Publications by authors named "Carla Minoia"

35 Publications

18F-FDG PET/CT Cannot Substitute Endoscopy in the Staging of Gastrointestinal Involvement in Mantle Cell Lymphoma. A Retrospective Multi-Center Cohort Analysis.

J Pers Med 2021 Feb 13;11(2). Epub 2021 Feb 13.

Haematology Unit, IRCCS Istituto Tumori "Giovanni Paolo II", 70124 Bari, Italy.

The detection of gastrointestinal (GI) involvement in Mantle Cell Lymphoma is often underestimated and may have an impact on outcome and clinical management. We aimed to evaluate whether baseline 18F-FDG PET/CT presents comparable results to endoscopic biopsy in the diagnosis of GI localizations. In our retrospective cohort of 79 patients, sensitivity and specificity of 18F-FDG PET/CT were low for the stomach, with a fair concordance ( = 0.32), while higher concordance with pathologic results ( = 0.65) was detected in the colorectal tract. Thus, gastric biopsy remains helpful in the staging of MCL despite 18F-FDG PET/CT, while colonoscopy could be omitted in asymptomatic patients. The validation of our data in prospective cohorts is desirable.
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http://dx.doi.org/10.3390/jpm11020123DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7918751PMC
February 2021

A strengthening the reporting of observational studies in epidemiology (STROBE): Are HE4 and CA 125 suitable to detect a Paget disease of the vulva?

Medicine (Baltimore) 2021 Feb;100(5):e24485

Clinical Patology Laboratory, IRCCS Istituto Tumori "Giovanni Paolo II".

Abstract: Paget disease is a complex disorder that can be identified in the breast (mammary Paget disease) or in other locations (extramammary Paget's disease) such as ano-genital skin (Paget disease of the vulva -PVD). This condition is associated with low mortality, but a late diagnosis and recurrence can negatively impact the prognosis. Therefore, the main objective of this study is to evaluate if the human epididymis protein 4 (HE4) and cancer antigen125 (CA125) can promote recognition of PVD in early stages and during the relapses.we have conducted a prospective, observational and laboratory-based study, that included 50 patients, whose 25 healthy women represented the control group and 25 PVD patients, which have been operated in our Oncology Institute, from May 2017 to September 2019. Both in the control group and in PVD patients, the CA-125 and HE4 were evaluated before surgery and after 6 months. Finally, a comparison of markers serum level, both between before/after surgery and with control group, and a ROC (Receiver Operating Characteristic) curve were performed.Dosing the markers in PVD patients, 3/25 (12%) showed a higher value of CA125 and 11/25 (44%) an increased HE4. In addition, after surgical treatment there were no statistically significant difference between levels of CA-125 (P = .3) and HE4 (P = .19). On the other hand, comparing HE4 in PVD patients with the control group, a statistically significant difference was found (P-value = .0036). Contrary, comparing CA-125 in PVD patients with the control group (P-value= .1969), no statistically significant difference was evidenced. Moreover, ROC (Receiver Operating Characteristic) curve showed low sensitivity and specificity for CA125 with area under curve (AUC) = 0.5608. Instead, the ROC curve of HE4 revealed a sensitivity and specificity of 76% and 88% respectively (AUC = 0.7408) using a cut-off at 90 pmol/L.Despite the limited cases, our data showed that CA125 is not a sensitive marker for PVD. On the other hand, in 44% of PVD we've seen an increase in HE4. So, this could be a starting point for further research that could confirm the possibility to use this marker in order to support PVD early identification.
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http://dx.doi.org/10.1097/MD.0000000000024485DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7870238PMC
February 2021

Is whole body low dose CT still necessary in the era of F-FDG PET/CT for the assessment of bone disease in multiple myeloma patients?

Hell J Nucl Med 2020 Sep-Dec;23(3):264-271. Epub 2020 Dec 14.

Department of Medicine and Health Sciences "V. Tiberio", University of Molise, Campobasso, Italy.

Objective: Whole body low dose computed tomography (WBLDCT) is the first-choice imaging modality to identify bone involvement in multiple myeloma (MM). Because the unenhanced LDCT co-registered to positron emission tomography (PET) (LDCT/PET) has similar technical characteristics to WBLDCT, we aimed to assess its reliability in the detection of bone disease, for employing fluorine-18-fluorodeoxyglucose (F-FDG) PET/CT as unique multimodality imaging method in MM patients.

