Characteristics and outcome of primary resistant disease in paediatric acute myeloid leukaemia.

A significant proportion of events in paediatric acute myeloid leukaemia (AML) are caused by resistant disease (RD). We investigated clinical and biological characteristics in 66 patients with RD from 1013 children with AML registered and treated according to the NOPHO-AML 93, NOPHO-AML 2004, DB AML-01 and NOPHO-DBH AML 2012 protocols. Risk factors for RD were age10 years or older and a white-blood-cell count (WBC) of 100 × 109 /L or more at diagnosis. The five-year overall survival (OS) was 38% (95% confidence interval [CI]: 28%-52%). Of the 63 children that received salvage therapy with chemotherapy, 59% (N = 37) achieved complete remission (CR) with OS 57% (95% CI: 42%-75%) compared to 12% (95% CI: 4%-35%) for children that did not achieve CR. Giving more than two salvage chemotherapy courses did not increase CR rates. OS for all 43 patients receiving allogeneic haematopoietic stem cell transplantation (HSCT) was 49% (95% CI: 36%-66%). Those achieving CR and proceeding to HSCT had an OS of 56% (95% CI: 41%-77%, N = 30). This study showed that almost 40% of children with primary resistant AML can be cured with salvage therapy followed by HSCT. Children that did not achieve CR after two salvage courses with chemotherapy did not benefit from additional chemotherapy.

RESILIENT part 1: a phase 2 dose-exploration and dose-expansion study of second-line liposomal irinotecan in adults with small cell lung cancer.

BACKGROUND: RESILIENT (NCT03088813) is a phase 2/3 study assessing the safety, tolerability, and efficacy of liposomal irinotecan monotherapy in patients with small cell lung cancer and disease progression on/after first-line platinum-based therapy. Here, we present results from RESILIENT part 1. METHODS: This open-label, single-arm, safety run-in evaluation with dose-exploration and dose-expansion phases included patients ≥18 years old with Eastern Cooperative Oncology Group performance status of 0/1; those with asymptomatic central nervous system metastases were eligible. The primary objectives were to evaluate safety and tolerability and recommend a dose for further development. Efficacy end points were objective response rate (ORR), progression-free survival (PFS), and overall survival (OS). RESULTS: During dose exploration, 5 patients received intravenous liposomal irinotecan at 85 mg/m2 (deemed not tolerable; dose-limiting toxicity) and 12 patients received 70 mg/m2 (deemed tolerable). During dose expansion, 13 additional patients received intravenous liposomal irinotecan at 70 mg/m2 . Of these 25 patients (median age [range], 59.0 [48.0-73.0] years, 92.0% with metastatic disease), 10 experienced grade ≥3 treatment-related treatment-emergent adverse events (TEAEs), most commonly diarrhea (20.0%) and neutropenia (16.0%), and 3 had serious treatment-related TEAEs, of whom 2 died. ORR was 44.0% (95% confidence interval [CI]: 24.40-65.07; 1 complete response, 10 partial responses) and median (95% CI) PFS and OS were 3.98 (1.45-4.24) months and 8.08 (5.16-9.82) months, respectively. CONCLUSION: Overall, no new safety signals were identified with liposomal irinotecan, and antitumor activity was promising. RESILIENT part 2, a randomized, controlled, phase 3 study of liposomal irinotecan versus topotecan, is ongoing. LAY SUMMARY: Small cell lung cancer (SCLC) is an aggressive disease with few treatment options after platinum-based therapy. Administering 1 option, irinotecan, as a "liposomal" formulation, may extend drug exposure and improve outcomes. The RESILIENT part 1 trial assessed the safety and efficacy of liposomal irinotecan in 25 adults with SCLC after disease progression despite platinum-based therapy. No new safety concerns were reported. The most common moderate-to-severe side effects were diarrhea (20% of patients) and neutropenia (16%). Tumors responded to treatment in 44% of patients. Average survival was 8.08 months, and time to disease progression was 3.98 months. Liposomal irinotecan trials are ongoing.

