Efficacy and safety of mogamulizumab by patient baseline blood tumour burden: a post hoc analysis of the MAVORIC trial.

BACKGROUND: Mogamulizumab was compared with vorinostat in the phase 3 MAVORIC trial (NCT01728805) in 372 patients with relapsed/refractory mycosis fungoides (MF) or Sézary syndrome (SS) who had failed ≥1 prior systemic therapy. Mogamulizumab significantly prolonged progression-free survival (PFS), with a superior objective response rate (ORR) vs. vorinostat. OBJECTIVES: This post hoc analysis was performed to evaluate the effect of baseline blood tumour burden on patient response to mogamulizumab. METHODS: PFS, ORR, time to next treatment (TTNT), skin response (modified Severity-Weighted Assessment Tool [mSWAT]) and safety were assessed in patients stratified by blood classification (B0 [n = 126], B1 [n = 62], or B2 [n = 184], indicating increasing blood involvement). RESULTS: Investigator-assessed PFS was longer for mogamulizumab versus vorinostat across all blood classes, significantly so for B1 and B2 patients. ORR was higher with mogamulizumab than with vorinostat in all blood classification groups and more markedly so with escalating B class (B0: 15.6% vs. 6.5%, P = 0.0549; B1: 25.8% vs. 6.5%, P = 0.2758; B2: 37.4% vs. 3.2%, P < 0.0001). TTNT was significantly longer for patients treated with mogamulizumab versus vorinostat with B1 (12.63 vs. 3.07 months; HR 0.32 [95% CI 0.16-0.67]; P = 0.0018) and B2 (13.07 vs. 3.53 months; HR 0.30 [95% CI 0.21-0.43]; P < 0.0001) blood involvement. In the mogamulizumab arm, 81 patients (43.5%) had ≥50% change in the mSWAT vs. 41 patients (22.0%) with vorinostat; mSWAT improvements with mogamulizumab occurred most often in B1 and B2 patients. Rapid, sustained reductions were seen in CD4+ CD26- cell counts and CD4:CD8 ratios in mogamulizumab patients for all B classes. Treatment-emergent adverse events were less frequent overall with mogamulizumab and similar in frequency regardless of B class. CONCLUSIONS: This post hoc analysis indicates greater clinical benefit with mogamulizumab vs. vorinostat in patients with MF and SS classified as having B1 and B2 blood involvement.

Utility of ¹8fluoro-deoxyglucose positron emission tomography for prognosis and response assessments in a phase 2 study of romidepsin in patients with relapsed or refractory peripheral T-cell lymphoma.

BACKGROUND: For patients with peripheral T-cell lymphoma (PTCL), the value of (18)fluoro-deoxyglucose positron emission tomography (FDG-PET) scans for assessing prognosis and response to treatment remains unclear. The utility of FDG-PET, in addition to conventional radiology, was examined as a planned exploratory end point in the pivotal phase 2 trial of romidepsin for the treatment of relapsed/refractory PTCL. PATIENTS AND METHODS: Patients received romidepsin at a dose of 14 mg/m(2) on days 1, 8, and 15 of 28-day cycles. The primary end point was the rate of confirmed/unconfirmed complete response (CR/CRu) as assessed by International Workshop Criteria (IWC) using conventional radiology. For the exploratory PET end point, patients with at least baseline FDG-PET scans were assessed by IWC + PET criteria. RESULTS: Of 130 patients, 110 had baseline FDG-PET scans, and 105 were PET positive at baseline. The use of IWC + PET criteria increased the objective response rate to 30% compared with 26% by conventional radiology. Durations of response were well differentiated by both conventional radiology response criteria [CR/CRu versus partial response (PR), P = 0.0001] and PET status (negative versus positive, P < 0.0001). Patients who achieved CR/CRu had prolonged progression-free survival (PFS, median 25.9 months) compared with other response groups (P = 0.0007). Patients who achieved PR or stable disease (SD) had similar PFS (median 7.2 and 6.3 months, respectively, P = 0.6427). When grouping PR and SD patients by PET status, patients with PET-negative versus PET-positive disease had a median PFS of 18.2 versus 7.1 months (P = 0.0923). CONCLUSIONS: Routine use of FDG-PET does not obviate conventional staging, but may aid in determining prognosis and refine response assessments for patients with PTCL, particularly for those who do not achieve CR/CRu by conventional staging. The optimal way to incorporate FDG-PET scans for patients with PTCL remains to be determined. TRIAL REGISTRATION: NCT00426764.

