Citations

BACKGROUND: Delayed hypopituitarism is the most common complication after stereotactic radiosurgery (SRS) for pituitary adenomas. OBJECTIVE: To investigate the relationship between neuroanatomic structure distances from the radiation target and anterior pituitary function preservation after SRS through multicenter study. METHODS: We retrospectively reviewed the International Radiosurgery Research Foundation database from January 2002 to December 2021 for adult patients undergoing SRS for pituitary adenomas with >6 months of follow-up. Distances between centers or edges of hypothalamic-pituitary axis structures and SRS target volumes were measured using MRI. The primary outcome was anterior pituitary function preservation. Predictors were analyzed using multivariable logistic regression and area under the receiver operating curve (AUROC) curve analyses. RESULTS: Four hundred eighty-seven patients were categorized by preservation (n = 384) and no preservation (n = 103) of anterior pituitary function. The mean margin dose was 19.1(6.2) Gy. Larger distance from the center of the stalk to the tumor margin isodose was a positive predictor (adjusted odds ratio [aOR] = 1.162 [1.046-1.291], P = .005), while pre-SRS hypopituitarism (aOR = 0.646 [0.405-1.031], P = .067) and larger treatment volume (aOR = 0.965 [0.929-1.002], P = .061) were near negative predictors of the primary outcome. An interaction between the treatment volume and center stalk to margin isodose distance was found (aOR = 0.980 [0.961-0.999], P = .045). Center stalk to margin isodose distance had an AUROC of 0.620 (0.557-0.693), at 3.95-mm distance. For patients with treatment volumes of <2.34 mL, center stalk to margin isodose distance had an AUROC of 0.719 (0.614-0.823), at 2.95-mm distance. CONCLUSION: Achieving a distance between the center of the pituitary stalk and the tumor margin isodose ≥3.95 mm predicted anterior pituitary function preservation. For smaller treatment volumes <2.34 mL, the optimal distance was ≥2.95 mm. This may be modifiable during trans-sphenoidal resection to preserve pituitary function.

17 Background: Rectal cancer is among the top ten cancers in Kenya with most patients presenting with locally advanced rectal cancer (LARC). Management requires multimodality treatment including neo-adjuvant therapy and surgery. There is limited data on the outcome for patients with LARC from Kenya and the broader region. The aim of our study was to evaluate outcomes of LARC from a tertiary hospital in Nairobi, Kenya, to identify barriers to care and methods to improve cancer outcomes. Methods: We conducted a retrospective study of patients with LARC treated at the Kenyatta National Hospital between January 2016 and January 2020. Patients with histologic confirmation of rectal cancer, received neo-adjuvant treatment, and had available survival data in the electronic medical record were included in the analysis. A data abstraction tool was used to collect patient demographics and cancer outcomes including age, gender, tumor stage, cancer and vital status. Overall and progression-free survival were estimated using the Kaplan-Meier method. Results: A total of 182 patients were identified that met inclusion on the study. The median age of 53 years (range, 21 - 82) years, 52.5% were female and 94.5% had cT3 (57.5%) or cT4 (37%) disease and 75% of patients had N+ disease. The time from symptoms onset to diagnosis and diagnosis date to treatment was 14 and 3.6 months, respectively. months76% of patients were from rural regions of Kenya. Most patients (95%) received long-course chemoradiation (50.4 Gy/28 fractions) with concurrent Capecitabine 825 mg/m2 chemotherapy. Only 5% (n=9) of patients had resection after neoadjuvant therapy. The median progression free and overall survival after neo-adjuvant treatment respectively was 24 months (IQR: 23 – 25 months) and 36 months (IQR: 24 – 36 months), respectively. Presence of comorbidities (OR =7.87, 95% CI: 3.46 – 17.89, p<0.001), tumor staging cT3 (OR = 2.34, 95% CI: 1.13 – 7.49, p =0.013), tumor staging cT4 (OR =4.02, 95% CI: 2.12 – 10.34, p =0.004) and increase in duration of symptoms by one month (OR =1.04, 95% CI: 1.01 – 2.14, p =0.003) were significantly associated with lower overall survival. Conclusions: Our results represent one of the largest series of outcomes for rectal cancer from Sub-Saharan Africa and serves as a baseline for clinical improvement. The long interval from symptom onset to diagnosis represents an area for patient intervention and development of screening protocols. Further exploration into the barriers that limit access to surgery is warranted and development of a non-operative protocol may serve the patient population due to the limited capacity of surgery.

