First-Line Therapy for Nodal T-cell Non-Hodgkin Lymphomas: an Unmet Need in Hematology.

PURPOSEOF REVIEW: The main aim of this review is to summarize first-line therapy of nodal T-cell non-Hodgkin lymphoma. RECENT FINDINGS: Current treatment with CHOP chemotherapy results in poor outcomes in the majority of patients. However, there are advances within the field. First breakthrough is the ECHELON-2 trial which showed that the addition of brentuximab vedotin improves outcomes in anaplastic large cell lymphoma. However, other types of peripheral T-cell non-Hodgkin lymphoma were underrepresented with optimal treatment not known. Second breakthrough is an increase of autologous stem cell transplantation usage in the first complete metabolic remission, except in ALK + anaplastic large cell lymphoma, offering better disease control. Despite advances in the field, CHOP remains the standard treatment for the majority of these lymphomas, but multiple trials are underway with the aim to improve this unmet need in hematology and, hopefully, leading us to a new era in the treatment of peripheral T-cell lymphomas.

Brentuximab-induced splinter nail haemorrhages in a patient with Sézary syndrome: A case report.

Sézary syndrome is a systemic variant of cutaneous T-cell lymphoma characterized by erythroderma, lymphadenopathy and circulating atypical lymphocytes (Sézary cells). It may present with nonspecific lesions on multiple digits. We describe an atypical case of brentuximab-induced splinter nail haemorrhages in a patient with Sézary syndrome, associated with a poor prognosis during follow-up. Concomitantly with the appearance of nail lesions, significant lymphocytosis was detected as well as infiltration of bone marrow and nail matrices. The lesions followed a precise sequence, which can be traced back to the monthly application of brentuximab and its direct cytotoxic effect on CD30+ T lymphocytes in the nail matrix. Brentuximab-induced nail lesions might be associated with decreased efficacy of brentuximab in this patient with advanced cutaneous T-cell lymphoma.

Molecular Characterisation of Epstein-Barr Virus in Classical Hodgkin Lymphoma.

Hodgkin lymphomas (HLs) are a heterogeneous group of lymphoid neoplasia associated with Epstein-Barr virus (EBV) infection. EBV, considered to be an important etiological co-factor in approximately 1% of human malignancies, can be classified into two genotypes based on EBNA-2, EBNA-3A and EBNA-3C sequences, and into genetic variants based on the sequence variation of the gene coding for the LMP1 protein. Here, we present the results on the distribution of EBV genotypes 1 and 2 as well as LMP1 gene variants in 50 patients with EBV-positive classical HL selected from a cohort of 289 histologically verified cases collected over a 9-year period in a tertiary clinical center in the Southeast of Europe. The population-based sequencing of the EBNA-3C gene showed the exclusive presence of EBV genotype 1 in all cHL samples. The analysis of EBV LMP1 variant distribution showed a predominance of the wild-type strain B95-8 and the Mediterranean subtype with 30 bp deletion. These findings could contribute to the understanding of EBV immunobiology in cHL as well as to the development of a prophylactic and therapeutic vaccine.

Torquated large ovarian lymphoma as a cause of acute abdomen: a case report of diffuse large B-cell ovarian lymphoma with a germinal center B-cell-like phenotype.

BACKGROUND: Ovarian lymphoma is a rare neoplasm and most commonly represents secondary ovarian involvement in overt systemic disease, usually of the non-Hodgkin's type. AIM: To report a case of acute abdomen caused by torquated large ovarian lymphoma. CASE REPORT: We report the case of 65-year-old patient admitted to our hospital with signs and symptoms of acute abdomen. Findings were suggestive of left ovary torsion due to the neoplasm. After detorsion, mobilization, and adhesiolysis, a bilateral adnexectomy was performed. Histopathological and immunohistochemical analysis of the left ovarian tumor was performed and diagnosis of diffuse large B­cell lymphoma (DLBCL) with a GCB (germinal center B­cell-like) phenotype was made. Additional bone marrow biopsy and imaging techniques excluded other sites of involvement, confirming diagnosis of primary ovarian DLBCL. CONCLUSION: The prognosis of ovarian lymphomas may be poorer than for other lymphomas because of late diagnosis. The best treatment option appears to be systemic chemotherapy.