Subjects And Methods: Thirty three consecutive MM patients were prospectively enrolled and evaluated with WBLDCT to assess bone involvement. In addition, patients underwent F-FDG PET/CT using a disease-tailored optimized LDCT protocol. To compare both methods, skeletal anatomical regions were identified and a per-region and per-patient analysis were performed using Cohen's k test. Low dose computed tomography/PET sensitivity, specificity and accuracy were also calculated.

Results: The two imaging modalities resulted highly concordant considering both patient-based (k=0.841) and region-based analysis; some discrepancies were observed in dorsal spine (k=0.809) and thorax (k=0.756). Low dose computed tomography/PET sensitivity, specificity and accuracy were 89.4%, 98.3% and 93.5%, respectively.

Conclusion: Low dose computed tomography co-registered PET has comparable performance to WBLDCT. If confirmed on a lager sample, these encouraging results suggest the possibility to use this multimodal hybrid imaging as the only method for MM evaluation, rather than both exams, providing both morphologic and metabolic information in one session with impact on patient compliance, health care spending and especially radiation exposure.
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http://dx.doi.org/10.1967/s002449912206DOI Listing
December 2020

Germinal ovarian tumors in reproductive age women: Fertility-sparing and outcome.

Medicine (Baltimore) 2020 Sep;99(39):e22146

Department of Biomedical Sciences and Human Oncology, Unit of Obstetrics and Gynaecology.

MOGCTs (malignant ovarian germ cell tumors) are rare tumors that mainly affect patients of reproductive age. The aim of this study was to evaluate the fertility and survival outcomes in young women with MOCGTs treated with fertility-sparing surgery (FSS).From 2000 to 2018, data from 28 patients of reproductive age with a diagnosis of MOGCT at the University of Bari were collected. Most received FSS, and in patients treated conservatively, the reproductive outcome and survival were investigated. Data of patient demographics, clinical presentation, oncology marker dosage, staging, type of surgery, histological examination, survival, and reproductive outcome were collected from hospital and office charts. All informed consent was obtained from all patients. The median age was 24 (range: 9-45 years). The majority of the patients had stage IIIC. Twenty-four woman received FSS consisting of unilateral ovariectomy and omentectomy, whereas only 4 women, based on their stage (IIIC), received a radical surgery (hysterectomy with bilateral adnexectomy, lymphadenectomy, and omentectomy). Our study shows that FSS in MOGCTs can produce good results both on reproductive outcomes and on survival. Indeed, in our group, there was only 1 case of exitus as result of recurrence. Furthermore, patients after FSS maintained normal ovarian function and 5 of 5 women who tried to get pregnant succeeded spontaneously. The median follow-up was 90 months (range 3-159).Conservative surgery for MOGCTs should be considered for women of reproductive age who wish to preserve fertility.
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http://dx.doi.org/10.1097/MD.0000000000022146DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7523774PMC
September 2020

Psychological Distress in Outpatients With Lymphoma During the COVID-19 Pandemic.

Front Oncol 2020 10;10:1270. Epub 2020 Jul 10.

Hematology Unit, IRCCS Istituto Tumori "Giovanni Paolo II", Bari, Italy.

Cancer patients are a population at high risk of contracting COVID-19 and, also of developing severe complications due to the infection, which is especially true when they are undergoing immunosuppressive treatment. Despite this, they had still to go to hospital to receive chemotherapy during lockdown. In this context, we have evaluated the psychological status of onco-hematological outpatients receiving infusion and not deferrable anti-neoplastic treatment for lymphoproliferative neoplasms, with the aim of both measuring the levels of post-traumatic symptoms, depression, and anxiety during the pandemic and also of investigating the perception of risk of potential nosocomial infection. The Impact of Event Scale-Revised (IES-R) and the Hospital Anxiety and Depression Scale (HADS) were administered to all patients. Moreover, patients were investigated about their worries regarding the impact of COVID-19 on their lives as onco-hematologic patients. Since the 2nd to the 29th April 2020 (during the first phase of the lockdown period in Italy), 77 outpatients were prospectively evaluated. They were diagnosed with non-Hodgkin's lymphoma, classical Hodgkin lymphoma, and Chronic lymphocytic leukemia/Small lymphocytic lymphoma. The mean age was 56.6 (range 22-85). We found that 36% of patients had anxiety (HADS-A), 31% depression (HADS-D), and 43% were above the cut-off for the HADS-General Scale; 36% fulfilled the diagnostic criteria for post-traumatic stress disorder (PTSD). Women and younger patients were found to be more vulnerable to anxiety and PTSD. The study firstly analyzes the psychological impact of the COVID-19 pandemic on the frail population of patients affected by lymphoproliferative neoplasms, to underly the importance of screening patients for emotional and distress conditions and then offering them psychological support.
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http://dx.doi.org/10.3389/fonc.2020.01270DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7365920PMC
July 2020