Tagraxofusp, a novel CD123-directed cytotoxin to treat blastic plasmacytoid dendritic cell neoplasm.

Tagraxofusp is a toxin-cytokine fusion protein consisting of engineered diphtheria toxin (DT) and interleukin-3 (IL-3). The IL-3 domain binds to the cluster of differentiation 123 (CD123) and translocates DT into the cytosol, which leads to cell death. Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare and aggressive hematologic malignancy with a strong expression of CD123. Historical data show that the prognosis of BPDCN is poor, with a median overall survival of 9 to 13 months. On December 21, 2018, the United States Food and Drug Administration (FDA) approved tagraxofusp for the treatment of adults and children with newly diagnosed or relapsed/refractory BPDCN, becoming the first FDA-approved drug for this disease. In this review, we examine the preclinical studies and phase I/II clinical studies that led to FDA approval of tagraxofusp, focusing on its molecular pharmacology, pharmacokinetics, efficacy and safety profile. We also discuss future directions regarding BPDCN management.

Absence of polycythemia in a child with a unique erythropoietin receptor mutation in a family with autosomal dominant primary polycythemia.

Primary familial and congenital polycythemia (PFCP or familial erythrocytosis) is a rare proliferative disorder of erythroid progenitor cells, characterized by elevated erythrocyte mass and hemoglobin concentration, hypersensitivity of erythroid progenitors to erythropoietin (EPO), and autosomal dominant inheritance or sporadic occurrence. A number of EPO receptor (EPOR) mutations were found in subjects with PFCP; most of these mutations resulted in the truncation of the COOH-terminal of the EPOR protein. We studied a family with autosomal dominant inheritance of PFCP in which four subjects were affected in three generations. We screened the affected individuals for EPOR gene mutations using SSCP analysis and found a C5964G mutation in exon VIII that changes tyrosine codon 426 to a translation termination codon resulting in an EPOR protein truncated by 83 amino acids. The mutant C5964G-EPOR exhibited hypersensitive EPO-dependent proliferation compared to the wild-type EPOR when tested in a murine interleukin-3-dependent myeloid cell line (FDC-P1). We also examined the segregation of the mutation with PFCP in the family and found that a child in the third generation inherited the mutation without having laboratory evidence of polycythemia. Further in vitro analysis of the erythroid progenitor cells of this affected child revealed that the progenitor cells were hypersensitive to EPO (a hallmark of PFCP) suggesting the presence of the disease at the level of progenitor cells. Failure of this child to develop polycythemia suggests the existence of as yet unidentified environmental or genetic factors that may suppress disease development.

[Epithelioid hemangioma of the foot]. / Epiteloidný hemangióm nohy.

Epithelioid hemangioma (angiolymphoid hyperplasia with eosinophilia, EH/ALHE) is a rare benign angioproliferative lesion which typically occurs in the region of the head and neck. In the literature, occurence on the extremity is only rarely described. A case of multiple occurence of EH/ALHE in the skin of the toes and metatarsal bone with osteolysis is reported. Occurence on the extremity, superficial and deep affection and some "atypical" microscopic features may cause diagnostic dilemma. The key diagnostic features of EH/ALHE are vascular channels lined with epithelioid endothelial cells, surrounding layer of myopericytes, absence of atypia and mitotic activity and characteristic inflammation. Immunohistochemistry may be helpful in settling the diagnosis.

Mutation in the negative regulatory element of the erythropoietin receptor gene in a case of sporadic primary polycythemia.

A 42-year-old Caucasian male with sporadic primary polycythemia has been followed by us for 13 years. During the time of observation, his hemoglobin had been stable, and he has never had an elevated white count or platelet count or any other stigmata of polycythemia vera (PV). Both of his parents, his three children, and all siblings have been hematologically normal. The in vitro culture of erythroid progenitors revealed an absence of autonomous erythropoietin (Epo)-independent erythroid colonies but demonstrated a marked increase in the sensitivity of erythroid progenitors to Epo. We have undertaken a study designed to determine whether a mutation in the Epo receptor (Epo-R) gene could cause the polycythemia phenotype seen in either dominant or recessive primary polycythemia described by us and others, or in polycythemia vera. We have sequenced the cytoplasmic positive and negative regulatory domains of the Epo-R genomic DNA, and a transversion of C to T in nucleotide 6148 was found in one of the patient's chromosomes. This mutation is located in the negative regulatory domain and results in a change from proline to serine (P488S). We have subsequently analyzed more than 40 chromosomes from unrelated normal subjects, as well as autosomal dominant, recessive, and sporadic primary polycythemia and polycythemia vera subjects. In no instance was the same or any other mutation in the Epo-R found. To determine if this Epo-R mutation is a cause of increased sensitivity of erythroid progenitors to erythropoietin, Ba/F3 cells (interleukin-3-dependent murine lymphoid line) were transfected with normal and mutated Epo-R cDNA, rendering the transfected cells viable and able to proliferate in Epo. Transfectants with wild-type and mutant Epo-R cDNA exhibited no difference in the presence of Epo. More recently, we were able to obtain DNA from the seven family members of the propositus and found that the nonpolycythemic mother and one of the siblings have the same Epo-R mutation. We conclude that this first described mutation of Epo-R encountered in humans does not appear on its own to explain the polycythemia phenotype; however, the possibility that it may interact with some other acquired or congenital abnormality in generating the polycythemia phenotype cannot be excluded.

