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Quizartinib is an FMS‐like tyrosine kinase 3 (FLT3) inhibitor that has shown robust clinical activity in patients with FLT3‐internal tandem duplication–mutated relapsed/refractory acute myeloid leukemia (AML). This analysis evaluated the population pharmacokinetics (PK) of quizartinib and its active metabolite, AC886, in a pooled analysis of data from 649 healthy volunteers or patients with AML from 8 clinical trials including the phase 3 QuANTUM‐R study. Quizartinib was given as a single dose or multiple once‐daily doses of 20, 30, 60, or 90 mg. Nonlinear mixed‐effects modeling was performed using observed concentrations of quizartinib and AC886. Strong CYP3A inhibitor use resulted in an 82% increase in the area under the curve (AUC) and a 72% increase in the maximum concentration (Cmax) of quizartinib. Albumin level, age, and body surface area were statistically significant covariates on quizartinib PK. However, their individual effects on quizartinib AUC and Cmax were <20%. For AC886, strong CYP3A inhibitor use, body surface area and black/African American race were significant covariates. Except for strong CYP3A inhibitor use, the effects on the overall exposure (AUC of quizartinib + AC886) were <20%. The population PK model provided an adequate description of the observed concentrations of quizartinib and AC886 in both healthy volunteers and patients with AML. Only concomitant use of strong CYP3A inhibitors had a clinically meaningful effect on quizartinib PK exposure. [ABSTRACT FROM AUTHOR]

Cancer of unknown primary (CUP) denotes a malignancy with histologically confirmed metastatic spread while the primary tumor remains elusive. Here, we address prognostic and therapeutic implications of mutations and copy number variations (CNVs) detected in tumor tissue in the context of a comprehensive clinical risk assessment. Targeted panel sequencing was performed in 252 CUP patients. 71.8% of patients had unfavorable CUP according to ESMO guidelines. 74.7% were adeno‐ and 13.7% squamous cell carcinomas. DNA was extracted from microdissected formalin‐fixed, paraffin‐embedded tissues. For library preparation, mostly multiplex PCR‐based Ion Torrent AmpliSeq™ technology with Oncomine comprehensive assays was used. Most frequent genetic alterations were mutations/deletions of TP53 (49.6%), CDKN2A (19.0%) and NOTCH1 (14.1%) as well as oncogenic activation of KRAS (23.4%), FGFR4 (14.9%) and PIK3CA (10.7%). KRAS activation was predominantly found in adenocarcinomas (p = 0.01), PIK3CA activation in squamous cell carcinomas (p = 0.03). Male sex, high ECOG score, unfavorable CUP, higher number of involved organs and RAS activation predicted decreased event‐free and overall survival in multivariate analysis. Deletions of CDKN2A were prognostically adverse regarding overall survival. TP53 mutations did not significantly influence prognosis in the overall cohort, but worsened prognosis in otherwise favorable CUP subtypes. Although not standard in CUP, for 17/198 (8.6%) patients molecularly targeted treatment was recommended and 10 patients (5.1%) were treated accordingly. In conclusion, besides the identification of drug targets, panel sequencing in CUP is prognostically relevant, with RAS activation and CDKN2A deletion emerging as novel independent risk factors in a comprehensive assessment with clinicopathological data. What's new? While some cancers of unknown primary (CUP) respond to treatment, most have poor survival rates. In this study, the authors used next‐generation sequencing (NGS) to identify specific genetic mutations that indicate a poorer prognosis in CUP. These included CDKN2A deletion and RAS activation, while TP53 mutations indicated poor prognosis mainly in squamous cell carcinoma CUP and in clinically favorable CUP subtypes. NGS results were also able to guide targeted treatment in some CUPs, demonstrating that routine NGS‐based sequencing can enable access to individualized treatment in clinical practice, outside clinical trials. [ABSTRACT FROM AUTHOR]

