Treatment Strategies In High-risk Patients Research Articles

DEDICATE trial: the devil lies in the definition of "low risk".

Transcatheter aortic-valve replacement (TAVR) has evolved from a treatment strategy for high-risk patients to an option for low-risk individuals, prompting the need for rigorous comparisons with surgical aortic-valve replacement (SAVR). The German-Austrian Prospective Randomized Trial of Transcatheter Aortic Valve Implantation Versus Conventional Surgical Aortic Valve Replacement in Low and Intermediate Risk Patients (DEDICATE) trial compares low- and intermediate-risk patient undergoing SAVR and TAVR. This review outlines the trial design, key findings, strengths, and weaknesses of the study and also highlights the urgent need for standardized definitions of low-risk patients in future trials to ensure accurate comparisons and robust conclusions.

Predicting prostate adenocarcinoma patients’ survival and immune signature: a novel risk model based on telomere-related genes

Alterations in telomeres constitute some of the earliest occurrences in the tumourigenesis of prostate adenocarcinoma (PRAD) and persist throughout the progression of the tumour. While the activity of telomerase and the length of telomeres have been demonstrated to correlate with the prognosis of PRAD, the prognostic potential of telomere-related genes (TRGs) in this disease remains unexplored. Utilising mRNA expression data from the Cancer Genome Atlas (TCGA), we devised a risk model and a nomogram to predict the survival outcomes of patients with PRAD. Subsequently, our investigations extended to the relationship between the risk model and immune cell infiltration, sensitivity to chemotherapeutic drugs, and specific signalling pathways. The risk model we developed is predicated on seven key TRGs, and immunohistochemistry results revealed significant differential expression of three TRGs in tumours and paracancerous tissues. Based on the risk scores, PRAD patients were stratified into high-risk and low-risk cohorts. The Receiver operating characteristics (ROC) and Kaplan–Meier survival analyses corroborated the exceptional predictive performance of our novel risk model. Multivariate Cox regression analysis indicated that the risk score was an independent risk factor associated with Overall Survival (OS) and was significantly associated with T and N stages of PRAD patients. Notably, the high-risk group exhibited a greater response to chemotherapy and immunosuppression compared to the low-risk group, offering potential guidance for treatment strategies for high-risk patients. In conclusion, our new risk model, based on TRGs, serves as a reliable prognostic indicator for PRAD. The model holds significant value in guiding the selection of immunotherapy and chemotherapy in the clinical management of PRAD patients.

Analysis of metabolic syndrome in bilateral upper urinary tract stones: A retrospective study of 3905 cases

Bilateral upper urinary tract stones are significantly related to renal function damage. However, few studies characterized the risk factors of bilateral upper urinary tract stones. We retrospectively enrolled 3905 patients with urinary tract stones from March 2019 to March 2022 at the Second Hospital of Tianjin Medical University. Patients were divided into two groups according to the location of the stones, and the related data were evaluated. In this study, 2485 unilateral and 1420 bilateral stone patients were included. Multivariate logistic regression analysis showed that BMI, gout, hyperparathyroidism, uric acid stone, urine PH, 24-h urinary calcium, blood uric acid, and metabolic syndrome (Mets) were independent risk factors for bilateral stone formation(P < 0.05). Based on these results, we construct a discrimination model. This model revealed good discrimination with an area under the receiver operating characteristic curves of 0.617, and the sensitivity and specificity were 0.592 and 0.586, respectively. Furthermore, the number of Mets components increased the risk of bilateral upper urinary tract stones. Hypertension, hyperglycemia, and low HDL level were strongly associated with bilateral upper urinary tract stones (P < 0.05). Patients with 5 components Mets had 1.89-fold higher risk of bilateral upper urinary tract stones than those with 1 component Mets (OR 3.381; 95 % CI 1.221–9.360; P = 0.013). Additionally, male patients with Mets had higher risk of bilateral upper urinary tract stones than female patients. Our analysis revealed that eight clinical factors were associated with the formation of bilateral upper urinary tract stones, namely BMI, gout, hyperparathyroidism, uric acid stone, urine PH, 24-h urinary calcium, blood uric acid, and Mets. This study could help clinicians adjust treatment strategies for high-risk patients with bilateral upper urinary tract stones.

