Diabetes is related with increased cancer mortality across multiple cancer types. Its role in lung cancer mortality is still unclear. We aim to determine the prognostic value of fasting plasma ...glucose (FPG) and diabetes mellitus in patients with locally advanced non-small cell lung cancer (NSCLC) treated with concurrent chemoradiotherapy.
One-hundred seventy patients with stage III NSCLC received definitive concurrent chemoradiotherapy from 2010 to 2014. Clinico-pathological data and clinical outcome was retrospectively registered. Fifty-six patients (33%), met criteria for type 2 diabetes mellitus (T2DM) at baseline. The prognostic value of FPG and other clinical variables was assessed. Overall survival (OS) and progression-free survival (PFS) were estimated using the Kaplan-Meier method and Cox proportional models and log-rank test were used.
With a median follow-up of 36 months, median PFS was 8.0 months and median OS was 15.0 months in patients with FPG ≥7 mmol/L compared to 20 months (HR 1.13; 95% CI 1.07-1.19, p < 0.001) and 31 months (HR 1.09; 95% CI 1.04-1.15; p < 0.001) respectively, for patients with FPG < 7 mmol/L. In the multivariate analysis of the entire cohort adjusted by platinum compound and comorbidities, high levels of FPG as a continuous variable (HR 1.14; 95% CI 1.07-1.21; p < 0.001), the presence of comorbidity (HR 1.72; 95% CI 1.12-2.63; p = 0.012), and treatment with carboplatin (HR 1.95; 95% CI 1.26-2.99; p = 0.002) were independent predictors for shorter OS. In additional multivariate models considering non-diabetic patients as a reference group, diabetic patients with poor metabolic control (HbA1c > 8.5%) (HR 4.53; 95% CI 2.21-9.30; p < 0.001) and those receiving insulin (HR 3.22; 95% CI 1.90-5.46 p < 0.001) had significantly independent worse OS.
Baseline FPG level is an independent predictor of survival in our cohort of patients with locally advanced NSCLC treated with concurrent chemoradiotherapy. Studies in larger cohorts of patients are warranted to confirm this relevant association.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
In Burkitt lymphoma/leukemia (BL), achievement of complete remission with first-line chemotherapy remains a challenging issue, as most patients who respond remain disease-free, whereas those ...refractory have few options of being rescued with salvage therapies. The mechanisms underlying BL chemoresistance and how it can be circumvented remain undetermined. We previously reported the frequent inactivation of the proapoptotic BIM gene in B-cell lymphomas. Here we show that BIM epigenetic silencing by concurrent promoter hypermethylation and deacetylation occurs frequently in primary BL samples and BL-derived cell lines. Remarkably, patients with BL with hypermethylated BIM presented lower complete remission rate (24% vs 79%; P = .002) and shorter overall survival (P = .007) than those with BIM-expressing lymphomas, indicating that BIM transcriptional repression may mediate tumor chemoresistance. Accordingly, by combining in vitro and in vivo studies of human BL-xenografts grown in immunodeficient RAG2−/−γc−/− mice and of murine B220+IgM+ B-cell lymphomas generated in Eµ-MYC and Eµ-MYC-BIM+/− transgenes, we demonstrate that lymphoma chemoresistance is dictated by BIM gene dosage and is reversible on BIM reactivation by genetic manipulation or after treatment with histone-deacetylase inhibitors. We suggest that the combination of histone-deacetylase inhibitors and high-dose chemotherapy may overcome chemoresistance, achieve durable remission, and improve survival of patients with BL.
Immune mechanisms have evolved to cope with local entry of microbes acting in a confined fashion but eventually inducing systemic immune memory. Indeed, in situ delivery of a number of agents into ...tumors can mimic in the malignant tissue the phenomena that control intracellular infection leading to the killing of infected cells. Vascular endothelium activation and lymphocyte attraction, together with dendritic cell-mediated cross-priming, are the key elements. Intratumoral therapy with pathogen-associated molecular patterns or recombinant viruses is being tested in the clinic. Cell therapies can be also delivered intratumorally, including infusion of autologous dendritic cells and even tumor-reactive T lymphocytes. Intralesional virotherapy with an HSV vector expressing GM-CSF has been recently approved by the Food and Drug Administration for the treatment of unresectable melanoma. Immunomodulatory monoclonal Abs have also been successfully applied intratumorally in animal models. Local delivery means less systemic toxicity while focusing the immune response on the malignancy and the affected draining lymph nodes.