The relationship of TP53 R72P polymorphism to disease outcome and TP53 mutation in myelodysplastic syndromes.

Nonsynonymous TP53 exon 4 single-nucleotide polymorphism (SNP), R72P, is linked to cancer and mutagen susceptibility. R72P associations with specific cancer risk, particularly hematological malignancies, have been conflicting. Myelodysplastic syndrome (MDS) with chromosome 5q deletion is characterized by erythroid hypoplasia arising from lineage-specific p53 accumulation resulting from ribosomal insufficiency. We hypothesized that apoptotically diminished R72P C-allele may influence predisposition to del(5q) MDS. Bone marrow and blood DNA was sequenced from 705 MDS cases (333 del(5q), 372 non-del(5q)) and 157 controls. Genotype distribution did not significantly differ between del(5q) cases (12.6% CC, 38.1% CG, 49.2% GG), non-del(5q) cases (9.7% CC, 44.6% CG, 45.7% GG) and controls (7.6% CC, 37.6% CG, 54.8% GG) (P=0.13). Allele frequency did not differ between non-del(5q) and del(5q) cases (P=0.91) but trended towards increased C-allele frequency comparing non-del(5q) (P=0.08) and del(5q) (P=0.10) cases with controls. Median lenalidomide response duration increased proportionate to C-allele dosage in del(5q) patients (2.2 (CC), 1.3 (CG) and 0.89 years (GG)). Furthermore, C-allele homozygosity in del(5q) was associated with prolonged overall and progression-free survival and non-terminal interstitial deletions that excluded 5q34, whereas G-allele homozygozity was associated with inferior outcome and terminal deletions involving 5q34 (P=0.05). These findings comprise the largest MDS R72P SNP analysis.

A crossover study of focused cognitive therapy for panic disorder.

OBJECTIVE: This study sought to determine the short- and long-term effects of focused cognitive therapy for panic disorder. METHOD: Thirty-three psychiatric outpatients with the DSM-III diagnosis of panic disorder were randomly assigned to either 12 weeks of individual, focused cognitive therapy or 8 weeks of brief supportive psychotherapy based on principles of client-centered therapy. The patients who received supportive psychotherapy were subsequently given the opportunity to cross over to cognitive therapy for 12 weeks. Patients were rated for panic and depression before therapy, after 4 and 8 weeks of therapy, and at 6-month and 1-year follow-up. RESULTS: Clinician ratings and self-ratings of panic frequency and intensity indicated that the focused cognitive therapy group achieved significantly greater reductions in panic symptoms and general anxiety after 8 weeks of treatment than did the group that received brief supportive psychotherapy. At 8 weeks, 71% of the cognitive therapy group were panic free, compared to 25% of the psychotherapy group. Moreover, 94% of the psychotherapy patients elected to cross over to 12 weeks of cognitive therapy. At 1-year follow-up, 87% of the group that received cognitive therapy only and 79% of the group that crossed over into cognitive therapy remained free of panic attacks. CONCLUSIONS: Focused cognitive therapy offers a promising nonpharmacological alternative for the treatment of panic disorder.

Salivary gland anlage tumor. A case with widespread necrosis and large cyst formation.

We describe a case of the salivary gland anlage tumor (congenital pleomorphic adenoma). The tumor arose in the nasopharynx as a pedunculated mass. Microscopically most of the tumor contained large necrotic areas which revealed squamous cell metaplasia resulting in the formation of large cysts. This feature has never been described previously in this tumor and might lead to an erroneous diagnosis.

Adrenal myelolipoma. 6 cases and a review of the literature.