Infra-inguinal bypass surgery vs endovascular revascularization for chronic limb-threatening ischemia in average- and high-risk patients

ObjectiveThis study aimed to evaluate treatment outcomes after bypass surgery or endovascular therapy (EVT) in average- and high-risk patients with chronic limb-threatening ischemia (CLTI). MethodsWe retrospectively analyzed multicenter data of patients who underwent infra-inguinal revascularization for CLTI between 2015 and 2022. A high-risk patient was defined as one with estimated 30-day mortality rate ≥5% or 2-year survival rate ≤50%, as determined by the Surgical Reconstruction vs Peripheral Intervention in Patients With Critical Limb Ischemia (SPINACH) calculator. The amputation-free survival (AFS), limb salvage (LS), wound healing, and 30-day mortality were compared separately for the average- and high-risk patients between the bypass and EVT with propensity score matching. ResultsWe analyzed 239 and 31 propensity score-matched pairs in the average- and high-risk patients with CLTI. In the average-risk patients, the 2-year AFS and LS rates were 78.1% and 94.4% in the bypass group and 63.0% and 87.7% in the EVT group (P < .001 and P = .007), respectively. The 1-year wound healing rates were 88.6% in the bypass group and 76.8% in the EVT group, respectively (P < .001). The 30-day mortality was 0.8% in the bypass surgery and 0.8% in the EVT group (P = .996). In the high-risk patients, there was no differences in the AFS, LS, and wound healing between the groups (P = .591, P = .148, and P = .074). The 30-day mortality was 3.2% in the bypass group and 3.2% in the EVT group (P = .991). ConclusionsBypass surgery is superior to EVT with respect to the AFS, LS, and wound healing in the average-risk patients. EVT is a feasible first-line treatment strategy for high-risk patients with CLTI undergoing revascularization, based on the lack of significant differences in the 2-year AFS rate, between the bypass surgery and EVT cohorts.

Does preoperative multidisciplinary team assessment of high-risk patients improve the safety and outcomes of patients undergoing surgery?

BackgroundInternational guidelines recommend preoperative multidisciplinary team (MDT) assessment for high-risk surgical patients. Preoperative MDT meetings can help to improve surgical care, but there is little evidence on whether they improve patient outcomes.MethodsThis paper aims to share our experience of MDT meetings for high-risk surgical patients to underline their added value to the current standard of care. An observational study of a retrospective cohort of preoperative high-risk MDT meetings of a tertiary referral hospital between January 2015 and December 2020. For 249 patients the outcomes preoperative data, MDT decisions, and patient outcomes were collected from electronic health records.Main resultsA total of 249 patients were discussed at high-risk MDT meetings. Most of the patients (97%) were assessed as having an American Society of Anesthesiology score ≥ 3, and 219 (88%) had a European Society of Cardiology and European Society of Anaesthesiology risk score of intermediate or high. After MDT assessment, 154 (62%) were directly approved for surgery, and 39 (16%) were considered ineligible for surgery. The remaining 56 (23%) patients underwent additional assessments before reconsideration at a high-risk MDT meeting. The main reason for patients being discussed at the high-risk MDT meeting was to assess the risk-benefit ratio of surgery. Ultimately, 184 (74%) patients underwent surgery. Of the operated patients, 122 (66%) did not have a major complication in the postoperative period, and 149 patients (81%) were alive after one year.ConclusionsThis cohort study shows the vulnerability and complexity of high-risk patients but also shows that the use of an MDT assessment contributes too improved peri- and postoperative treatment strategies in high-risk patients. Most patients underwent surgery after careful risk assessment and, if deemed necessary, preoperative and perioperative treatment optimization to reduce their risk.

Individual and combined associations of estimated pulse wave velocity and systemic inflammation response index with risk of stroke in middle-aged and older Chinese adults: a prospective cohort study.