Sirtuins are NAD
-dependent deacetylases that regulate cell metabolism through protein acetylation/deacetylation, and SIRT3 is the major deacetylase among mitochondrial isoforms. Here, we elucidated ...the possible role of acetylation of cyclophilin D, a key regulator of the mitochondrial permeability transition pore (mPTP), in mitochondria-mediated cardiac dysfunction induced by ischemia-reperfusion (IR) in wild type (WT) and SIRT3 knockout (SIRT3
) mice.
Isolated and Langendorff-mode perfused hearts of WT and SIRT3
mice were subjected to 25-min global ischemia followed by 60-min of reperfusion in the presence or absence of the mPTP inhibitor, sanglifehrin A (SfA).
Analysis of mitochondrial sirtuins demonstrated that SIRT3 deficiency upregulated SIRT4 with no effect on SIRT5 expression. Hearts of SIRT3
mice exhibited significantly less recovery of cardiac function at the end of IR compared to WT mice. Intact (non-perfused) SIRT3
hearts exhibited an increased rate of Ca
-induced swelling in mitochondria as an indicator of mPTP opening. However, there was no difference in mPTP opening and cyclophilin D acetylation between WT and SIRT3
hearts subjected to IR injury. Ca
-stimulated H
O
production was significantly higher in SIRT3
mitochondria that was prevented by SfA. Superoxide dismutase activity was lower in SIRT3
heart mitochondria subjected to IR which correlated with an increase in protein carbonylation. However, mitochondrial DNA integrity was not affected in SIRT3
hearts after IR.
SIRT3 deficiency exacerbates cardiac dysfunction during post-ischemic recovery, and increases mPTP opening and ROS generation without oxidative damage to mitochondrial proteins and DNA.
With the increased legalization of cannabis, a new unknown emerges for orthopaedic surgeons and their patients. This systematic review aimed to (1) evaluate complications of cannabis use; (2) ...determine the effects of cannabis on pain and opioid consumption; and (3) evaluate healthcare utilizations associated with cannabis use among patients undergoing total joint arthroplasty (TJA).
A systematic review was performed. A search of the literature was performed in 5 databases. We included studies between January 2012 and July 2022 reporting cannabis use and complications, pain management, opioid consumption, length of stay, costs, or functional outcomes following TJA. A meta-analysis of odds ratios (ORs) and continuous variables was performed. A total of 19 articles were included in our final analysis.
Cannabis use was associated with higher odds for deep vein thrombosis (DVT) (OR: 1.46, 95% Confidence Interval CI: 1.13 to 1.89) and revisions (OR: 1.47 95% CI: 1.41 to 1.53) in total knee arthroplasty (TKA). Cannabis use was associated with similar odds for DVT in total hip arthroplasty (THA) (OR: 1.30 95% CI: 0.79 to 2.13), pulmonary embolus in both TKA (OR: 1.29 95% CI: 0.95 to 1.77), THA (OR: 0.55 95% CI: 0.09 to 3.28), and cardiovascular complications in TKA (OR: 1.97 95% Cl: 0.93 to 4.14). Cannabis use did not alter pain scores, opioid consumption, or cost of care in THA (estimate: $2,550.51 95% CI: $356.58 to $5,457.62) but was associated with higher costs in TKA (estimate: $3,552.46 95% CI: $1,729.71 to $5,375.22). There was no difference in lengths of stay or functional outcomes; however, there may be a potentially increased risk for prosthetic complications, pneumonia, and cerebrovascular accidents among cannabis users.
Cannabis use may be associated with an increased risk of DVTs, revisions, pneumonia, cerebrovascular accidents, and cardiac complications after TJA. Higher-level studies are needed to ascertain the impact of cannabis use for patients undergoing TJA.
