Chromothripsis orchestrates leukemic transformation in blast phase MPN through targetable amplification of DYRK1A.

Chromothripsis, the process of catastrophic shattering and haphazard repair of chromosomes, is a common event in cancer. Whether chromothripsis might constitute an actionable molecular event amenable to therapeutic targeting remains an open question. We describe recurrent chromothripsis of chromosome 21 in a subset of patients in blast phase of a myeloproliferative neoplasm (BP-MPN), which alongside other structural variants leads to amplification of a region of chromosome 21 in ∼25% of patients ('chr21amp'). We report that chr21amp BP-MPN has a particularly aggressive and treatment-resistant phenotype. The chr21amp event is highly clonal and present throughout the hematopoietic hierarchy. DYRK1A , a serine threonine kinase and transcription factor, is the only gene in the 2.7Mb minimally amplified region which showed both increased expression and chromatin accessibility compared to non-chr21amp BP-MPN controls. We demonstrate that DYRK1A is a central node at the nexus of multiple cellular functions critical for BP-MPN development, including DNA repair, STAT signalling and BCL2 overexpression. DYRK1A is essential for BP-MPN cell proliferation in vitro and in vivo , and DYRK1A inhibition synergises with BCL2 targeting to induce BP-MPN cell apoptosis. Collectively, these findings define the chr21amp event as a prognostic biomarker in BP-MPN and link chromothripsis to a druggable target.

Minimal methylation classifier (MIMIC): A novel method for derivation and rapid diagnostic detection of disease-associated DNA methylation signatures.

Rapid and reliable detection of disease-associated DNA methylation patterns has major potential to advance molecular diagnostics and underpin research investigations. We describe the development and validation of minimal methylation classifier (MIMIC), combining CpG signature design from genome-wide datasets, multiplex-PCR and detection by single-base extension and MALDI-TOF mass spectrometry, in a novel method to assess multi-locus DNA methylation profiles within routine clinically-applicable assays. We illustrate the application of MIMIC to successfully identify the methylation-dependent diagnostic molecular subgroups of medulloblastoma (the most common malignant childhood brain tumour), using scant/low-quality samples remaining from the most recently completed pan-European medulloblastoma clinical trial, refractory to analysis by conventional genome-wide DNA methylation analysis. Using this approach, we identify critical DNA methylation patterns from previously inaccessible cohorts, and reveal novel survival differences between the medulloblastoma disease subgroups with significant potential for clinical exploitation.

Prognostic value of rare IKZF1 deletion in childhood B-cell precursor acute lymphoblastic leukemia: an international collaborative study.

Deletions in IKZF1 are found in ~15% of children with B-cell precursor acute lymphoblastic leukemia (BCP-ALL). There is strong evidence for the poor prognosis of IKZF1 deletions affecting exons 4-7 and exons 1-8, but evidence for the remaining 33% of cases harboring other variants of IKZF1 deletions is lacking. In an international multicenter study we analyzed the prognostic value of these rare variants in a case-control design. Each IKZF1-deleted case was matched to three IKZF1 wild-type controls based on cytogenetic subtype, treatment protocol, risk stratification arm, white blood cell count and age. Hazard ratios for the prognostic impact of rare IKZF1 deletions on event-free survival were calculated by matched pair Cox regression. Matched pair analysis for all 134 cases with rare IKZF1 deletions together revealed a poor prognosis (P<0.001) that was evident in each risk stratification arm. Rare variant types with the most unfavorable event-free survival were DEL 2-7 (P=0.03), DEL 2-8 (P=0.002) and DEL-Other (P<0.001). The prognosis of each type of rare variant was equal or worse compared with the well-known major DEL 4-7 and DEL 1-8 IKZF1 deletion variants. We therefore conclude that all variants of rare IKZF1 deletions are associated with an unfavorable prognosis in pediatric BCP-ALL.

Artificial Intelligence Systems as Prognostic and Predictive Tools in Ovarian Cancer.