Estimated pulse wave velocity (ePWV) and systemic inflammatory response index (SIRI) have been recently investigated as a marker of arterial stiffness and a novel systemic inflammatory indicator. This study aims to examine the independent and combined association of ePWV and SIRI with incident stroke and its subtypes. Data of the Dongfeng-Tongji cohort study was analyzed for 9,154 middle-aged and older adults, who were free of cardiovascular disease and cancer and were followed up to document incident stroke. But their association with incident stroke events and its subtypes have not been well studied. Multivariable adjusted Cox regression models were used to determine the independent and combined association of ePWV and SIRI with incident stroke events. Over a 7.22-year follow-up, the cohort documented 491 stroke cases (387 ischemic stroke and 104 hemorrhagic stroke). The multivariate adjusted model showed that with each one-unit increase in the level of ePWV, the corresponding hazard ratios (HRs) (95% CI) for total stroke, ischemic stroke, and hemorrhagic stroke were 1.53 (95% CI, 1.23-1.90), 1.42 (95% CI, 1.11-1.83), and 1.92 (95% CI, 1.21-3.03), respectively. Similarly, with each one-unit increase in log-transformed levels of SIRI, the corresponding HRs (95% CI) for total stroke, ischemic stroke, and hemorrhagic stroke were 1.23 (95% CI,1.04-1.47), 1.16 (95% CI, 0.96-1.41), and 1.52 (95% CI, 1.05-2.20), respectively. There appeared to be a combined effect of ePWV and SIRI on stroke; Participants with high levels of both ePWV and SIRI had a higher risk of total stroke and hemorrhagic stroke, with multiple adjusted HR of 2.43 (95% CI, 1.09-5.42). Additionally, the incorporation of ePWV in addition to traditional cardiovascular risk factors significantly improved the predictive accuracy for total stroke with C statistic increased from 0.684 (95% CI, 0.661-0.707) to 0.687 (95% CI, 0.664-0.710; x2 = 6.65; p for difference = 0.010), and (suggestively) for ischemic stroke with C statistic increased from 0.684 (95% CI, 0.659-0.71) to 0.691(95% CI, 0.666-0.717; x2 = 3.13, p for difference = 0.077), respectively. The presence of both high ePWV and SIRI individually, as well as together, was found to be associated with an increased incidence of stroke. The combined stroke risk assessment using these two indicators could potentially improve non-invasive assessment and treatment strategies for high-risk patients, as these indicators are easily accessible in clinical practice.

Risk factors for adverse outcomes at various phases of endoscopic ultrasound-guided treatment of pancreatic fluid collections: Data from a multi-institutional consortium.

No comprehensive study has examined short- and long-term adverse outcomes of endoscopic ultrasound (EUS)-guided treatment of pancreatic fluid collections (PFCs) including walled-off necrosis (WON) and pseudocysts. In a multi-institutional cohort of 357 patients receiving EUS-guided treatment of PFCs (228 with WON and 129 with pseudocysts), we examined PFC type-specific risk factors for procedure-related adverse events (AEs), clinical failure, and recurrence. Odds ratios (ORs) and hazard ratios (HRs) with 95% confidence intervals (CIs) were computed using the logistic and Cox regression models, respectively, adjusting for potential confounders. Adverse events were observed predominantly in WON, and risk factors were WON extension to the pelvis (OR 2.49; 95% CI 1.00-6.19) and endoscopic necrosectomy (OR 5.15; 95% CI 1.61-16.5). Risk factors for clinical failure in WON treatment included higher Charlson Comorbidity Index (OR for ≥3 vs. ≤2, 2.58; 95% CI 1.05-6.35), extension to the pelvis (OR 3.63; 95% CI 1.57-8.43), nonuse of a lumen-apposing metal stent (OR 2.88; 95% CI 1.10-7.54), and percutaneous drainage (OR 3.73; 95% CI 1.27-10.9). Patients with pseudocysts extending to the paracolic gutter and the need for more than two endoscopic/percutaneous procedures had ORs for clinical failure of 5.28 (95% CI 1.10-25.3) and 5.52 (95% CI 1.61-18.9), respectively. Pseudocysts requiring the multigateway approach were associated with a high risk of recurrence (HR 4.00; 95% CI 1.11-11.6). The adverse outcomes at various phases of EUS-guided PFC treatment may be predictable based on clinical parameters. Further research is warranted to optimize treatment strategies for high-risk patients.