Cancer of unknown primary (CUP) denotes cancer cases where metastatic spread is histologically confirmed, but no respective primary tumor can be identified. The challenging diagnosis of CUP is further complicated in cases with previously identified malignancies or with dubious clonal relationship between metastatic sites due to ambiguous histology. Our study aims at elucidating clonal relationships by comparing the respective mutational spectra. Targeted next‐generation sequencing (NGS) employing formalin‐fixed and paraffin‐embedded (FFPE) tumor tissue was performed on 174 consecutive CUP patients. Among these, 43/174 (24.7%) patients had a documented prior malignancy. Data on pairwise targeted NGS testing to address clonal relationships between the previous malignancy and the presumed CUP (n = 11) or between different CUP metastatic sites (n = 7) was available in 18 patients. NGS could clarify clonal relationships in 16/18 cases. Among the 11 CUP patients with antecedent malignancies, four cases were clonally independent of the previous malignancy but harbored deleterious germline mutations in BRCA/BAP1/ATM genes. Seven CUP cases were clonally related to the antecedent malignancy, changing the CUP diagnosis to relapse of the prior malignancy. In the seven CUP cases, with doubtfully related metastatic sites, NGS confirmed clonal relationship in five cases and was inconclusive in two. In conclusion, NGS proved an efficient tool to elucidate clonal relationships in clinically challenging CUP cases. Our study cautions against a premature diagnosis of CUP. Relapses of antecedent malignancies should be carefully considered. CUPs clonally independent from the antecedent malignancy should raise a red flag of a potential cancer‐predisposing germline mutation. What's new? Cancer of unknown primary (CUP) often presents a difficult challenge. Is it a recurrence of a previous cancer or metastasis of a new malignancy? In this study, the authors used targeted next‐generation sequencing (NGS) to compare the genetic signatures of CUPs with signatures of the patients' previous cancers. This pair‐wise testing revealed that many CUPs are clonally related to previous cancers. In cases where CUPs are clonally independent from a previous malignancy, the authors note that this should raise a red flag of a potential cancer‐predisposing germline mutation. [ABSTRACT FROM AUTHOR]

The article discusses the efficiency and impact of the Aurora B kinase inhibitor BI 81128 along with the combination of the medication cytarabine on patients diagnosed with acute myeloid leukaemia (AML). It talks about the clinical trial conducted to understand the efficiency, safety and the pharmacokinetics (PK) of the inhibitor in the patients with AML.

The article focuses on the efficiency of the Hedgehog pathway inhibitor (HPI) Vismodegib in the treatment of patients experiencing a relapse of acute myeloid leukaemia (AML). It talks about the Hedgehog signalling being important in maintaining leukaemia stem cells (LSCs) in the patient's body. It tells about Vismodegib being able to bind Smoothened (SMO) in the body.

The article presents the phase one results of a study on volasertib as monotherapy or in combination with cytarabine in patients with relapsed/refractory acute myeloid leukemia (AML). Topics discussed include dose escalations and dose-limiting toxicities, most common treatment-related adverse events (AEs,) and safety profile of volasertib in AML patients.

Abstract: Objective: To improve monitoring of myeloid neoplasms by flow cytometry‐based minimal residual disease (MRD) analysis, we analyzed the significance of leukemia‐associated immunophenotype (LAIP) markers in 44 patients. Methods: In a pilot study cohort, peripheral blood or bone marrow samples from 13 patients with myeloid neoplasms and one case of B lymphoblastic leukemia in complete hematologic remission after allogeneic bone marrow or stem cell transplantation were subjected to selection for leukemia‐specific phenotypes by fluorescence‐activated cell sorting using individual marker combinations, followed by PCR‐based chimerism analysis. Results: The feasibility of this method could be demonstrated, with selection being successful in 12 cases, including two cases where mixed chimerism was found exclusively in sorted cells. Interestingly, four specimens displayed full donor chimerism in cells expressing the presumably aberrant combination CD34+/CD7+. Further analyses, including assessment of an independent cohort of 25 patients not affected by neoplastic bone marrow infiltration, revealed that normal myeloid precursors usually include a population coexpressing CD34, CD13, CD33, and CD7. Conclusion: We conclude that the combination CD34+/CD7+ might not be suitable as an LAIP for MRD diagnostics and that a subset of normal myeloid precursors in the bone marrow expresses CD7. [ABSTRACT FROM AUTHOR]