Primary renal well-differentiated neuroendocrine tumour (carcinoid): next-generation sequencing study of 11 cases.

AIMS: Primary renal well-differentiated neuroendocrine tumour (NET) (hereafter referred to as renal NET) is rare, with ~100 cases having been reported in the literature. There are also limited data on the molecular-genetic background of primary renal NETs. METHODS AND RESULTS: We analysed 11 renal NETs by using next-generation sequencing (NGS) to identify characteristic genetic aberrations. All tumours were positive for synaptophysin, and also expressed insulinoma-associated protein 1 (10/11), chromogranin-A (8/11), and CD56 (3/11). Cytoplasmic positivity of CD99 was present in eight of 11 cases, and strong nuclear expression of α-thalassaemia/mental retardation syndrome X-linked (ATRX) was retained in all 11 cases. Molecular-genetic analysis of aberration of VHL gave negative results in all cases. Loss of heterozygosity on chromosome 3p21 was found in three of nine analysable cases. NGS was successful in nine cases, showing a total of 56 variants being left after the updated filtering process, representing an average of five variants per sample. All analysable cases were negative for ATRX and DAXX (death-domain associated protein X) mutations. The most frequently mutated genes were CDH1 and TET2, with three mutations in two cases. Mutations in AKT3, ROS1, PIK3R2, BCR and MYC were found in two cases. The remaining 41 genes were found to be mutated only in individual cases. In four cases, the mutations affected a subset of genes related to angiogenesis. CONCLUSIONS: Overall, the mutation profile of primary renal NETs is variable, and none of the studied genes or affected pathways seems to be specific for renal NET.

Unlocking Cancer Glycomes from Histopathological Formalin-fixed and Paraffin-embedded (FFPE) Tissue Microdissections.

N- and O-glycans are attractive clinical biomarkers as glycosylation changes in response to diseases. The limited availability of defined clinical specimens impedes glyco-biomarker identification and validation in large patient cohorts. Formalin-fixed paraffin-embedded (FFPE) clinical specimens are the common form of sample preservation in clinical pathology, but qualitative and quantitative N- and O-glycomics of such samples has not been feasible to date. Here, we report a highly sensitive and glycan isomer selective method for simultaneous N- and O-glycomics from histopathological slides. As few as 2000 cells isolated from FFPE tissue sections by laser capture microdissection were sufficient for in-depth histopathology-glycomics using porous graphitized carbon nanoLC ESI-MS/MS. N- and O-glycan profiles were similar between unstained and hematoxylin and eosin stained FFPE samples but differed slightly compared with fresh tissue. This method provides the key to unlock glyco-biomarker information from FFPE histopathological tissues archived in pathology laboratories worldwide.

Infundibulocystic Structures and Prominent Squamous Metaplasia in Sebaceoma-A Rare Feature. A Clinicopathologic Study of 10 Cases.

The authors describe 10 cases of sebaceoma that manifested prominent infundibulocystic structures in all cases and, additionally, conspicuous squamous metaplasia in 6 neoplasms. All tumors occurred on the scalp or the face (2 cases lacked clinical information) and presented as a solitary lesion, measuring from 5 to 20 mm. The patients' age ranged from 22 to 89 years. The main component of all tumors was small, uniform basaloid cells (immature sebocytes) intermixed with mature sebocytes clearly arranged in nodules, classifying the lesions as a sebaceoma. In all neoplasms, the tumor cells showed organoid growth patterns of sebaceoma, including rippled, sinusoidal/labyrinthine, and carcinoid-like, occurring alone or in combination. Additionally, numerous infundibulocystic structures were readily noticed and were either distributed multifocally or unilocular within the tumors. In some cases, they were segregated from the main tumor bulk. The authors posit that these structures, which are different from both sebaceous ductal differentiation and squamous metaplasia, represent an authentic follicular differentiation. The infundibulocystic features (combined with squamous metaplasia), when prominent and in a limited biopsy specimen, may cause a confusion with trichoadenoma or even microcystic adnexal carcinoma.

