compared with the other 3 groups (P<.05), but the amount of antibiotic released did not directly relate to porosity for any construct type. Interlocking nails coated with antibiotic-supplemented cement may provide greater antibiotic delivery to infected long bone nonunion compared with guidewires. A thin mantle of cement may allow greater elution, possibly as a result of cooler exothermic reactions. [Orthopedics. 2017; 40(3):e436-e442.].