Canakinumab as monotherapy for treatment of familial Mediterranean fever - first report in Central and Eastern Europe region.

Autoinflammatory disorders (AID) are characterized by spontaneous attacks of acute inflammation with a broad spectrum of clinical symptoms. Ongoing inflammation and reoccurrence of acute flares can lead to the development of amyloidosis. One group of AID is represented by monogenic periodic fever syndromes while familial Mediterranean fever (FMF) is the most common form of AID from this group. Its prevalence in Central and Eastern Europe was reported to be very low. We report a case of FMF patient with a very severe clinical course of FMF and intolerance to colchicine, which is a gold standard for FMF treatment. The clinical effect of the application of anakinra was insufficient and accompanied with side effects and low tolerability. Switching to canakinumab (human monoclonal antibody against IL-1ß) at dose of 150 mg every 4 weeks induced a rapid remission of the disease activity and inflammatory markers. However, due to relapse of acute flares after three weeks from application, the escalation of dose to 300 mg every 4 weeks induced a complete remission of symptoms and significantly improved the quality of life. This is the first report of successful canakinumab administration in FMF patient in Central and Eastern Europe, a region with very low incidence of FMF (Tab. 1, Ref. 16).

A Phase I Study of Clofarabine With Multiagent Chemotherapy in Childhood High Risk Relapse of Acute Lymphoblastic Leukemia (VANDEVOL Study of the French SFCE Acute Leukemia Committee).

BACKGROUND: Current outcome of very early relapse of acute lymphoblastic leukemia (ALL) in children remains poor. As a single agent, clofarabine provided a response rate of 26% in childhood ALL second relapse and, in combination with cyclophosphamide and etoposide, a 44% complete remission and complete remission without platelet recovery (CR+CRp) rate. Further multi-drug combinations need to be investigated. We used the VANDA regimen as a template, cytarabine being replaced by clofarabine. PATIENTS AND METHODS: A phase I study combining escalating doses of clofarabine (25% increments from 20 to 40 mg/m(2)/d) with fixed doses of mitoxantrone, etoposide, asparaginase, and dexamethasone was undertaken in children presenting with very early or second or post-transplant ALL relapse. RESULTS: Twenty patients were enrolled, 19 were evaluable. Four patients had previously been allografted. Dose-limiting toxicity (DLT) appeared at dose level 3 (32 mg/m(2)), one out of six patients experienced a liver DLT. At dose level 4 (40 mg/m(2)), four DLT occurred (two fungal infection and two liver DLT). The maximum tolerated dose (MTD) of clofarabine was thus determined to be 32 mg/m(2). There was no toxic death. Eleven (57.9%) patients achieved a CR. Six patients proceeded to allogeneic stem cell transplantation. CONCLUSION: Clofarabine MTD was 32 mg/m(2)/d in this combination which appeared feasible and effective in this population.

Idiopathic intracranial hypertension: a possible complication in the natural history of advanced prostate cancer.

Idiopathic intracranial hypertension is a variety of intracranial hypertension that is extremely rare in men. Obesity and hypogonadism are the most important predictive factors. Etiological hypotheses include increased central venous pressure, and various hormonal and metabolic changes commonly found in obese patients. We described the case of an obese man with prostate cancer who showed a consistent bodyweight increase during treatment with taxanes and prednisone. He was hospitalized because of a severe loss of vision as a consequence of idiopathic intracranial hypertension. A complete symptom remission was obtained after 3 weeks of anti-edema therapies (steroids, acetazolamide). Castration-resistant prostate cancer is a risk factor for idiopathic intracranial hypertension. Long-term androgen deprivation therapy, bodyweight increase, and fluid retention during chronic steroid administration and taxane chemotherapy might favor the disease onset. This severe complication has a good outcome, and should be suspected in the presence of symptoms and signs of intracranial hypertension.

Association between glucocorticoid receptor beta and steroid resistance: A systematic review.