Fertility Preservation in Cancer Patients During the Coronavirus (COVID-19) Pandemic.

Front Oncol 2020 4;10:1009. Epub 2020 Jun 4.

Gynecologic Oncology Unit, IRCCS Istituto Tumori "Giovanni Paolo II", Bari, Italy.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), also identified as Corona virus disease 19 (COVID-19), has recently produced a dramatic and widespread sanitary emergency. However, despite the necessity to assist a substantial number of affected patients, it is also essential to, at the same time, guarantee the usual clinical care, particularly to cancer patients, including fertility preservation (FP) strategies before the beginning of the anti-cancer treatments. The FP techniques for adult female patients include oocyte and embryo cryopreservation, which require both adequate ovarian reserve (OR) and controlled ovarian stimulation (COS) to promote multiple follicular growth. However, ovarian tissue cryopreservation is an additional FP practice suitable when an anti-cancer treatment is urgently required, whereas, for male patients, sperm cryopreservation is a simple and well-adopted procedure. Here, we focus on the current conditions in terms of agreements and rules of FP procedures during this COVID-19 pandemic to achieve and provide useful recommendations for the adoption of these techniques in patients with cancer.
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http://dx.doi.org/10.3389/fonc.2020.01009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7326003PMC
June 2020

Novel aspects on gonadotoxicity and fertility preservation in lymphoproliferative neoplasms.

Crit Rev Oncol Hematol 2020 Jul 15;151:102981. Epub 2020 May 15.

Haematology Unit, National Cancer Center, IRCCS Istituto Tumori "Giovanni Paolo II", viale O. Flacco 65, Bari, Italy. Electronic address:

The topic of fertility preservation in patients with a lymphoproliferative disease offers new aspects of debate, due to the introduction of novel chemotherapeutic regimens and small molecules in the clinical landscape. Cancer related infertility is mostly dependent on gonadotoxic treatments and fertile female patients are today addressed to the oocyte cryopreservation or to ovarian cortex fragment cryopreservation. These methods present advantages and disadvantages, which will be discussed in the present review, together with the options for male patients. The recent discovery of functional ovarian stem cells (OCSs) in woman ovarian cortex, opens new avenues offering a innovative procedure for fertility preservation through as model of regenerative medicine. Here, we review the gonadotoxic potential of "classical" chemotherapeutic treatments as well as of "novel" targeted therapies actually employed for lymphoproliferative neoplasms in young patients and revisit both the today available and future chances to preserve and restore fertility after the cancer healing.
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http://dx.doi.org/10.1016/j.critrevonc.2020.102981DOI Listing
July 2020

The Role of Circulating Adiponectin and SNP276G>T at Gene in -mutant Women.

Cancer Genomics Proteomics 2020 May-Jun;17(3):301-307

Epidemiology and Prevention Unit - Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milan, Italy.

Background: Environmental factors may influence the lifetime risk of cancer (penetrance) in women with a BRCA mutation.

Materials And Methods: In 89 BRCA-mutant women, affected or unaffected by breast/ovarian cancer, we explored serum levels of adipokines and their relation with the polymorphism SNP276G>T as modulators of BRCA penetrance.