BACKGROUND: The ability to provide accurate prognostic and predictive information to patients is becoming increasingly important as clinicians enter an era of personalized medicine. For a disease as heterogeneous as epithelial ovarian cancer, conventional algorithms become too complex for routine clinical use. This study therefore investigated the potential for an artificial intelligence model to provide this information and compared it with conventional statistical approaches. METHODS: The authors created a database comprising 668 cases of epithelial ovarian cancer during a 10-year period and collected data routinely available in a clinical environment. They also collected survival data for all the patients, then constructed an artificial intelligence model capable of comparing a variety of algorithms and classifiers alongside conventional statistical approaches such as logistic regression. RESULTS: The model was used to predict overall survival and demonstrated that an artificial neural network (ANN) algorithm was capable of predicting survival with high accuracy (93 %) and an area under the curve (AUC) of 0.74 and that this outperformed logistic regression. The model also was used to predict the outcome of surgery and again showed that ANN could predict outcome (complete/optimal cytoreduction vs. suboptimal cytoreduction) with 77 % accuracy and an AUC of 0.73. CONCLUSIONS: These data are encouraging and demonstrate that artificial intelligence systems may have a role in providing prognostic and predictive data for patients. The performance of these systems likely will improve with increasing data set size, and this needs further investigation.

Comparison of two surgical methods, primary closure and rotational flap, in patients with chronic pilonidal sinus.

INTRODUCTION: Pilonidal sinus is a common infectious process which occurs in buttocks and sacral area which involves a wide range of symptoms that are different from an asymptomatic sinus abscess to acute and chronic sinus track. Basically non-surgical treatment for this disease is not recommended. In this study, we have been compared two methods of primary repair and rotation flap in terms of factors such as duration of hospitalization, recurrence, infection etc. METHODS: 80 patients with chronic pilonidal sinus were randomly divided into two groups and underwent surgery. Diabetic and obese patients with underlying diseases and patients with acute pilonidal abscess or prior surgery were excluded. The patients' hospital stay, duration of postoperative pain, itching and hematoma, were investigated. RESULTS: In this study, patients' sex and mean age were examined in terms of frequency of complications of hematoma, wound infection, recurrence, itching, and duration of hospitalization and the presence of seroma, there is no significant difference between the two methods of primary surgical repair and rotation flap (P> 0.05) But in terms of the opening of the surgical wound, in primary surgical method, 5 patients (12.5%), wound dehiscence were reported, in rotation flap, any case of wound dehiscence were reported. There is significant difference between wound dehiscence in patients with chronic pilonidal sinus and two methods of surgery. (P=0.02). The mean duration of pain relief was 15.2 ± 3.35 days in the primary surgical repair method and rotation flap was 7 ± 2.3 days. According to the test there is significant difference between mean duration of pain relief and two surgical methods. (P=0.001). The mean duration of sutures was 15.3 ± 2.3 days in the primary repair method and in rotational flap was 12 ± 3.6 days. There is significant difference between the mean duration of sutures and two surgical methods (P=0.001) CONCLUSION: Considering these results, rotational flap is the preferred method due to fewer complications, lower recurrence after surgery and faster healing time of surgical wounds and as a result, the effective force's early return to economic cycle. Finally, we can say that each surgeon according to the type and size of the sinuses and occupational status and social class, personality and individuality of the patient can select the appropriate method of surgery. 

Survey of early complications of primary skin graft and secondary skin graft (delayed) surgery after resection of burn waste in hospitalized burn patients.

INTRODUCTION: Burning is the second most common cause of home injuries in Iran that is often the cause of conflicts between children and young adults. Burning can lead to early and late complications that scar and contracture are the most common. Burn waste treatment is done by two methods: excision and then skin graft after the formation of granulation tissue; and excision and graft simultaneously that in this study, these two methods are compared. METHODS: This was performed as a quasi-experimental analysis and retrospective study on all patients who were hospitalized for burn scar. All patients who have associated with weak eningimmune diseases such as diabetes, acquired immunodeficiency or congenital, taking steroids and patients undergoing chemotherapy etc. are excluded. The method of grafting in patients is primary graft procedure that was compared with patients who are treated using secondary graft. Data collected through review of patients' hospital and clinic chart. RESULTS: The mean burn percentage in the primary repair group was 14.4% and in the delayed repair group was 16.6%, respectively. The incidence of hematoma in both groups was zero. Skin necrosis and graft rejection and infection in the primary repair group was in 3.7% of patients and in the delayed repair group was in 1.2% of cases (P=0.5) CONCLUSION: Based on the findings of this study, no difference was observed between the two methods of excision and primary graft with delayed graft in the incidence of graft rejection. Due to the shorter treatment of primary graft and patient satisfaction and also according to the findings of this study excision and primary graft method seems appropriate method for treating old waste burning.