BACKGROUND: Glucocorticoids are the most commonly used anti-inflammatory drugs for a variety of diseases, despite the fact that resistance to them is growing in a number of conditions. There is currently no biomarker that can be used to identify steroid resistance. According to a number of studies, an overexpression of the glucocorticoid receptor beta (GR-ß) isoform is associated with steroid-resistant illness. Our goal is to find out whether or not steroid-resistant disorders are associated with an increased level of GR-ß expression. METHODS: We conducted searches in the databases of Web of Science and PubMed until January 17, 2023. This systematic review was done according to the preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. The Joanna Briggs Institute Appraisal scale was used to assess the quality of the included studies. RESULTS: After the initial search, we identified 556 papers and finally included 20 studies. Twelve of these studies found an elevated level of GR-ß in the steroid resistant group. All five studies on asthma, two out of three on nasal polyps, both studies on ulcerative colitis found an up regulation of GR-ß in steroid resistant group as compared to steroid-sensitive groups. GR-ß was also shown to be elevated in patients with allergic rhinitis, Crohn's disease and rheumatoid arthritis. In the majority of the investigations, higher levels of GR-ß were identified in peripheral blood mononuclear cells through the use of reverse transcription polymerase chain reaction. CONCLUSION: GR-ß was associated with steroid-resistant diseases. It was overexpressed in steroid-resistant diseases and has the potential to be used as a biomarker for disorders involving steroid resistance.

High-Grade Endometrial Cancer: Molecular Subtypes, Current Challenges, and Treatment Options.

Although many recent advancements have been made in women's health, perhaps one of the most neglected areas of research is the diagnosis and treatment of high-grade endometrial cancer (EnCa). The molecular classification of EnCa in concert with histology was a major step forward. The integration of profiling for mismatch repair deficiency and Human Epidermal Growth Factor 2 (HER2) overexpression, can further inform treatment options, especially for drug resistant recurrent disease. Recent early phase trials suggest that regardless of subtype, combination therapy with agents that have distinct mechanisms of action is a fruitful approach to the treatment of high-grade EnCa. Unfortunately, although the importance of diagnosis and treatment of high-grade EnCa is well recognized, it is understudied compared to other gynecologic and breast cancers. There remains a tremendous need to couple molecular profiling and biomarker development with promising treatment options to inform new treatment strategies with higher efficacy and safety for all who suffer from high-grade recurrent EnCa.

Outcomes following induction failure in Japanese children with acute lymphoblastic leukemia.

The characteristics and prognosis of Japanese children with acute lymphoblastic leukemia (ALL) who fail to achieve complete remission after remission induction chemotherapy (i.e., experience induction failure) are poorly understood. Therefore, we retrospectively analyzed data of patients enrolled in Japanese clinical trials for newly diagnosed ALL between 1996 and 2009. Among 4956 participants, 89 (1.8%) experienced induction failure. With a 6.0-year median follow-up, the 5-year overall survival rate of the entire cohort was 43.0% ± 5.5%. Survival rates did not differ between patients with B-cell precursor ALL (BCP-ALL) and T-cell ALL (T-ALL). In multivariate analysis, day 15 M3 marrow (bone marrow blast count ≥ 25%) was significantly correlated with poorer survival in the whole or BCP-ALL cohorts. In T-ALL, age < 6 years was significantly associated with poor survival. However, due to the small sample size, this correlation must be further investigated. Most T-ALL and BCR-ABL-positive BCP-ALL patients underwent allogeneic stem cell transplantation (allo-SCT). Survival rates did not differ between BCR-ABL-negative BCP-ALL patients who did and did not undergo allo-SCT, possibly due to the inclusion of lower-risk patients in the latter group. In conclusion, the induction failure rate and survival after diagnosis of induction failure in our study were comparable to previously reported figures.

Resistant and Relapsing Collapsing Glomerulopathy Successfully Treated with Rituximab-A Case Report.