Results: Affected women had significantly lower adiponectin than healthy women. Affected women with rs1501299 TT had significantly lower adiponectin and higher leptin than GT and GG genotypes. GT genotype was significantly associated with the disease status [odds ratio (OR)=3.24, 95% confidence interval (95% CI)=1.03-10.17]. Women in the lower tertile of serum adiponectin had a RR of BRCA-associated cancer of 2.80, 95% CI=1.1-7.1 (p for trend=0.03) compared with women in the higher tertile.

Conclusion: In the SNP rs1501299 the T allele was significantly associated with lower serum levels of adiponectin in affected women, suggesting that the T allele might be related to cancer.
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http://dx.doi.org/10.21873/cgp.20190DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7259884PMC
November 2020

Management of lymphoma survivor patients in Italy: an evaluation by Fondazione Italiana Linfomi.

Tumori 2021 Feb 2;107(1):91-94. Epub 2020 Mar 2.

Haematology Unit, IRCCS Istituto Tumori "Giovanni Paolo II," Bari, Italy.

Several outpatient models for the follow-up of cancer survivors have been developed worldwide. A multidisciplinary approach is often necessary to guarantee the best monitoring of long-term toxicities. Guidelines also indicate a close education on healthy lifestyles. In this context, we have analyzed the Italian follow-up modalities of lymphoma survivors, with the aim to have a starting line to hypothesize and plan the best model for Italian hematology centers.
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http://dx.doi.org/10.1177/0300891620905649DOI Listing
February 2021

Brentuximab vedotin in association with bendamustine in refractory or multiple relapsed Hodgkin lymphoma. A retrospective real-world study.

Eur J Haematol 2020 Jun 13;104(6):581-587. Epub 2020 Mar 13.

Department of Oncology, Hematology and BMT Unit, Casa di Cura La Maddalena, Palermo, Italy.

Objective And Methods: In order to assess the efficacy of brentuximab vedotin (Bv) in combination with bendamustine (B) in multiple relapsed or refractory (RR) classic Hodgkin lymphoma (cHL), medical records of 47 patients treated with BvB in second relapse or beyond were reviewed.

Results: The median number of previous treatments was 2 (1-4). Bv was given at 1.8 mg/kg on day 1 and bendamustine at 90 mg/m on days 1 and 2 of a 21-day cycle. The median number of BvB cycles was 4 (2-7), and all patients were evaluable for efficacy. The CR and OR rates were 49% and 79%, respectively; 67% of responding patients and 2 in stable disease proceeded to a SCT procedure. After a median follow-up of 19 months (5-47), median PFS was 18 months (95%CI: 23-29), and the 2-year OS was 72%. Significantly longer PFS and OS were observed in patients attaining a major clinical response to treatment and in those who received consolidation with SCT. Fifteen (32%) patients experienced severe (G > 2) toxicity. The main toxicities were neutropenia (23%), gastrointestinal (10%), peripheral sensory neuropathy (11%), and infection (4%).

Conclusion: Our real-world results suggest that BvB is an effective third-line rescue and bridge-to-transplant regimen for RR-cHL patients.
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http://dx.doi.org/10.1111/ejh.13400DOI Listing
June 2020

Long-Lasting Remission in De Novo Breast Myeloid Sarcoma Treated with Decitabine and Radiotherapy.

Diagnostics (Basel) 2019 Jul 27;9(3). Epub 2019 Jul 27.

Haematology Unit, IRCCS Istituto Tumori "Giovanni Paolo II", 70124 Bari, Italy.

Myeloid sarcoma (MS) represents a rare disease with an adverse clinical outcome for patients not candidate to acute myeloid leukemia (AML)-like chemotherapies. Here we present the case of an elderly patient affected by a bilateral breast localization of MS treated with the hypomethylating agent decitabine associated to radiotherapy. The association of the two treatment modalities has allowed an optimal and long-lasting disease control.
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http://dx.doi.org/10.3390/diagnostics9030084DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6787642PMC
July 2019

Effects of Physical Exercise Intervention on Psychological and Physical Fitness in Lymphoma Patients.

Medicina (Kaunas) 2019 Jul 16;55(7). Epub 2019 Jul 16.

Haematology Unit, IRCCS Cancer Institute "Giovanni Paolo II", 70124 Bari, Italy.