Objective To evaluate the prognostic impact of gene expression levels ( ELs) of two tumor suppressor genes, sprouty 4 ( SPRY4, located on 5q) and lysine methyltransferase 2C ( KMT2C, located on 7q) in correlation with clinical characteristics and genetic abnormalities assessed at initial diagnosis in acute myeloid leukemia ( AML). Method Gene expression levels were measured on cDNA by RT- qPCR from diagnostic bone marrow samples of 275 intensively treated adult AML patients (median age, 48 years). Results KMT2C ELs were significantly lower in abn7q/-7 ( P = .001), whereas SPRY4 ELs were not associated with abn5q/-5. Higher KMT2C and SPRY4 ELs were significantly associated with lower genetic risk groups as defined by the European LeukemiaNet classification. Additionally, KMT2C ELs were lower in cytogenetically normal patients with DNMT3A ( P = .01) or FLT3- ITD mutations ( P = .05). KMT2C ELs were not associated with prognosis, whereas higher SPRY4 ELs showed a favorable impact on event-free ( EFS, P = .01), relapse-free ( RFS, P = .01) and in-trend on overall survival ( P = .06) for cytogenetically abnormal patients, which was confirmed in multivariable analysis for EFS ( HR, 0.84; 95%- CI, 0.73-0.97; P = .02) and RFS ( HR, 0.85; 95%- CI, 0.73-0.98; P = .02). Conclusion Our data indicate that KMT2C ELs are associated with specific genetic features and that SPRY4 ELs may add prognostic information. [ABSTRACT FROM AUTHOR]

In the multicentre prospective randomized HD2002 trial, rituximab maintenance therapy (375 mg/m² every 3 months for 2 years) versus observation was evaluated for CD20+ B-cell lymphoma. Out of 321 patients [161 randomized to the treatment group (TG), 160 to the observation group (OG)], 295 data sets were evaluable for statistical analysis. Estimated 5-year relapse-free survival (RFS) was 81% in the TG and 70% in the OG (logrank test, P = 0.047). In the diffuse large B-cell lymphoma (DLBCL) subgroup (n = 152), 5-year RFS was excellent, at 87% in the TG and 84% in the OG (logrank test, P = 0.35). Of note, only in male patients of the DLBCL subgroup was RFS significantly superior in the TG in comparison to the OG (5-year RFS: 88% vs. 74%; logrank test, P = 0.05). Cox regression analysis showed a significant interaction between treatment and gender regarding overall survival (OS) (P = 0.006) and RFS (P = 0.02), with a lower hazard in females than males in the OG [OS: hazard ratio (HR) (female:male) = 0.11; 95% confidence interval (CI) = 0.00-1.03; RFS: HR (female:male) = 0.27; 95% CI = 0.05-0.97], and no significant differences between males and females in the TG. We conclude that Rituximab maintenance therapy improves survival in male patients with DLBCL. [ABSTRACT FROM AUTHOR]

Cancer of unknown primary site (CUP) may be called an 'orphan' disease, as it is diagnosed when metastases are detected while the primary tumor typically remains undetected, and because little research has been done on its primary causes. So far, few epidemiological studies, if any, have addressed possible risk factors for CUP. We analyzed data from the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort ( N = 476,940). During prospective follow-up, a total of 651 cases of incident cases of CUP were detected (ICD-O-2 code C809). Proportional hazards models were conducted to examine the associations of lifetime history of smoking habits, alcohol consumption, levels of education and anthropometric indices of adiposity with risk of being diagnosed with CUP. Risk of being diagnosed with CUP was strongly related to smoking, with a relative risk of 3.66 [95% C.I., 2.24-5.97] for current, heavy smokers (26+ cigarettes/day) compared to never smokers (adjusted for alcohol consumption, body mass index, waist circumference and level of education) and a relative risk of 5.12 [3.09-8.47] for cases with CUP who died within 12 months. For alcohol consumption and level of education, weaker associations were observed but attenuated and no longer statistically significant after adjusting for smoking and indices of obesity. Finally, risk of CUP was increased by approximately 30 per cent for subjects in the highest versus lowest quartiles of waist circumference. Our analyses provide further documentation, in addition to autopsy studies, that a substantial proportion of cancers of unknown primary site may have their origin in smoking-related tumors, in particular. [ABSTRACT FROM AUTHOR]