Use of antiseizure medications after traumatic brain injury

Background: Post-traumatic seizures and epilepsy are major complications that increase the mortality rate among patients with traumatic brain injury (TBI) and hinder functional recovery. It is important to establish prophylaxis and treatment strategies for high-risk patients. The use of antiseizure medications may not only adversely affect the cognitive function following TBI but also may be associated with a worse rehabilitation outcome.Current Concepts: The level of evidence in the current international guidelines related to the prophylaxis and management of post-traumatic seizure is not robust. Furthermore, the use of antiseizure medications after TBI remains unclear, indicating substantial variations in clinical practice.Discussion and Conclusion: Prophylactic antiseizure medications can reduce the risk of early seizures and partially prevent the secondary injury process of TBI; however, they do not seem to inhibit epileptogenesis. Therefore, if the benefits of preventing early seizures outweigh the potential risks associated with antiseizure medication, it is recommended to use them for a short period of about one week after the injury. Then, it is not recommended to continue using them routinely without considering the individual risk of seizure recurrence and potential adverse effects of long-term use. The treatment duration of anticonvulsant in patients with post-traumatic epilepsy should also be determined based on the individual risk of seizure recurrence, and the decision should take into account the opinions of both the patient and the caregiver, while considering not only the potential benefits but also the risks associated with long-term use.

Contribution of the Oral and Gastrointestinal Microbiomes to Bloodstream Infections in Leukemia Patients.

Bloodstream infections (BSIs) pose a significant mortality risk for acute myeloid leukemia (AML) patients. It has been previously reported that intestinal domination (>30% relative abundance [RA] attributed to a single taxon) with the infecting taxa often precedes BSI in stem cell transplant patients. Using 16S rRNA amplicon sequencing, we analyzed oral and stool samples from 63 AML patients with BSIs to determine the correlation between the infectious agent and microbiome composition. Whole-genome sequencing and antimicrobial susceptibilities were performed on all BSI isolates. Species-level detection of the infectious agent and presence of antibiotic resistance determinants in the stool (blaCTX-M-15, blaCTX-M-14, cfrA, and vanA) were confirmed via digital droplet PCR (ddPCR). Individuals with Escherichia coli (stool P < 0.001), Pseudomonas aeruginosa (oral P = 0.004, stool P < 0.001), and viridans group streptococci (VGS) (oral P = 0.001) bacteremia had a significantly higher relative abundance of those respective genera than other BSI patients, which appeared to be site specific. Although 78% of patients showed presence of the infectious genera in the stool and/or saliva, only 7 exhibited microbiome domination. ddPCR confirmed species specificity of the 16S data and detected the antibiotic resistance determinants found in the BSI isolates within concurrent stools. Although gastrointestinal (GI) domination by an infecting organism was not present at the time of most BSIs in AML, the pathogens, along with AMR elements, were detectable in the majority of patients. Thus, rapid genetic assessment of oral and stool samples for the presence of potential pathogens and AMR determinants might inform personalized therapeutic approaches in immunocompromised patients with suspected infection. IMPORTANCE A major cause of mortality in hematologic malignancy patients is BSI. Previous studies have demonstrated that bacterial translocation from the GI microbiome is a major source of BSIs and is often preceded by increased levels of the infectious taxa in the GI (>30% abundance by 16S rRNA sequencing). In this study, we sought to better understand how domination and abundance levels of the oral and gut microbiome relate to bacteremia occurrence in acute myeloid leukemia patients. We conclude that analyses of both oral and stool samples can help identify BSI and antimicrobial resistance determinants, thus potentially improving the timing and tailoring of antibiotic treatment strategies for high-risk patients.

Early Treatment with Fluvoxamine among Patients with COVID-19: A Cost-Consequence Model.

To date, two published randomized trials have indicated a clinical benefit of early treatment with fluvoxamine versus placebo for adults with symptomatic COVID-19. Using the results of the largest of these trials, the TOGETHER trial, we conducted a cost-consequence analysis to assess the health system benefits of preventing progression to severe COVID-19 in outpatient populations in the United States. A decision-analytic model in the form of a decision tree was constructed to evaluate two treatment strategies for high-risk patients with confirmed, symptomatic COVID-19 in the primary analysis: treatment with a 10-day course of fluvoxamine (100 mg twice daily) and current standard-of-care. A secondary analysis comparing a 5-day course of nirmatrelvir-ritonavir was also conducted. We used a time horizon of 28 days. Reported outcomes included cost-savings and hospitalization days avoided. The results of our analysis indicated that administration of fluvoxamine to symptomatic outpatients at high risk of progressing to severe COVID-19 was substantially cost-saving, in the amount of $232 per eligible patient and prevented an average of 0.15 hospital days per patient treated, compared with standard of care. Nirmatrelvir-ritonavir was also shown to be cost-saving despite its higher acquisition cost and provided savings to the healthcare system of $625 per patient treated. These findings suggest that fluvoxamine is likely to be a cost-effective addition to frontline COVID-19 mitigation strategies in many settings, particularly where access to nirmaltrevir-ritonavir or monoclonal antibodies is limited.