Lymphoma patients experience a psychological and physiological decline that could be reversed by exercise. However, little is known about the effects of the exercise on psychological and physical fitness variables. Therefore, the purpose of this longitudinal study was to assess self-efficacy, fatigue and physical fitness before and after an eight-week exercise intervention. Thirty-six participants (54.4 ± 19.1 years) performed a supervised exercise program (~60 min, 2d·wk). Each session included a combined progressive training of cardiorespiratory, resistance, flexibility and postural education exercises. Self-efficacy and fatigue were measured with the Regulatory Emotional Self-Efficacy scale and 0-10 rating scale, respectively. Physical fitness was assessed with the body mass index, lower back flexibility, static balance, muscle strength and functional mobility. Adherence to exercise was high (91.2% ± 4.8%) and no major health problems were noted in the patients over the intervention period. At baseline, significant differences were found between Hodgkin's lymphoma and non-Hodgkin's lymphoma patients by age and all dependent measures ( < 0.05). Fatigue significantly decreased and the perceived capability to regulate negative affect and to express positive emotions improved after exercise ( < 0.001). Significant improvements were found for body mass index, trunk lateral flexibility, monopodalic balance, isometric handgrip force and functional mobility ( < 0.001). Fatigue was significantly correlated with handgrip force ( = -0.56, < 0.001) and functional mobility ( = -0.69, < 0.001). The supervised exercise program improved psychological and physical fitness without causing adverse effects and health problems. Therefore, exercise to improve fitness levels and reduce perceived fatigue should be considered in the management of lymphoma patients.
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http://dx.doi.org/10.3390/medicina55070379DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6681308PMC
July 2019

1q23.1 homozygous deletion and downregulation of Fc receptor-like family genes confer poor prognosis in chronic lymphocytic leukemia.

Clin Exp Med 2019 May 15;19(2):261-267. Epub 2019 Mar 15.

Department of Biology, University of Bari "Aldo Moro", Via G. Orabona No. 4, 70126, Bari, Italy.

The identification of chromosome 1 translocations and deletions is a rare and poorly investigated event in chronic lymphocytic leukemia (CLL). Nevertheless, the identification of novel additional molecular alterations is of great interest, opening to new prognostic and therapeutic strategies for such heterogeneous hematological disease. We here describe a patient affected by CLL with a mutated IGHV status, showing a balanced t(1;3)(q23.1;q21.3) translocation and a der(18)t(1;18)(q24.2;p11.32), accompanying the recurrent 13q14 heterozygous deletion in all analyzed cells at onset. By combining whole-genome sequencing, SNP array, RNA sequencing, and FISH analyses, we defined a 1q23.1 biallelic minimally deleted region flanking translocations breakpoints at both derivative chromosome 1 homologues. The deletion resulted in the downregulation of the Fc receptor-like family genes FCRL1, FCRL2, and FCRL3 and in the lack of expression of FCRL5, observed by RT-qPCR. The mutational status of TP53, NOTCH1, SF3B1, MYD88, FBXW7, and XPO1 was investigated by targeted next-generation sequencing, detecting a frameshift deletion within NOTCH1 (c.7544_7545delCT). We hypothesize a loss of tumor suppressor function for FCRL genes, cooperating with NOTCH1 mutation and 13q14 genomic loss in our patient, both conferring a negative prognosis, independently from the known biological prognostic factors of CLL.
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http://dx.doi.org/10.1007/s10238-019-00551-0DOI Listing
May 2019

Rituximab and the risk of transformation of follicular lymphoma: a retrospective pooled analysis.

Lancet Haematol 2018 Aug 4;5(8):e359-e367. Epub 2018 Jul 4.

Hospices Civils de Lyon, Universite Claude Bernard Lyon 1, Department of Haematology, Pierre Benite, France.

Background: Histological transformation of follicular lymphoma to aggressive lymphoma is a serious event with a substantial effect on patient outcome. The aim of the Aristotle study was to assess the effect of rituximab on the risk of histological transformation and its outcome.

Methods: 11 cooperative groups or institutions across Europe contributed data to this study. Eligible patients (≥18 years) had histologically confirmed follicular lymphoma grade 1, 2, or 3a, diagnosed between Jan 2, 1997, and Dec 20, 2013. Histological transformation was defined as a biopsy-proven aggressive lymphoma that occurred as a first event after first-line therapy. The primary endpoints were the cumulative hazard of histological transformation and survival after transformation.