Collapsing glomerulopathy (CG) or collapsing focal segmental glomerulosclerosis (cFSGS) is an aggressive disease with a high tendency of progression to end-stage renal disease due to common resistance to conventional immunosuppressants. Rituximab (RTX), a monoclonal antibody against CD20 B cells, showed some benefit in the treatment of CG. We are reporting about female patients with an idiopathic form of CG presenting with nephrotic syndrome (NS) and renal insufficiency resistant to several immunosuppressive agents such as steroids (ST), calcineurin inhibitors (CNI), and cyclophosphamide (CYC). This multidrug-resistant disease responded to RTX with complete remission. Forty-four months after initial RTX administration, a relapse of CG with severe NS and acute renal insufficiency occurred. Repeated application of RTX led to complete remission again. To the best of our knowledge, we are reporting the first case of the relapsing multidrug-resistant form of CG, which responded to RTX. Current data about the treatment of CG with RTX is lacking and is based on rare case reports and small case series. Thus, our report can contribute to determining the role of RTX in the treatment of CG.

Additional impact of mutational genotype on prognostic determination in resistant and relapsed acute myeloid leukaemia.

Outcome after failure of initial therapy in younger adult patients with acute myeloid leukaemia (AML) is highly variable. Cytogenetics, length of first remission (CR1) before relapse, and allogeneic transplantation are known prognostic factors, but the contribution of leukaemic genotype is less clear, particularly in resistant disease. Of 5,651 younger adult patients entered into UK MRC/NCRI AML trials between 1988 and 2014 with available FLT3ITD and NPM1 genotype, 326 (6%) had resistant disease and 2338 (41 %) relapsed after achieving CR1. Overall survival (OS) was significantly higher in relapsed compared to resistant disease (p = 0·03). Independent favourable prognostic factors for OS in resistant disease included lower blast cell percentage after two courses of induction therapy (p = 0.0006) and NPM1 mutant (NPM1MUT) (p = 0.04). In relapsed disease, longer CR1 was a favourable independent factor for attainment of CR2 (p < 0.0001) and OS from time of relapse (p < 0.0001), but CR2 rate and OS from relapse were significantly worse in those who had received an allograft in CR1 (respectively p < 0.05, p < 0·002). NPM1MUT was marginally beneficial for OS (p = 0.04). FLT3ITD and DNMT3AMUT were adverse factors for OS (respectively p < 0.0001, p = 0.02). Mutational analysis adds additional independent prognostic information to demographic features and previous therapy in patients with resistant and relapsed disease.

Molecular diagnosis and molecular profiling to detect treatment-resistant ovarian cancer.

INTRODUCTION: Epithelial ovarian cancer remains the gynecologic tumor with the highest rate of recurrence after initial optimal cytoreductive surgery followed by adjuvant chemotherapy. Unfortunately, with the development of recurrent ovarian cancer often comes the discovery of chemo-resistant disease. The absence of improvement in long term survival, notwithstanding the use of newer agents as is seen in other cancers, emphasizes the need for improved understanding of the processes that lead to chemo-resistant disease. AREAS COVERED: This review will cover the following topics: 1. Molecular and cellular mechanisms in platinum and paclitaxel resistance 2. Other molecular mediators of chemo-resistance 3. Expression of stem cell markers in ovarian cancer and relationship to chemo-resistance 4. MicroRNA and long non-coding RNA expression in chemo-resistant ovarian cancer 5. Determination of chromosomal aberrations as markers of chemo-resistance 6. Molecular profiling in chemo-resistant disease. A standard MEDLINE search was performed using the key words; ovarian cancer, chemo-resistant disease, molecular profiling, cancer stem cells and chemotherapy. Expert Commentary: Over the next few years the challenge remains to precisely determine the mechanisms responsible for the onset and maintenance of chemo-resistance and to effectively target these mechanisms.

E74-like factor inhibition induces reacquisition of hormone sensitiveness decreasing period circadian protein homolog 1 expression in prostate cancer cells.