Adrenal myelolipoma is an uncommon, benign and hormonally inactive tumor. Most lesions are asymptomatic and usually are discovered incidentally at autopsy studies. Authors report on 6 patients (5 women, 1 man) with adrenal myelolipomas (5 right, 1 left), analyze their morphological findings and association with an adrenal hormonal overproduction. Five of the patients underwent surgery because of tumor size, in 3 of them histological evaluation confirmed myelolipoma and in 2 cases an adrenocortical adenoma with foci of myelolipoma. All the patients were asymptomatic and in 4 cases hormonal overproduction was not found. One female patient has oveproduction of dehydroepiandrosteron-sulphate (DHEAS) indicating a 3beta hydroxylase deficiency in this tumor and 1 patient has primary aldosteronism with a histological finding of an association of adrenocortical adenoma with foci of myelolipoma. Neither Cushings syndrome nor congenital adrenal hyperplasia were present in our group of patients.

Amplification of N-myc oncogene in human melanoma cells.

Tissue specimens from two melanoma patients and two patients with laryngeal carcinoma were studied for the expression of c-myc, N-myc and v-src oncogenes. Out of three different probes, only the N-myc probe one signalled amplification. While the two patients with laryngeal carcinoma showed only single copy of the N-myc gene in tumor cells, amplification of this gene was found in both two melanoma patients. The patients with 1 extra copy of the N-myc gene and its protein product had an early recurrence but is still alive, while the other melanoma patient with 4 extra copies of the gene, relapsed very early and died of melanoma within 7 months after diagnosis. Thus a higher amplification (4 extra copies) seems to correlate with very poor outcome of the disease.

The effect of cluster size, dimensionality, and the number of clusters on recovery of true cluster structure.

An evaluation of four clustering methods and four external criterion measures was conducted with respect to the effect of the number of clusters, dimensionality, and relative cluster sizes on the recovery of true cluster structure. The four methods were the single link, complete link, group average (UPGMA), and Ward's minimum variance algorithms. The results indicated that the four criterion measures were generally consistent with each other, of which two highly similar pairs were identified. The tirst pair consisted of the Rand and corrected Rand statistics, and the second pair was the Jaccard and the Fowlkes and Mallows indexes. With respect to the methods, recovery was found to improve as the number of clusters increased and as the number of dimensions increased. The relative cluster size factor produced differential performance effects, with Ward's procedure providing the best recovery when the clusters were of equal size. The group average method gave equivalent or better recovery when the clusters were of unequal size.

High performance liquid chromatography assay for piroxicam in pharmaceutical products.

A high performance liquid chromatographic assay for piroxicam in pharmaceutical preparations is described. The method uses a reversed-phase C18 column with pH 3 aqueous buffer/methanol, 55:45, v/v mobile phase, and is selective for piroxicam in the presence of other "oxicams," synthetic precursors, by-products, degradation products, metabolites, and related compounds. Applications to capsules, tablets, ointments, suppositories, ophthalmic suspensions, and rodent feeds are cited.

Aldosterone-producing adenoma associated with foci of myelolipoma.

The simultaneous occurrence of adrenal myelolipoma and endocrine disorders is rare. Myelolipomas have occasionally been found in patients with Cushing's syndrome, pheochromocytoma and hyperthyroidism. A recently published study described one well-documented case of adrenal adenoma and myelolipoma in a patient with Conn's syndrome. In this report the patient had a one-year history of treated hyperthyroidism and diagnosed aldosterone-producing adenoma. A disseminated adrenal myelolipoma was found within the adrenocortical adenoma. To our knowledge this histological finding has not been previously reported in association with both Conn's syndrome and hyperthyroidism.

Actinomycosis of the urachus persistens penetrating into the ileum.

A 16-year-old boy is presented with the problem of free micturition, having a palpable, painless tumour spreading from the symphysis to the umbilicus. Cystoscopy revealed an impression in the vertex of the urinary bladder covered by the inflamed mucous membrane with a bulbar oedema. Fistulography showed transitional urachus persistens communicating with the terminal loops of the ileum. During surgery, a solid, fan-like fibrous connective tissue was removed, together with the vertex of the urinary bladder and peritoneum. Adhering loops of the terminal ileum were sharply separated and sutured. Histopathological examination confirmed actinomycosis of the urachus persistens penetrating into the ileum.

[Renal oncocytoma and its morphology, diagnosis and therapy]. / Onkocytóm oblicky a jeho morfológia, diagnostika a liecba.