Findings: Information was available for 10 001 patients with follicular lymphoma, 8116 of whom were eligible for analysis. 509 histological transformations were reported. After a median follow-up of 87 months (range 1-221; 2·5-97·5th percentile 5-160), the 10-year cumulative hazard of histological transformation was 7·7% (95% CI 6·9-8·5). The 10-year cumulative hazard of histological transformation was 5·2% (95% CI 4·5-6·2) in patients who received rituximab and 8·7% (7·2-10·6) in those who did not (hazard ratio [HR] 0·73, 95% CI 0·58-0·90; p=0·004). The 10-year cumulative hazard of histological transformation was 5·9% (95% CI 5·0-7·0) for patients who received induction rituximab only and 3·6% (95% CI 2·3-5·5) for those treated with induction and maintenance rituximab (HR 0·55, 95% CI 0·37-0·81; p=0·003). This finding was confirmed in a multivariate analysis (p=0·016). 287 deaths were recorded in 509 patients with histological transformation, resulting in a 10-year survival after transformation of 32% (95% CI 26-38). Survival after transformation did not differ between patients not exposed to rituximab and those who received rituximab in induction only (HR 0·94, 95% CI 0·69-1·28; p=0·70), and those who received rituximab in induction and maintenance (0·96, 0·58-1·61; p=0·88).

Interpretation: The risk of histological transformation as a first event can be significantly reduced by the use of rituximab. These findings support the need to inform patients using rituximab nowadays that the risk of transformation is lower than it was before the introduction of rituxumab.

Funding: Associazione Angela Serra per la Ricerca sul Cancro, European Lymphoma Institute, European Hematology Association Lymphoma Group, Fondazione Italiana Linfomi, Spanish Group of Lymphoma and Bone Marrow Transplantation.
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http://dx.doi.org/10.1016/S2352-3026(18)30090-5DOI Listing
August 2018

Improvable Lifestyle Factors in Lymphoma Survivors.

Acta Haematol 2018;139(4):235-237. Epub 2018 Jun 21.

Haematology Unit, IRCCS Istituto Tumori "Giovanni Paolo II", Bari, Italy.

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http://dx.doi.org/10.1159/000489252DOI Listing
March 2019

Novel acquisitions on biology and management of transformed follicular lymphoma.

Hematol Oncol 2018 Oct 30;36(4):617-623. Epub 2018 Mar 30.

Oncology Institute of Southern Switzerland (IOSI), Bellinzona, Switzerland.

Follicular lymphoma (FL) generally has an indolent clinical course, but in some patients, a histological transformation (HT) into aggressive entities may take place and often lead to a poorer survival. The rituximab era has seen an improved outcome of FL, including those with HT. The current treatment strategies for transformed FL are based on immunochemotherapy for the cases with HT at the time of diagnosis or as the first event after watchful waiting. Patients transforming after prior treatment of FL usually benefit from autologous stem cell transplant. Unfortunately, early assessment of the transformation risk remains elusive. Recent studies delved the mechanisms of HT, showing that this is a complex process, resulting from a number of epigenetic and genetic lesions occurring in the tumour cell population as well as progressive changes in the tumour microenvironment. This novel knowledge has prompted clinical investigations on a variety of new therapeutic strategies.
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http://dx.doi.org/10.1002/hon.2508DOI Listing
October 2018

Risk of lymphoma subtypes by occupational exposure in Southern Italy.

J Occup Med Toxicol 2017 23;12:31. Epub 2017 Nov 23.

Department of Public Health, Clinical & Molecular Medicine, Occupational Health Section, University of Cagliari, 09100 Cagliari, Italy.

Background: Occupational exposure is known to play a role in the aetiology of lymphomas. The aim of the present work was to explore the occupational risk of the major B-cell lymphoma subtypes using a case-control study design.

Methods: From 2009 to 2014, we recruited 158 lymphoma cases and 76 controls in the provinces of Bari and Taranto (Apulia, Southern Italy). A retrospective assessment of occupational exposure based on complete work histories and the Carcinogen Exposure (CAREX) job-exposure matrix was performed.