PURPOSE: Initiating as an androgen-dependent adenocarcinoma, prostate cancer (PCa) gradually progresses to a castrate-resistant disease following androgen deprivation therapy with a propensity to metastasize. METHODS: In order to resolve the mechanism of castrate-resistant PCa, we performed a cDNA-microarray assay of two PCa cell lines, LNCaP (androgen dependent) and C4-2 (androgen independent). Among them, we focused on a novel Ets transcription factor, E74-like factor 5 (ELF5), the expression level of which was extremely high in C4-2 in comparison with LNCaP both in the microarray analysis and real-time polymerase chain reaction analysis, and investigated the biological role in acquisition of androgen-refractory PCa growth. RESULTS: Western blot analysis and morphological analysis using confocal immunofluorescence microscopy demonstrated that ELF5 was expressed mainly in cytosol both in LNCaP and C4-2. Inhibition of ELF5 expression using ELF5-small interfering RNA in C4-2 induced decreased expression of androgen receptor corepressor, period circadian protein homolog 1, and MTT assay of C4-2 after ELF5 small interfering RNA transfection showed the same cell growth pattern of LNCaP. CONCLUSIONS: Our in vitro experiments of cell growth and microarray analysis have demonstrated for the first time that decreased expression of period circadian protein homolog 1 due to ELF5 inhibition may induce the possibility of reacquisition of hormone sensitiveness of PCa cells. We suggest that ELF5 could be a novel potential target for the treatment of hormone-refractory PCa patients.

Epigenetic and oncogenic regulation of SLC16A7 (MCT2) results in protein over-expression, impacting on signalling and cellular phenotypes in prostate cancer.

Monocarboxylate Transporter 2 (MCT2) is a major pyruvate transporter encoded by the SLC16A7 gene. Recent studies pointed to a consistent overexpression of MCT2 in prostate cancer (PCa) suggesting MCT2 as a putative biomarker and molecular target. Despite the importance of this observation the mechanisms involved in MCT2 regulation are unknown. Through an integrative analysis we have discovered that selective demethylation of an internal SLC16A7/MCT2 promoter is a recurrent event in independent PCa cohorts. This demethylation is associated with expression of isoforms differing only in 5'-UTR translational control motifs, providing one contributing mechanism for MCT2 protein overexpression in PCa. Genes co-expressed with SLC16A7/MCT2 also clustered in oncogenic-related pathways and effectors of these signalling pathways were found to bind at the SLC16A7/MCT2 gene locus. Finally, MCT2 knock-down attenuated the growth of PCa cells. The present study unveils an unexpected epigenetic regulation of SLC16A7/MCT2 isoforms and identifies a link between SLC16A7/MCT2, Androgen Receptor (AR), ETS-related gene (ERG) and other oncogenic pathways in PCa. These results underscore the importance of combining data from epigenetic, transcriptomic and protein level changes to allow more comprehensive insights into the mechanisms underlying protein expression, that in our case provide additional weight to MCT2 as a candidate biomarker and molecular target in PCa.

Impact of combination chemotherapy with itraconazole on survival for patients with recurrent or persistent ovarian clear cell carcinoma.

BACKGROUND: Recurrent ovarian clear cell carcinoma (CCC) rarely responds to cytotoxic agents. Itraconazole is a potent inhibitor of the P-glycoprotein efflux pump, angiogenesis, and the Hedgehog pathway. We evaluated the efficacy of chemotherapy with itraconazole for CCC. PATIENTS AND METHODS: Medical charts of patients with CCC who had received chemotherapy with itraconazole were retrospectively reviewed. RESULTS: Among nine patients with CCC, five had a history of progression with paclitaxel and carboplatin, and none had received prior treatment with bevacizumab or other targeted therapy. Eight patients received docetaxel (35 mg/m(2), day 1) and carboplatin-based (area under the curve, 4 mg·min(-1)·mL(-1); day 1) chemotherapy with an oral itraconazole solution (400 mg, days -2 to 2), repeated every two weeks. The response rate, median progression-free survival and overall survival were 44% (95% confidence interval [(CI)=12-77%], 544 days (95% CI=82-544 days) and 1,047 days (95% CI=462-1332 days), respectively. CONCLUSION: Chemotherapy with itraconazole is promising for patients with CCC.