Background: COVID-19 is associated with higher morbidity and mortality in patients with chronic liver diseases (CLDs). However, our understanding of the long-term outcomes of COVID-19 in patients with CLD is limited. Methods: We conducted a multicenter, observational cohort study of adult patients with CLD who were diagnosed with COVID-19 before May 30, 2020, to determine long-term clinical outcomes. We used a control group of patients with CLD confirmed negative for COVID-19. Results: We followed 666 patients with CLD (median age 58 years, 52.8% male) for a median of 384 (interquartile range: 31–462) days. The long-term mortality was 8.1%; with 3.6% experiencing delayed COVID-19-related mortality. Compared to a propensity-matched control group of patients with CLD without COVID-19 (n=1332), patients with CLD with COVID-19 had worse long-term survival [p<0.001; hazards ratio (HR): 1.69; 95% CI: 1.19–2.41] and higher rate of hospitalization (p<0.001, HR: 2.00, 1.62–2.48) over a 1-year follow-up period. Overall, 29.9% of patients reported symptoms of long-COVID-19. On multivariable analysis, female sex (p=0.05, HR: 2.45, 1.01–2.11), Hispanic ethnicity (p=0.003, HR: 1.94, 1.26–2.99), and severe COVID-19 requiring mechanical ventilation (p=0.028, HR: 1.74, 1.06–2.86) predicted long-COVID-19. In survivors, liver-related laboratory parameters showed significant improvement after COVID-19 resolution. COVID-19 vaccine status was available for 72% (n=470) of patients with CLD and history of COVID-19, of whom, 70% (n=326) had received the COVID-19 vaccine. Conclusions: Our large, longitudinal, multicenter study demonstrates a high burden of long-term mortality and morbidity in patients with CLD and COVID-19. Symptoms consistent with long-COVID-19 were present in 30% of patients with CLD. These results illustrate the prolonged implications of COVID-19 both for recovering patients and for health care systems.

Abstract Multiple myeloma (MM) bone disease is a significant cause of morbidity but there is a paucity of data on the impact of malignant plasma cells on adjacent trabecular bone within the BM. Here, we characterize the proteome of trabecular bone tissue from BM biopsies of 56 patients with monoclonal gammopathy of undetermined significance (MGUS), smoldering (SMM), newly diagnosed (NDMM), relapsed MM (RMM), and normal controls. Proteins involved in extracellular matrix (ECM) formation and immunity pathways were decreased in SMM and active MM. Among the proteins most decreased were immunoglobulins, type IV collagen, and TIMP3, suggesting increased immunoparesis and decreased ECM remodelling within trabecular bone. Proteins most increased in SMM/MM were APP (enhances osteoclast activity), ENPP1 (enhances bone mineralization), and MZB1 (required for normal plasmablast differentiation). Pathway analyses showed that proteins involved in gamma -carboxylation, a pathway implicated in osteocalcin function, osteoblast differentiation, and normal hematopoiesis, were also overexpressed in SMM/MM. This study is the first comprehensive proteomic atlas of the BM bone proteome in dysproteinemias. We identify new key proteins and pathways for MM bone disease and potentially impaired hematopoiesis, and show for the first time that gamma -carboxylation pathways are increased in the bone tissue of SMM/MM.

BACKGROUND: Decompression of the injured spinal cord confers neuroprotection. Compared with timing of surgery, verification of surgical decompression is understudied. OBJECTIVE: To compare the judgment of cervical spinal cord decompression using real-time intraoperative ultrasound (IOUS) following laminectomy with postoperative MRI and CT myelography. METHODS: Fifty-one patients were retrospectively reviewed. Completeness of decompression was evaluated by real-time IOUS and compared with postoperative MRI (47 cases) and CT myelography (4 cases). RESULTS: Five cases (9.8%) underwent additional laminectomy after initial IOUS evaluation to yield a final judgment of adequate decompression using IOUS in all 51 cases (100%). Postoperative MRI/CT myelography showed adequate decompression in 43 cases (84.31%). Six cases had insufficient bony decompression, of which 3 (50%) had cerebrospinal fluid effacement at >1 level. Two cases had severe circumferential intradural swelling despite adequate bony decompression. Between groups with and without adequate decompression on postoperative MRI/CT myelography, there were significant differences for American Spinal Injury Association motor score, American Spinal Injury Association Impairment Scale grade, AO Spine injury morphology, and intramedullary lesion length (IMLL). Multivariate analysis using stepwise variable selection and logistic regression showed that preoperative IMLL was the most significant predictor of inadequate decompression on postoperative imaging ( P = .024). CONCLUSION: Patients with severe clinical injury and large IMLL were more likely to have inadequate decompression on postoperative MRI/CT myelography. IOUS can serve as a supplement to postoperative MRI/CT myelography for the assessment of spinal cord decompression. However, further investigation, additional surgeon experience, and anticipation of prolonged swelling after surgery are required.