[Croatian guidelines for gastric cancer prevention by eradication of Helicobacter pylori infection]. / Hrvatski postupnik za prevenciju zelucanog raka eradikacijom infekcije Helicobacterom pylori.

Gastric cancer is the fourth most common type of cancer and the second leading cause of cancer-related death in the world. Although gastric cancer has a multifactorial etiology, infection with Helicobacter pylori is highly associated with gastric carcinogenesis. Carcinogenesis is also influenced by some environmental factors and host genetic diversity, which engenders differential host inflammatory responses that can influence clinical outcome. Chronic gastritis induced by H. pylori is the strongest known risk factor for adenocarcinoma of the distal stomach, but the effects of bacterial eradication on carcinogenesis have remained unclear up to now. Although eradication of H. pylori infection appears to reduce the risk of gastric cancer, several recent controlled interventional trials by H. pylori eradication to prevent gastric cancer have yielded disappointing results. To clarify this problem in a high-risk population, the investigators conducted a prospective, randomized, double-blind, placebo-controlled, population-based studies. The results of previous studies highlight the importance of longer and careful follow-up after eradication therapy. It seems that eradication treatment is effective in preventing gastric cancer if it is given before preneoplastic conditions/lesions, gastric atrophy, metaplasia, and dysplasia, have had time to develop. Furthermore, the significant efficacy of treatment observed in younger patients suggests the need to eradicate H. pylori as early as possible. This consensus aimed to propose guidelines for the diagnosis, management and control of individuals with chronic gastritis, atrophy, intestinal metaplasia, or dysplasia.

[Lymphoma diagnosis and treatment - second Croatian consensus]. / Dijagnostika i lijecenje limfoma - drugi hrvatski konsenzus.

New, extended and modernized recommendations for diagnostics and treatment of lymphomas were accepted at a meeting held in March 2012 with the participation of major Croatian experts. They encompass morphological, radiological and nuclear diagnostics, systemic treatment, radiotherapy and follow-up of most tumors of lymphoid tissues occurring in adults. The recommendations were agreed upon by consensus. Reporters presented data and suggested recommendations which had been first discussed in working groups and then agreed upon on the plenary session.

Retroperitoneal Paraganglioma Treated With Tumor Resection and Replacement of the Inferior Vena Cava.

Retroperitoneal paragangliomas are tumors of neuroectodermal origin rarely appearing in the pediatric population. We report a case of a large paraganglioma infiltrating the right kidney and inferior vena cava in a 16-year-old boy who initially presented with a right-sided varicocele. Right retroperitoneal paraganglioma was embolized preoperatively, followed by total tumor excision, right nephrectomy, inferior vena cava resection, and reconstruction using a prosthetic vascular graft. Retroperitoneal tumors requiring surgery can successfully be treated by radical resection and replacement of the inferior vena cava in experienced centers.

[Surgical approach to atypical wounds (clinical cases). Subcutaneous ischemic arteriolosclerosis (Martorell ulcer, calciphylaxis, eutrophication)]. / Kirurski pristup atipicnim ranama (klinicki primjeri) Supkutana ishemicka arterioloskleroza (Martorellov vrijed, kalcifilaksija, eutrofikacija).