We retrospectively analyzed and compared the efficacy and toxicity of azacitidine ( AZA) and low-dose cytarabine ( LD- Ara- C) in 65 palliative patients with acute myeloid leukemia ( AML) showing high bone marrow blast counts (≥30%) before start of treatment. Twenty-seven and 38 patients received AZA and LD- Ara- C, respectively. The median patient age was 71 yr. Patient and disease characteristics did not differ between the treatment groups, except for BM blast counts, and peripheral leukocyte and blast counts which were significantly higher in the LD- Ara- C group. AZA and LD- Ara- C were first-line treatment in 12 (44%) and 17 patients (45%), respectively. Response and hematologic improvement rates were low and similar in both treatment groups. In both treatment groups, most common non-hematologic toxicities included febrile neutropenia, pneumonia, and bleedings without significant differences regarding frequencies. Estimated 1-yr survival rates were 15% (95% CI 8-22) and 13% (95% CI 7-19) in the AZA and LD- Ara- C groups, respectively, without statistically significant difference. In multivariate analysis ( n = 65), previous treatment ( HR 2.27, 95% CI 1.00-5.22, P = 0.05) and adverse cytogenetics ( HR 2.50, 95% CI 1.20-5.22, P = 0.02) were independent predictors of poor survival. In our center and within the limitations of a retrospective study, both treatment regimens showed similar but limited efficacy in palliative patients with AML and high BM blast counts. [ABSTRACT FROM AUTHOR]

Polo-like kinases (Plks) play an important role in cell cycle checkpoint controls and are over-expressed in acute myeloid leukaemia ( AML). BI 2536, a novel Plk inhibitor, induces mitotic arrest and apoptosis. In this phase I/II trial of BI 2536 in 68 elderly patients with relapsed/refractory AML, three schedules were investigated (day 1, days 1-3, and days 1 + 8). Maximum tolerated dose was 350 and 200 mg in the day 1 and days 1 + 8 schedules, respectively. The day 1-3 schedule appeared equivalent to the day 1 schedule and was discontinued early. BI 2536 exhibited multi-compartmental pharmacokinetic behaviour. The majority of patients showed an increase of bone marrow cells in G2/M with a characteristic pattern of mitotic catastrophe. The overall response rate in the day 1 and day 1 + 8 schedules was 9% (5/54) with 2 complete and 3 partial responses. The majority of drug-related adverse events grade ≥3 were haematological. Taken together, Plk inhibition induced cell cycle arrest in AML blasts in vivo and BI 2536 monotherapy showed modest clinical activity in this poor prognosis patient group. [ABSTRACT FROM AUTHOR]

Abstract: Centrosome abnormalities occur commonly in cancer, and contribute to chromosomal instability and tumorigenesis. New evidence on a phylogenetically conserved mechanism termed ‘centrosomal clustering’ provides exciting insights into how cells with supernumerary centrosomes adapt to avoid lethal multipolar divisions. Here, we highlight the emerging molecular basis of centrosome clustering, and its impact on asymmetric divisions of stem cells, chromosomal (in)stability and malignant transformation. Finally, pharmacological inhibition of centrosome clustering promises to selectively target tumor cells. [Copyright &y& Elsevier]

The article discusses a study on the role of charged multivesicular body protein 5 (CHMP5) in acute myeloid leukemia (AML). A short-hairpin ribonucleic acid (RNA)-based RNA interference (RNAi) screening of functionally uncharacterized human genes was performed to determine whether the genes can inhibit apoptosis. A new antiapoptotic function for charged multivesicular body protein 5 (CHMP5) was identified. CHMP5 silencing was found to induce caspase cascade activation by means of extrinsic apoptosis pathway.