Uveal melanoma (UM) is a rare disease that can be deadly in spite of adequate local treatment. Systemic therapy with chemotherapy is usually ineffective and new-targeted therapies have not improved ...results considerably. The eye creates an immunosuppressive environment in order to protect eyesight. UM cells use similar processes to escape immune surveillance. Regarding innate immunity the production of macrophage inhibiting factor (MIF) and TGF-β, added to MHC class I upregulation, inhibits the action of natural killer (NK) cells. UM cells produce cytokines such as IL-6 and IL-10 that favor macrophage differentiation to the M2 subtype, which promote tumor growth instead of an effective immune response. UM cells also impair the adaptive immune response through production of indoleamine 2,3-dioxygenase (IDO), overexpression of programmed death ligand-1 (PD-L1), alteration of FasL expression, and resistance to perforin. This biological background suggests that immunotherapy could be effective in fighting UM. A Phase II clinical trial with Ipilimumab has shown promising results with mean Overall Survival rate of ten months, and close to 50% of the patients alive at one year. Clinical trials with anti-PD1 antibodies in monotherapy and in combination with anti-CTLA4 are currently recruiting patients worldwide.
Orthopaedic practices in the U.S. face a growing demand for total joint arthroplasties (TJAs), while the orthopaedic workforce size has been stagnant for decades. This study aimed to estimate annual ...TJA demand and orthopaedic surgeon workforce supply from 2020 to 2050, and to develop an arthroplasty surgeon growth indicator (ASGI), based on the arthroplasty-to-surgeon ratio (ASR), to gauge nationwide supply and demand trends.
National Inpatient Sample and Association of American Medical Colleges data were reviewed for individuals who underwent primary TJA and for active orthopaedic surgeons (2010 to 2020), respectively. The projected annual TJA volume and number of orthopaedic surgeons were modeled using negative binominal and linear regression, respectively. The ASR is the number of actual (or projected) annual total hip (THA) and/or knee (TKA) arthroplasties divided by the number of actual (or projected) orthopaedic surgeons. ASGI values were calculated using the 2017 ASR values as the reference, with the resulting 2017 ASGI defined as 100.
The ASR calculation for 2017 showed an annual caseload per orthopaedic surgeon (n = 19,001) of 24.1 THAs, 41.1 TKAs, and 65.2 TJAs. By 2050, the TJA volume was projected to be 1,219,852 THAs (95% confidence interval CI: 464,808 to 3,201,804) and 1,037,474 TKAs (95% CI: 575,589 to 1,870,037). The number of orthopaedic surgeons was projected to decrease by 14% from 2020 to 2050 (18,834 95% CI: 18,573 to 19,095 to 16,189 95% CI: 14,724 to 17,655). This would yield ASRs of 75.4 THAs (95% CI: 31.6 to 181.4), 64.1 TKAs (95% CI: 39.1 to 105.9), and 139.4 TJAs (95% CI: 70.7 to 287.3) by 2050. The TJA ASGI would double from 100 in 2017 to 213.9 (95% CI: 108.4 to 440.7) in 2050.
Based on historical trends in TJA volumes and active orthopaedic surgeons, the average TJA caseload per orthopaedic surgeon may need to double by 2050 to meet projected U.S. demand. Further studies are needed to determine how the workforce can best meet this demand without compromising the quality of care in a value-driven health-care model. However, increasing the number of trained orthopaedic surgeons by 10% every 5 years may be a potential solution.
Background:
Mortality after total hip arthroplasty (THA) is a rare but devastating complication. This meta-analysis aimed to: (1) determine the mortality rates at 30 days, 90 days, 1 year, 5 years ...and 10 years after THA; (2) identify risk factors and causes of mortality after THA.
Methods:
Pubmed, MEDLINE, Cochrane, EBSCO Host, and Google Scholar databases were queried for studies reporting mortality rates after primary elective, unilateral THA. Inverse-proportion models were constructed to quantify the incidence of all-cause mortality at 30 days, 90 days, 1 year, 5 years and 10 years after THA. Random-effects multiple regression was performed to investigate the potential effect modifiers of age (at time of THA), body mass index, and gender.