Atypical wounds are probably the most delicate modern medicine topics as well as the most demanding surgical issue. Recently, we submitted an original report of two similar atypical vascular cases at our surgery department. Both presented a rare type of atypical, potentially fatal, vascular illness due to acute ischemic subcutaneous arteriolosclerosis. Because of the strikingly similar common pathophysiological features, Martorell hypertensive ischemic leg ulcer (HYTILU) and calciphylaxis require identical approach and therapy, both systemic and surgical. Even an experienced clinician can easily confuse it with other atypical wounds, namely pyoderma gangrenosum, which due to the corticosteroid induced immunodeficiency can be detrimental, since the two different approach strategies are required. Based on typical localization, necrotic painful skin necroses, progressive local deterioration, often difficult secondary infections along with long term hypertension and diabetes history could elucidate suspicion of ischemic subcutaneous arteriosclerosis. Hypertension (and often diabetes), local findings and histologically proven subcutaneous arteriolosclerosis are mandatory to make the diagnosis. Rapid local amelioration following correct treatment approach additionally confirms the presumed diagnosis. Besides the minutely repetitive surgical debridement, negative wound pressure therapy and split skin transplantation, one should consider systemic medication (analgesics, antioxidants, LMWH, sodium thiosulfate and antibiotics). Considering the cases presented, opportune decisions along with moderate aggressive and modern holistic surgical approach should inevitably resolve hard to heal atypical wounds.

Macrophage Infiltration Correlates with Genomic Instability in Classic Hodgkin Lymphoma.

Hodgkin lymphoma (HL) is a biologically diverse group of lymphoid tumors, which accounts for 1% of all de novo neoplasms in the world's population. It is divided into two main groups: the more common classic Hodgkin lymphoma (cHL) and the less common nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL). cHL is further divided into four subtypes, which differ in morphology and the contents of tumor microenvironment. Macrophages are one of the components of tumor microenvironment known to contribute to creating an immunosuppressive microenvironment, which inhibits the activity of cells expressing granzyme B against tumor cells, even when tumor cells are infected with Epstein-Barr virus (EBV). Our research aimed to explore the association between the specific contents of tumor microenvironment and the genetic anomalies in tumor cells. The presence and the relative percentage of cytotoxic T lymphocytes and macrophages was detected by immunohistochemical staining of the antigens specific for certain cell populations. Fluorescent in situ hybridization was used to detect anomalies in the genome of tumor cells and in situ hybridization was used to detect the presence of EBV. Our results show an association between the number of CD163+ macrophages and the number of TP53 copies or BCL6 gene translocation. Patients who had a higher number of CD163+ macrophages infiltrating tumor tissue and three or higher number of copies of TP53 showed poorer survival. We conclude that the presence of macrophages may contribute to genetic instability in cHL, which drives the progression of cHL and decreases survival of the patients.

Do Semaphorins Play a Role in Development of Fibrosis in Patients with Nonalcoholic Fatty Liver Disease?

Nonalcoholic fatty liver disease (NAFLD) is associated with systemic changes in immune response linked with chronic low-grade inflammation and disease progression. Semaphorins, a large family of biological response modifiers, were recently recognized as one of the key regulators of immune responses, possibly also associated with chronic liver diseases. The aim of this study was to identify semaphorins associated with NAFLD and their relationship with steatosis and fibrosis stages. In this prospective, case-control study, serum semaphorin concentrations (SEMA3A, -3C, -4A, -4D, -5A and -7A) were measured in 95 NAFLD patients and 35 healthy controls. Significantly higher concentrations of SEMA3A, -3C and -4D and lower concentrations of SEAMA5A and -7A were found in NAFLD. While there was no difference according to steatosis grades, SEMA3C and SEMA4D significantly increased and SEMA3A significantly decreased with fibrosis stages and had better accuracy in predicting fibrosis compared to the FIB-4 score. Immunohistochemistry confirmed higher expression of SEMA4D in hepatocytes, endothelial cells and lymphocytes in NAFLD livers. The SEMA5A rs1319222 TT genotype was more frequent in the NAFLD group and was associated with higher liver stiffness measurements. In conclusion, we provide the first evidence of the association of semaphorins with fibrosis in patients with NAFLD.

CD4+/CD57+/CD69+ T lymphocytes and CD14+ dendritic cells accumulate in advanced follicular lymphoma.