Abstract Background and study aims Concomitant hiatal hernia (HH) repair with transoral incisionless fundoplication (TIF) is a therapeutic option for patients with HH > 2 cm and gastroesophageal reflux disease (GERD). Data comparing this approach with laparoscopic Nissen fundoplication (LNF) are lacking. We performed an exploratory analysis to compare these two approaches' adverse events (AEs) and clinical outcomes. Patients and methods This was a multicenter retrospective cohort study of HH repair followed by LNF versus HH repair followed by TIF in patients with GERD and moderate HH (2–5 cm). AEs were assessed using the Clavien-Dindo classification. Symptoms (heartburn/regurgitation, bloating, and dysphagia) were compared at 6 and 12 months. Results A total of 125 patients with HH repair with TIF and 70 with HH repair with LNF were compared. There was no difference in rates of discontinuing or decreasing proton pump inhibitor use, dysphagia, esophagitis, disrupted wrap, and HH recurrence between the two groups (P > 0.05). The length of hospital stay (1 day vs. 2 days), 30-day readmission rate (0 vs. 4.3 %), early AE rate (0 vs. 18.6 %), and early serious AE rate (0 vs. 4.3 %) favored TIF (all P < 0.05). The rate of new or worse than baseline bloating was lower in the TIF group at 6 months (13.8 % vs. 30.0 %, P = 0.009). Conclusions Concomitant HH repair with TIF is feasible and associated with lower early and serious AEs compared to LNF. Further comparative efficacy studies are warranted.

AbstractWell‐selected patients with kidney disease and diabetes mellitus who undergo simultaneous kidney‐pancreas transplantation often experience dramatic improvements in quality of life and long‐term survival compared to those who remain on medical therapy. Over the past several years the importance of frailty in the pancreas transplant candidate and recipient populations has grown. More patients with advanced age have entered the waitlist, and complications from prolonged diabetes, even in younger patients, have created increased evidence of risk for frailty. Given these concerns, and the broad challenges facing pancreas transplantation volumes overall, we generated this review to help establish the impact and implications. We summarize the interplay of immunological factors, aging, environmental factors, diabetes mellitus, and chronic kidney disease that put these patients at risk for frailty. We discuss its measurement and recommend a combination of two instruments (both well‐validated and one entirely objective). We describe the outcomes for patients before and after pancreas transplantation who may have frailty, and what interventions can be taken to mitigate its effects. Broader investigation into frailty in the pancreas transplant population is needed to better understand how to select patients for pancreas transplantation and to how manage its consequences thereafter.

Abstract The MHC class I antigen presentation pathway in melanoma cells has a well-established role in immune-mediated destruction of tumors. However, the clinical significance of the MHC class II antigen presentation pathway in melanoma cells is less clear. In antigen presenting cells, gamma-interferon-inducible lysosomal thiol reductase (GILT) is critical for MHC class II-restricted presentation of multiple melanoma antigens. While not expressed in benign melanocytes of nevi, GILT and MHC class II expression is induced in malignant melanocytes in a portion of melanoma specimens. Analysis of The Cancer Genome Atlas (TCGA) cutaneous melanoma dataset showed that high GILT mRNA expression was associated with improved overall survival. Expression of IFN-γ, TNF-α, and IL-1β was positively associated with GILT expression in the TCGA melanoma specimens. These cytokines were capable of inducing GILT expression in melanoma cells in vitro. GILT protein expression in melanocytes was induced in halo nevi, which are nevi undergoing immune-mediated regression, and is consistent with the association of GILT expression with improved survival in melanoma. To explore potential mechanisms of GILT’s association with patient outcome, we analyzed the mRNA expression pattern in the MHC class II antigen presentation pathway. In contrast to healthy skin where the MHC class II pathway was nearly uniformly expressed and intact, there was substantial variation in the MHC class II pathway of the TCGA melanoma dataset. Both an active and intact MHC class II pathway were associated with improved overall survival in melanoma. These studies support a role for GILT and the MHC class II antigen presentation pathway in melanoma outcome.

Abstract NK cells are a subpopulation of lymphocytes that kill virally infected cells and tumor cells without previous sensitization. Although exposure to distinct cytokines, including IL-2 and IL-12, can enhance these cytotoxic responses, the mechanism of this lymphokine-augmented killing remains unclear. Inasmuch as the cytotoxic event is a multistep process, there are many potential targets for lymphokine regulation. We focused on whether selected lymphokines directly modulate the intracellular signaling pathways critical for NK cell secretory function. In our experimental model, homogeneous, cloned human CD16+/CD3- NK cells were pretreated with either IL-2 or IL-12 and then stimulated with direct pharmacologic activators of the secretory response (e.g., PMA and ionomycin for intact cells or GTP gamma S for streptolysin-O permeabilized cells). Previous exposure of the cells to IL-2 or IL-12 enhanced the stimulus-induced release of granule-derived proteins (hexosaminidase and serine proteases) in a cytokine concentration- and time-dependent fashion. Furthermore, the cytokines increased the efficacies without changing the potencies of the secretagogues used in these studies. These results suggest that IL-2 and IL-12 augment NK cell-mediated cytotoxicity by increasing the maximal level of granule exocytosis evoked by Ca2+ and/or G protein-dependent intracellular signaling pathways.