Risk and response adapted therapy following autologous stem cell transplant in patients with newly diagnosed multiple myeloma (RADAR (UK-MRA Myeloma XV Trial): study protocol for a phase II/III randomised controlled trial

IntroductionMultiple myeloma is a plasma cell malignancy that accounts for 1%–2% of newly diagnosed cancers.At diagnosis, approximately 20% of patients can be identified, using cytogenetics, to have inferior survival (high-risk)....

Clinico-biological features of T-cell acute lymphoblastic leukemia with fusion proteins

T-cell acute lymphoblastic leukemias (T-ALL) represent 15% of pediatric and 25% of adult ALL. Since they have a particularly poor outcome in relapsed/refractory cases, identifying prognosis factors at diagnosis is crucial to adapting treatment for high-risk patients. Unlike acute myeloid leukemia and BCP ALL, chromosomal rearrangements leading to chimeric fusion-proteins with strong prognosis impact are sparsely reported in T-ALL. To address this issue an RT-MPLA assay was applied to a consecutive series of 522 adult and pediatric T-ALLs and identified a fusion transcript in 20% of cases. PICALM-MLLT10 (4%, n = 23), NUP214-ABL1 (3%, n = 19) and SET-NUP214 (3%, n = 18) were the most frequent. The clinico-biological characteristics linked to fusion transcripts in a subset of 235 patients (138 adults in the GRAALL2003/05 trials and 97 children from the FRALLE2000 trial) were analyzed to identify their prognosis impact. Patients with HOXA trans-deregulated T-ALLs with MLLT10, KMT2A and SET fusion transcripts (17%, 39/235) had a worse prognosis with a 5-year EFS of 35.7% vs 63.7% (HR = 1.63; p = 0.04) and a trend for a higher cumulative incidence of relapse (5-year CIR = 45.7% vs 25.2%, HR = 1.6; p = 0.11). Fusion transcripts status in T-ALL can be robustly identified by RT-MLPA, facilitating risk adapted treatment strategies for high-risk patients.

Escalation and de-escalation in HER2 positive early breast cancer.

Current standard for HER2+ early breast cancer patients includes chemotherapy and trastuzumab for 1 year. The purpose of this article is to review available evidence on escalated treatment strategies for high-risk patients and de-escalated treatments for patients at low risk of relapse or high risk of cardiac toxicity. Recent results have led to the approval of two adjuvant escalated treatment strategies: pertuzumab and trastuzumab combined with chemotherapy for up to 1 year for high-risk patients; extension of adjuvant anti-HER2 treatment with 1 year of neratinib. However, these treatments are associated with increased costs and toxicity, therefore careful patients' selection is highly required. With regard to de-escalated treatments, the anthracycline-free regimen of adjuvant paclitaxel and 1 year trastuzumab has entered clinical practice for early-stage patients. One year of trastuzumab remains the standard; however, shorter trastuzumab could be an option for low-risk patients and in case of increased risk of cardiotoxocity. Chemotherapy-free regimens are attractive but deserve further evaluation. There have been advances in treatment individualization for HER2+ early breast cancer patients. Integration of promising biomarkers into risk classification will further help progressing in the field.