Results: After adjusting for major confounding factors, farmers showed an increased risk of diffuse large B-cell lymphoma (DLBCL) [odds ratio (OR) = 10.9 (2.3-51.6)] and multiple myeloma (MM) [OR = 16.5 (1.4-195.7)]; exposure to the fungicide Captafol was significantly associated with risk of non-Hodgkin lymphoma (NHL) [OR = 2.6 (1.1-8.2)], particularly with the risk of DLBCL [OR = 5.3 (1.6-17.3)].

Conclusions: Agricultural activity seems to be a risk factor for developing lymphoma subtypes, particularly DLBCL, in the provinces of Bari and Taranto (Apulia Region, Southern Italy). Exposure to the pesticides Captafol, Paraquat and Radon might be implicated.

Trial Registration: Protocol number UNIBA 2207WEJLZB_004 registered 22/09/2008.
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http://dx.doi.org/10.1186/s12995-017-0177-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5701427PMC
November 2017

Improving Provision of Care for Long-term Survivors of Lymphoma.

Clin Lymphoma Myeloma Leuk 2017 Dec 17;17(12):e1-e9. Epub 2017 Aug 17.

Hematology and Cell Therapy Unit, IRCCS-Istituto Tumori "Giovanni Paolo II", Bari, Italy.

The progressive improvement of lymphoma therapies has led to a significant prolongation of patient survival and life expectancy. However, lymphoma survivors are at high risk of experiencing a range of early and late adverse effects associated with the extent of treatment exposure. Among these, second malignancies and cardiopulmonary diseases can be fatal, and neurocognitive dysfunction, endocrinopathy, muscle atrophy, and persistent fatigue can affect patients' quality of life for decades after treatment. Early recognition and reduction of risk factors and proper monitoring and treatment of these complications require well-defined follow-up criteria, close coordination among specialists of different disciplines, and a tailored model of survivorship care. We have summarized the major aspects of therapy-related effects in lymphoma patients, reviewed the current recommendations for follow-up protocols, and described a new hospital-based model of survivorship care provision from a recent multicenter Italian experience.
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http://dx.doi.org/10.1016/j.clml.2017.08.097DOI Listing
December 2017

Bendamustine, Low-dose dexamethasone, and lenalidomide (BdL) for the treatment of patients with relapsed/refractory multiple myeloma confirms very promising results in a phase I/II study.

Leuk Lymphoma 2017 03 21;58(3):552-559. Epub 2016 Jul 21.

b Department of Hemato-Oncology , Cosenza Hospital , Cosenza , Italy.

Lenalidomide and dexamethasone are an effective treatment for naïve and relapsed multiple myeloma (MM) patients. Bendamustine is a good option for B-cell malignancies showing only partial cross resistance with alkylating agents used in MM patients. Based on these considerations, we proposed a phase I/II study testing escalating doses of bendamustine and lenalidomide and fixed low doses of dexamethasone (BdL). Fifteen patients were enrolled in phase I study. Maximum tolerated dose was established at dose "level 0": bendamustine 40 mg/m days 1,2; lenalidomide 10 mg days 1-21; d 40 mg days 1,8,15,22 every 28-day cycle, for six cycles. We enrolled 23 patients in the phase II study. BdL combination showed mainly hematological toxicities, fever and infections. Overall response rate was 47%. After median follow up of 22 months, median PFS was 10 months. Two-years OS rate was 65%. BdL combination confirmed to be a promising treatment for patients with relapsed/refractory MM.
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http://dx.doi.org/10.1080/10428194.2016.1205741DOI Listing
March 2017

Can diffusion-weighed whole-body magnetic resonance imaging with body signal suppression play a role in the management of lymphoma patients?

J BUON 2016 Jan-Feb;21(1):282-3

Haematology Unit, National Cancer Research Centre, Istituto Tumori "Giovanni Paolo II", Bari, Italy;

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May 2016

The use of thrombopoietin-receptor agonists (TPO-RAs) in immune thrombocytopenia (ITP): a "real life" retrospective multicenter experience of the Rete Ematologica Pugliese (REP).

Ann Hematol 2016 Jan 24;95(2):239-44. Epub 2015 Nov 24.

Unit of Hematology with BMT, Department of Emergency and Organ Transplantation, University of Bari, Bari, Italy.