Follicular lymphoma is the second most frequent non-Hodgkin's lymphoma, accounting for around 20 % of all lymphomas in Western countries. Initially, it behaves indolently, but in time becomes more aggressive and less susceptible to chemotherapy. Multiple features correlate with the survival of the patients and the progression of the disease, such as therapy with rituximab, tumour microenvironment and the intrafollicular proliferation index. Our research was focused on the association of specific components of tumour microenvironment and the tumour behaviour. The presence and the relative percentage of T lymphocytes, follicular dendritic cells, dendritic cells and macrophages was detected by immunohistochemical staining of the antigens specific for certain cell populations. Our results show that T lymphocytes and dendritic cells affect tumour growth, possibly through interactions with tumour cells. Higher patients' ECOG score and the outcome of the disease are associated with the presence of CD14+ dendritic cells in tumour tissue, while the worse overall survival of patients is associated with the increased number of activated helper T lymphocytes that express marker of exhaustion CD57. Taken together, our results suggest that the efficiency of the immune response against follicular lymphoma depends on more than one type of immune cells. Also, we found that the phenotype of these cells, rather than just their number, affects the tumour behaviour and in consequence survival of the patients.

Different expression of DNMT1, PCNA, MCM2, CDT1, EZH2, GMNN and EP300 genes in lymphomagenesis of low vs. high grade lymphoma.

Tumour cells develop by accumulating changes in the genome that result in changes of main cellular processes. Aberrations of basic processes such as replication and chromatin reassembly are particularly important for genomic (in)stability. The aim of this study was to analyse the expression of genes whose products are crucial for the regulation of replication and chromatin reassembly during lymphomagenesis (DNMT1, PCNA, MCM2, CDT1, EZH2, GMNN, EP300). Non-tumour B cells were used as a control, and follicular lymphoma (FL) and the two most common groups of diffuse large B cell lymphoma (DLBCL) samples were used as a model for tumour progression. The results showed that there are significant changes in the expression of the analysed genes in lymphomagenesis, but also that these changes do not display linearity when assessed in relation to the degree of tumour aggression. Additionally, an integrated bioinformatics analysis of the difference in the expression of selected genes between tumour and non-tumour samples, and between tumour samples (FL vs. DLBCL) in five GEO datasets, did not show a consistent pattern of difference among the datasets.

Clinical Dilemmas in the Treatment of Elderly Patients Suffering from Hodgkin Lymphoma: A Review.

Elderly patients make up a significant number of cases of newly diagnosed Hodgkin lymphoma. However, unlike in young patients, the outcomes of elderly patients are poor, and they are under-represented in phase III trials. Prior to treatment initiation, geriatric assessment should ideally be performed to address the patient's fitness and decide whether to pursue a curative or palliative approach. The ABVD regimen is poorly tolerated in unfit patients, with high treatment-related mortality. Alternative chemotherapy approaches have been explored, with mixed results obtained concerning their feasibility and toxicity in phase II trials. The introduction of brentuximab vedotin-based regimens led to a paradigm shift in first- and further-line treatment of elderly Hodgkin lymphoma patients, providing adequate disease control within a broader patient population. As far as checkpoint inhibitors are concerned, we are only just beginning to understand the role in the treatment of this population. In relapsed/refractory settings there are few options, ranging from autologous stem cell transplantation in selected patients to pembrolizumab, but unfortunately, palliative care is the most common modality. Importantly, published studies are frequently burdened with numerous biases (such as low numbers of patients, selection bias and lack of geriatric assessment), leading to low level of evidence. Furthermore, there are few ongoing studies on this topic. Thus, elderly Hodgkin lymphoma patients are hard to treat and represent an unmet need in hematologic oncology. In conclusion, treatment needs to be personalized and tailored on a case-by-case basis. In this article, we outline treatment options for elderly Hodgkin lymphoma patients.

Retroperitoneal and metachronous testicular germ cell tumors with different histology and teratoma growing syndrome--a case report.