Oncocytoma includes 3-5% of all renal tumors. It does not manifest itself by typical symptoms and often is diagnostically confirmed in coincidence with examinations of other diseases. The preoperative diagnosis of oncocytoma is difficult. Oncocytoma must be taken into consideration in cases of bilateral multilocular tumors of the kidney. Neither RTG, USG and CT examinations, nor angiography give the specific picture of oncocytoma. One of the possibilities of diagnosis confirmation is the peroperative biopsy. If the latter confirms the diagnosis, then according to possibilities, operation with maintenance of unimpaired renal parenchyme should be performed. The prognosis of the disease is good and depends on the stage of cellular differentiation of tumor. The study presents observations of 4 patients subdued to surgery at the Urologic Clinic FHwP in Kosice since 1981 to 1990. The patients survive without metastases for 3-4 years.

[Hormonal and morphologic characteristics of adrenal incidentalomas]. / Hormonálna a morfologická charakteristika adrenálnych incidentalómov.

The authors analyse hormonal and morphological characteristics of adrenal incidentalomas, i.e. pathological adrenal masses accidentally found on CT scan performed due to extraadrenal causes of other causes of adrenal pathology. The group of patients was consisted by 42 patients at the age 24-79 years (27 females and 15 males). The most frequent clinical symptoms included arterial hypertension, diabetes mellitus and obesity. CT examinations revealed 36 cases of unilateral lesions (in 21 cases the lesions were localised on the right and in 15 cases on the left) and 6 bilateral lesions. The size of adrenal masses ranged from 7 mm to 12 cm. The CT examination helped in characterising myelolipomas in 3 cases, cysts in two cases, and pre-assuming malignity in 6 cases. Hormonal analyses have revealed primary aldosteronism in 2 cases, subclinical hypercortisolism in 1, steroid enzymopathy in 2 and secondary hyperaldosteronism in 2 patients. No patient had catecholamine overproduction. 19 patients were indicated for adrenalectomy with the following histological findings.: adenoma (n = 5), cyst (n = 2), myelolipoma (n = 3), carcinoma (n = 3), feochromocytoma, ganglioneuroma, metastases, lymphoma, sarcoidosis and pseudodrenal structure--Gravitz tumor (n = 1, respectively). The size of all neoplasms exceeded 3 cm, therefore the authors recommend adrenalectomy in incidentalomas with hormonal activity exceeding 3 cm in size. (Tab. 2, Fig. 1, Ref. 17.)

[Extrauterine choriocarcinoma--a rare form of gestational trophoblastic disease]. / Extrauternný choriokarcinóm--zriedkavá forma gestacnej trofoblastovej choroby.

Choriocarcinoma represents the most serious form of trophoblast gestation disease. In the majority of cases the carcinomatous tissues fill out the uterine cavity, or they grow in a form of nodes deep in the uterine wall. The primary extrauterine localization of this tumour is very rare. The authors describe two cases of choriocarcinomas with tubal or ovarian localization. (Fig. 4, Ref. 19.)

[Monocytoid B-lymphocyte lymphoma: a new type within the spectrum of non-Hodgkin's B-cell lymphoma]. / Monocytoidný B-lymfocytový lymfóm: nová jednotka v spektre non-Hodgkinových lymfómov B-pôvodu.

BACKGROUND: Clonal proliferation of monocytoid B-lymphocytes (MBLy)--monocytoid B-cell lymphoma (MBCL) represents a "new" type of lymphoma within the spectrum of B-cell malignancies. OBJECTIVES: The aim of the study was to evaluate the possibilities of a routine histological and immunohistochemical diagnosis of MBCL. METHODS: Three cases of MBCL diagnosed in peripheral lymph nodes (n = 2) and in mammary gland with infiltration of regional lymph node (n = 1) were analyzed both histologically and immunohistochemically using a panel approach (Ig chains, CD30 antigen, markers of B-cells, T-cells and of monocytes/histiocytes). RESULTS: Morphological appearance of neoplastic cells of MBCL is identical to that of MBLy in reactive conditions--kidney-shaped nuclei, bright clear PAS-negative cytoplasm, and small inconspicuous nucleoli. CONCLUSIONS: Morphological appearance together with immunophenotypic results (positivity of CD20 and Ki-B5, negativity of CD3, CD43, CD45RO, and of lysozyme, negativity of CD30) are considered to represent sufficient diagnostic criteria of MBCL, including its differential diagnosis of other B-cell low grade malignancies. An increase of large cell type MBLy might represent a feature of a secondary blastic transformation of MBCL. (Tab. 2, Fig. 5, Ref. 27.)