Secondary Oxalate Nephropathy: A Systematic Review

IntroductionLittle is known of the clinical outcomes of secondary oxalate nephropathy. To inform clinical practice, we performed a systematic review of case reports and case series to examine the clinical characteristics and outcomes of patients with secondary oxalate nephropathy.MethodsElectronic databases were searched for case reports and case series of individual cases or cohorts of patients with biopsy-proven oxalate nephropathy in native or transplanted kidneys from 1950 until January 2018.ResultsFifty-seven case reports and 10 case series met the inclusion criteria, totaling 108 patients. The case series were meta-analyzed. Mean age was 56.4 years old, 59% were men, and 15% were kidney transplant recipients. Fat malabsorption (88%) was the most commonly attributed cause of oxalate nephropathy, followed by excessive dietary oxalate consumption (20%). The mean baseline serum creatinine was 1.3 mg/dl and peaked at 4.6 mg/dl. Proteinuria, hematuria, and urinary crystals was reported in 69%, 32%, and 26% of patients, respectively. Mean 24-hour urinary oxalate excretion was 85.4 mg/d. In addition to universal oxalate crystal deposition in tubules and/or interstitium, kidney biopsy findings included acute tubular injury (71%), tubular damage and atrophy (69%), and interstitial mononuclear cell infiltration (72%); 55% of patients required dialysis. None had complete recovery, 42% had partial recovery, and 58% remained dialysis-dependent. Thirty-three percent of patients died.ConclusionSecondary oxalate nephropathy is a rare but potentially devastating condition. Renal replacement therapy is required in >50% of patients, and most patients remain dialysis-dependent. Studies are needed for effective preventive and treatment strategies in high-risk patients with hyperoxaluria-enabling conditions.

高齢者に対する胸部食道癌の手術治療戦略—2期分割手術の治療成績—

高齢者に対する胸部食道癌の手術治療戦略—2期分割手術の治療成績—

Autologous Hematopoietic Stem Cell Transplantation for Diffuse Large B-Cell Lymphoma.

High-dose chemotherapy supported by autologous stem cell support/transplantation (HDT/ASCT) has been a standard of care over the last two decades in patients with relapsed or refractory(R/R) diffuse large B-cell lymphoma (DLBCL), which is sensitive to salvage chemotherapy. HDT/ASCT for high-risk DLBCL in upfront setting remains controversial, so it is not recommended for clinical practice. Various promising salvage chemotherapy regimens have been reported in phase 2 studies; however, two large randomized phase 3 studies showed similar efficacy of R-ICE vs. R-DHAP and R-GDP vs. R-DHAP. Since the registry data shows feasibility and efficacy of HDT/ASCT in elderly R/R DLBCL patients, older age (> 65 years) itself is not a contraindication for HDT/ASCT. Rituximab maintenance failed to demonstrate a significant benefit compared with observation only after HDT/ASCT. While sensitive R/R DLBCL might be cured by HDT/ASCT even in third-line therapy, the prognosis of insensitive R/R DLBCL is extremely poor. Further study to establish treatment strategies for high-risk patients defined by prognostic factors or biomarkers, and insensitive patients is warranted.

Haematopoietic stem cell transplantation for refractory Langerhans cell histiocytosis: outcome by intensity of conditioning.

Patients with Langerhans cell histiocytosis (LCH) refractory to conventional chemotherapy have a poor outcome. There are currently two promising treatment strategies for high-risk patients: the first involves the combination of 2-chlorodeoxyadenosine and cytarabine; the other approach is allogeneic haematopoietic stem cell transplantation (HSCT). Here we evaluated 87 patients with high-risk LCH who were transplanted between 1990 and 2013. Prior to the year 2000, most patients underwent HSCT following myeloablative conditioning (MAC): only 5 of 20 patients (25%) survived with a high rate (55%) of transplant-related mortality (TRM). After the year 2000 an increasing number of patients underwent HSCT with reduced intensity conditioning (RIC): 49/67 (73%) patients survived, however, the improved survival was not overtly achieved by the introduction of RIC regimens with similar 3-year probability of survival after MAC (77%) and RIC transplantation (71%). There was no significant difference in TRM by conditioning regimen intensity but relapse rates were higher after RIC compared to MAC regimens (28% vs. 8%, P=0·02), although most patients relapsing after RIC transplantation could be salvaged with further chemotherapy. HSCT may be a curative approach in 3 out of 4 patients with high risk LCH refractory to chemotherapy: the optimal choice of HSCT conditioning remains uncertain.

Non-genetic risk factors and their influence on the management of patients in the clinic.

The development of inhibitors is the most serious iatrogenic complication affecting patients with haemophilia. This complication is associated with impaired vital or functional prognosis, reduced quality of life and increased cost of treatment. The reasons why some patients develop antibodies to factor replacement and others do not remain unclear. It is however clear that inhibitor development results from a complex multifactorial interaction between genetic and non-genetic risk factors. Environmental influences implicated in increasing the risk of inhibitor formation can be viewed as modifiable risk factors. Therefore, identification of the non-genetic risk factors may offer the possibility of personalising haemophilia therapy by modifying treatment strategies in high-risk patients in the critical early phase of factor VIII exposure. In this article, we review the non-genetic factors reported as well as the potential impact of danger signals and the different scores for inhibitor development risk stratification.