It is presented a case of a 32-year-old male with the three primary tumors diagnosed within a time period of 3 years; retroperitoneal nonseminoma in 2002, retroperitoneal mature teratoma in 2004, and metachronous testicular seminoma in 2005. We discuss the unusual presentation of these three rare events occurring in the same patient without known risk factors.

[Primary ovarian malignant mixed mesodermal tumor (MMMT) as a second primary tumor in a patient with invasive breast carcinoma--case report]. / Maligni mijesani mezodermalni tumor jajnika (MMMT)--drugi primarni tumor u bolesnice s invazivnim karcinomom dojke.

Malignant mixed mesodermal tumor (MMMT) of the ovary is a rare aggressive tumor that consists of an epithelial (carcinoma) and a stromal (sarcoma) component. MMMT accounts for less than 2% of ovarian cancers and has a very poor prognosis. We present a case and difficulties of diagnosing an ovarian MMMT in a postmenopausal woman with a history of invasive breast carcinoma treated postoperatively with radiotherapy and tamoxifen. A 52-year-old patient presented with unilateral ovarian tumor and moderately elevated CA125 (107 U/mL) and underwent laparotomy. Fine needle aspiration of the ovary and ascites for cytologic analysis, and tumor biopsy for histopathology were performed intraoperatively. Intraoperative cytologic sample showed necrotic background with rare single malignant cells with pale, abundant cytoplasm and conspicuous nucleoli suggesting clear cell carcinoma. Ascites sample showed inflammatory and reactive background with suspected papillary formations mimicking adenocarcinoma. Postoperatively, cytochemical PAS staining and immunocytologic staining with epithelial antigen (EA), cytokeratin (CK)7 and vimentin showed EA and PAS positivity for ovarian tumor, and EA and CK7 for ascites, suggesting a clear cell carcinoma. Histology revealed ovarian clear cell carcinoma. Three months later, the patient underwent hemicolectomy because of tumors on the right large bowel serosa with intraoperative morphological finding of metastatic malignant tumor without other specific features. Postoperative morphological analysis and immunohistochemical staining of the tumor revealed two malignant components, epithelial and stromal one. Repeat histologic analysis of the ovarian tumor confirmed ovarian MMMT (with a clear cell carcinoma component). Other studies of breast cancer emphasize that patients with invasive breast cancer and mutations of BRCA1 and BRCA2 genes are at an increased risk of primary ovarian cancer. Our study confirmed it and suggested considering a second primary malignant tumor of ovarian origin in patients with a history of breast carcinoma, postoperatively treated with radiotherapy and tamoxifen. Although rare, second primary ovarian tumors may present as MMMT.

[Extramedullary multiple myeloma of the colon--case presentation and literature review]. / Ekstramedularna infiltracija kolona u bolesnika s multiplim mijelomom--prikaz bolesnika i pregled literature.

Multiple myeloma with gastrointestinal infiltration is rare, and it has been usually described in some case reports or case series. Stomach and small intestine are mostly involved, while large bowell involvement is very rare. Multiple myeloma should be considered in the differential diagnosis of some other diseases of the large bowel associated with weight loss, diarrhoea, malabsorption, frequent lumbar pain, effort intolerance. Colonoscopic biopsy followed by histopathological examination is essential for the diagnosis of multiple myeloma. Multiple myeloma with extramedullary infiltration of the colon has no well defined treatment guideline. Localised infiltration of gastrointestinal tract could be treated by surgical resection, but as these tumors are radiosensitive, radiotherapy has also been used. Chemotherapy with pulsed dexamethasone and afterwards a combination of cyclophosphamide, vincristine, melphalan and prednisone has been described in some case studies. Some patients were treated with other therapies incuding thalidomide, bortezomib, autologous or allogeneic stem cell transplantation. The clinical presentation, diagnosis and therapy may be challenging, so we present a 66-year old patient with extramedullary multiple myeloma of the colon who was treated at our Department.