The article examines the crystal structure of the fungal metabolite (+)-geodin that was isolated from Aspergillus terreus. It contains two independent molecules in the asymmetric unit in which the second molecule has a slightly more planar cyclohexadiene ring than the first molecule. The compound's absolute structure has been unequivocally assigned with the spiro centre having the R configuration in both molecules.

Chromosomal instability (CIN), defined by an elevated frequency of the occurrence of novel chromosomal aberrations, is strongly implicated in the generation of aneuploidy, one of the hallmarks of human cancers. As for aneuploidy itself, the role of CIN in the evolution and progression of malignancy is a matter still open to debate. We investigated numerical as well as structural CIN in primary CD34-positive cells by determining the cell-to-cell variability of the chromosome content using fluorescence- in situ-hybridization (FISH). Thereby, CIN was measured in 65 patients with myelodysplastic syndromes (MDS), acute myeloid leukaemia (AML) and control subjects. Among MDS patients, a subgroup with elevated levels of CIN was identified. At a median follow-up of 17.2 months, all patients within this ‘high CIN’ subgroup had died or progressed to AML, while 80% of MDS patients with normal CIN levels had stable disease ( P < 0.001). Notably, there was no statistically significant difference between ‘normal CIN’ and ‘high CIN’ MDS patients regarding established risk factors. Hence, elevated CIN levels were associated with poor outcome, and our method provided additional prognostic information beyond conventional cytogenetics. Furthermore, in all three MDS patients for whom serial measurements were available, development of AML was preceded by increasing CIN levels. In conclusion, elevated CIN levels may be valuable as an early indicator of poor prognosis in MDS, hence corroborating the concept of CIN as a driving force in tumour progression. [ABSTRACT FROM AUTHOR]

Abstract: As the primary microtubule organizing center of most eukaryotic cells, centrosomes play a fundamental role in proper formation of the mitotic spindle and subsequent chromosome separation. Normally, the single centrosome of a G1 cell duplicates precisely once prior to mitosis in a process that is intimately linked to the cell division cycle via cyclin-dependent kinase (cdk) 2 activity that couples centrosome duplication to the onset of DNA replication at the G1/S transition. Accurate control of centrosome duplication is critical for symmetric mitotic spindle formation and thereby contributes to the maintenance of genome integrity. Numerical and structural centrosome abnormalities are hallmarks of almost all solid tumors and have been implicated in the generation of multipolar mitoses and chromosomal instability. In addition to solid neoplasias, centrosome aberrations have recently been described in several different hematological malignancies like acute myeloid leukemias, myelodysplastic syndromes, Hodgkin''s as well as non-Hodgkin''s lymphomas, chronic lymphocytic leukemias and multiple myelomas. In analogy to many solid tumors a correlation between centrosome abnormalities on the one hand and karyotype aberrations as well as clinical aggressiveness on the other hand seems to exist in myeloid malignancies, chronic lymphocytic leukemias and at least some types of non-Hodgkin''s lymphomas. Molecular mechanisms responsible for the development of centrosome aberrations are just beginning to be unraveled. In general, two models with distinct functional consequences can be envisioned. First, centrosome aberrations can arise as a consequence of abortive mitotic events and impaired cytokinesis. Second, evidence has been provided that centrosome amplification can also precede genomic instability and arise in normal, diploid cells. Accordingly, this review will focus on recent advances in the understanding of both, causes and consequences of centrosome aberrations in hematological malignancies. [Copyright &y& Elsevier]

A letter to the editor is presented about the increase in 2-hydroxyglutarate in patients with acute myeloid leukemia (AML), a clonal malignancy of myeloid blood progenitor cells.