PRIMA-1 (p53 Reactivation and Induction of Massive Apoptosis) Mediates Anti-Myeloma Effect through the ER Stress Pathway

It is well established that 17p13(del) and p53 mutations represent poor prognosis in MM patients. We have previously shown that p53 is a haploinsufficient tumor suppressor in myeloma and p53 expression level is correlated with functional status of the pathway. In addition, p53 expression levels do not always correlate with p53 genotype. The absence of p53 expression in myeloma cells severely abolishes the integrity of its downstream signaling response, thus, driving disease aggressiveness and drug resistance. There is a pressing need for a more effective treatment strategy for high-risk patients harbouring p53 abnormalities. PRIMA-1 is a first-in-class drug that was identified to specifically kill cancer cells harboring mutant p53. It has shown substantial efficacy in various solid tumors with mutant as well as non-mutant p53. However, the discovery of the anti-myeloma activity of PRIMA-1 is still at its infancy. By utilizing human myeloma cell lines (HMCLs) of different p53 status as our study model, we aim to identify the efficacy of PRIMA-1 in MM and to dissect the mechanisms behind PRIMA-1-induced toxicity. Despite its known ability to reactivate mutant-p53 function, we did not observe any restoration of mutant p53 transcriptional activities. The expression levels of the p53-direct-targets, p21, MDM2 and PUMA, were unchanged upon treatment in the p53-mutant-HMCLs. In fact, PRIMA-1 was found to be able to decrease the cell viability of all the HMCLs, irrespective of their p53 status (Mutant, WT, Null), strongly indicating a p53-independent response. Importantly, PRIMA-1 showed the highest cytotoxicity in a p53-deficient background (IC50 of 16uM in -/-, 55uM in WT/WT and 70uM in mutant HMCLs). This finding was validated when p53 silencing in a WT HMCL significantly enhanced its sensitivity to PRIMA-1. GEP analysis on the two most sensitive cell lines (JJN3 and KMS11) demonstrated significant enrichment of genes related to unfolded (p=1.90E-06 in JJN3 and 6.12E-08 in KMS11) and misfolded protein (p=2.99E-06 in JJN3 and 8.21E-08 in KMS11) responses. Subsequent validation by Western blot and qPCR confirmed the activation of ER stress pathway in response to PRIMA-1, evidenced by the up-regulation of ER stress markers such as GRP78, GADD34 and CHOP. Further investigations then revealed that the PERK/CHOP axis was most important as CHOP knockdown saw an attenuation of MM cells sensitivity to PRIMA-1-induced apoptosis. Recently, it was reported that cells with increased ER stress are more sensitive to bortezomib. Indeed, we showed that PRIMA-1 synergizes with bortezomib, and was able to rescue bortezomib resistance when both compounds were co-incubated in a bortezomib-resistant-HMCL. In conclusion, we identified a novel pathway by which PRIMA-1 exerts its toxicity in MM through induction of ER stress. This may be a novel therapeutic strategy to induce ER stress to sensitize cells to proteasome inhibitor. Owing to the versatility of the drug in targeting myeloma cells with or without p53 abnormalities; PRIMA-1 can potentially be used alone or in combination with other drugs such as bortezomib in a broad range of MM including those with high-risk disease. DisclosuresNo relevant conflicts of interest to declare.

Autologous Stem Cell Transplantation In Multiple Myeloma: Is It Still The Right Choice?

Autologous stem cell transplantation (ASCT) is considered the standard of care for multiple myeloma patients aged &lt;65 years with no relevant comorbidities. The addition of proteasome inhibitors and/or immunomodulatory drugs has significantly increased the percentage of patients achieving a complete remission after induction therapy, and these results are maintained after high-dose melphalan (Alkeran®), leading to a prolonged disease control. Studies are being carried out in order to evaluate whether short- term consolidation or long-term maintenance therapy can result in disease eradication at the molecular level, thus also increasing patient survival. The efficacy of these new drugs has raised the issue of deferring the transplant after achieving a second response upon relapse. Another controversial point is the optimal treatment strategy for high-risk patients, that do not benefit from ASCT, and for whom the efficacy of new drugs is still matter of debate.