Results:
A total of 53 studies (3,297,363 patients) were included. The overall mortality rate was 3.9%. The 30-day mortality was 0.49% (95% CI; 0.23–0.84). Mortality at 90 days was 0.47% (95% CI, 0.38–0.57). Mortality increased exponentially between 90 days and 5 years, with a 1-year mortality rate of 1.90% (95% CI, 1.22–2.73) and a 5-year mortality rate of 9.85% (95% CI, 5.53–15.22). At 10-year follow-up, the mortality rate was 16.43% (95% CI, 1.17–22.48). Increasing comorbidity indices, socioeconomic disadvantage, age, anaemia, and smoking were found to be risk factors for mortality. The most commonly reported causes of death were ischaemic heart disease, malignancy, and pulmonary disease.
Conclusions:
All-cause mortality remains low after contemporary THA. However, 1 out of 10 patients and 1 out of 6 patients were deceased after 5 years and 10 years of THA, respectively. As expected, age, but not BMI or gender, was significantly associated with mortality.
Approximately 80% of hip and knee surgeons will face malpractice litigation. Understanding contemporary reasons for litigation and legal outcomes in our field may help surgeons deliver more effective ...and satisfying care, while limiting their legal exposure. This study aimed to determine: 1) which orthopaedic subspecialties were most frequently litigated; 2) malpractice damages and negligence claimed; 3) the proportion of different case outcomes; and 4) factors associated with defense verdicts.
A nationwide database was queried for all orthopaedic medical malpractice claims (2015 to 2020), obtaining 164 claims from 17 states. Variables included were as follows: case outcome, indemnity payment, damages, negligence claimed, treatment, and patient characteristics. A binary logistic regression determined if any collected variable increased the likelihood of a defense verdict.
Hip and knee cases were the highest-represented (n = 49, 29.9%; knee: n = 26, 15.9%; hip: n = 23, 14.0%), followed by the spine (n = 36; 22.0%), trauma (n = 29;17.7%), hand and wrist (n = 16; 9.8%), sports (n = 16; 9.1%), foot and ankle (n = 7; 4.3%), pediatric (n = 6; 3.7%), and shoulder (n = 6; 3.7%). Within hip and knee surgery, defense verdicts occurred in 38 cases (77.6%), while 9 (18.4%) resulted in plaintiff verdicts (mean payment: $4,866,929) and 2 (4.1%) resulted in settlements (mean settlement: $1,550,000). Nonreversible damages (eg, paralysis, amputation, and death; P < .001) were associated with a decreased likelihood of a defense outcome.
Hip and knee cases were the highest-represented in orthopaedic malpractice litigation. Surgeons were more frequently found negligent when nonreversible damages occurred. Orthopaedic surgeons should be cognizant of litigation patterns while ensuring patient-centered high-quality care.
Technological innovation in orthopaedics is key to advancing patient care. As emerging technologies near maturity, clinicians must be able to objectively assess where and when these technologies can ...be implemented. Patent databases are an underappreciated resource for quantifying innovation, especially within orthopaedic surgery. This study used a patent database to assess patent activity and relative growth of technologies in musculoskeletal medicine and orthopaedics over a period of 46 years.
A total of 121,471 patent records were indexed from Lens.org , a patent database. These patents were grouped into subspecialty clusters and technology clusters using patent codes. Five-year (2014 to 2018), 10-year (2009 to 2018), and 30-year (1989 to 2018) compound annual growth rates were calculated and compared for each cluster.
Annual patent activity increased from one patent in 1973 to 4,866 patents in 2018. Of the eight subspecialty clusters, the largest number of patents were related to 'Inflammation' (n = 63,128; 40.57%). The 'Elbow', 'Shoulder', and 'Knee' clusters experienced increased annual patent activity since 2000. Of the 12 technological clusters, the largest number of patents were related to 'Drugs' (n = 55,324; 39.75%). The 'Custom/patient-specific instrumentation, 'Computer Modeling', 'Robotics', and 'Navigation' clusters saw growth in the average annual patent activity since 2000.
Innovation, as measured by patent activity in musculoskeletal medicine and orthopaedics, has seen notable growth since 1973. The 'Robotics' cluster seems poised to experience exponential growth in industry investment and technological developments over the next 5 to 10 years. The 'Diagnostics', 'Computer Modeling', 'Navigation', and 'Design and Manufacturing' clusters demonstrate potential for exponential growth in industry investment and technological developments within the next 10 to 20 years.
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