Immune thrombocytopenia (ITP) is a disease which sees one-third of patients failing first and subsequent therapeutic approaches, including splenectomy. Thrombopoietin-receptor agonists (TPO-RAs) are recommended for adults who relapse after splenectomy or who have contraindications for splenectomy. In this multicenter study, a total of 124 patients were retrospectively evaluated: 55 (44.3 %) were treated by romiplostim and 69 (55.6 %) by eltrombopag. Mean age, number of young patients (<60 years), time from primary diagnosis of ITP to TPO-RA treatment, and previous lines of therapy were similar in both groups. The overall response rate was 80 % (44/55) for romiplostim and 94.2 % (65/69) for eltrombopag; the duration of response and the time to response were similar (p = NS). The response rate to both drugs in non-splenectomized patients was higher than that of splenectomized patients (p < 0.05). The mean duration of response was 30 months for romiplostim and 15 months for eltrombopag, due to later commercialization of eltrombopag. Failure was the most frequent cause of discontinuation. Thrombotic events were the most consistent adverse events and were recorded in 2 and 3 % of patients treated by romiplostim and eltrombopag, respectively. In conclusion, romiplostim and eltrombopag are effective in the majority of patients with chronic ITP who failed several lines of therapy; whether TPO-RAs could substitute splenectomy is under discussion and studies are warranted.
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http://dx.doi.org/10.1007/s00277-015-2556-zDOI Listing
January 2016

Role of WB-MR/DWIBS compared to (18)F-FDG PET/CT in the therapy response assessment of lymphoma.

Radiol Med 2016 Feb 9;121(2):132-43. Epub 2015 Sep 9.

Department of Medicine and Health Science, University of Molise, Campobasso, Italy.

Introduction: This study prospectively evaluated whole-body magnetic resonance/diffusion-weighted imaging with body signal suppression (WB-MR/DWIBS) reliability compared to (18)F-FDG PET/CT in the treatment response assessment of classic Hodgkin lymphomas (HL) and aggressive non-Hodgkin lymphomas (aNHL).

Materials And Methods: Twenty-seven consecutive patients were prospectively enrolled at the time of diagnosis. Eighteen (11 HL and seven aNHL) were considered for the analysis. They received chemo/radiotherapy as induction and completed post-treatment evaluation performing both (18)F-FDG PET/CT and WB-MR/DWIBS. The revised response criteria for malignant lymphomas were used to assess the response to treatment. We evaluated the agreement between the two methods by Cohen's K test. Post-therapy WB-MR/DWIBS sensitivity, specificity, PPV, NPV and accuracy were then calculated, considering the 12 months of follow-up period as the gold standard.

Results: By using an evaluation on a lesion-by-lesion basis, WB-MR/DWIBS and (18)F-FDG PET/CT showed an overall good agreement (K = 0.796, 95% IC = 0.651-0.941), especially in the evaluation of the nodal basins in aNHL (K = 0.937, 95% IC = 0.814-1). In reference to the revised response criteria for malignant lymphomas, the two methods showed a good agreement (K = 0.824, 95% IC = 0.493-1). Post-therapy sensitivity, specificity, PPV, NPV and accuracy of WB-MR/DWIBS were 43, 91, 75, 71 and 72%, respectively.

Conclusion: WB-MR/DWIBS seems to be an appropriate method for the post-treatment assessment of patients affected by HL and aNHL. The small discrepancies between the two methods found within HL could be due to the biological and metabolic behavior of this group of diseases. Larger prospective studies are necessary to better define the role of WB-MR/DWIBS in this setting of patients.
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http://dx.doi.org/10.1007/s11547-015-0581-6DOI Listing
February 2016

Azacitidine in the front-line treatment of therapy-related myeloid neoplasms: a multicenter case series.

Anticancer Res 2015 Jan;35(1):461-6

Haematology Unit, IRCCS National Cancer Research Centre "Giovanni Paolo II", Bari, Italy.

Background/aim: A continued increase in the incidence of therapy-related myeloid neoplasms (t-MN) is expected due to the improvement of chemotherapeutic treatments for solid and haematological malignancies. The use of 5-azacytidine (AZA) is emerging in these patients. We, therefore, analyzed the outcome of patients with t-MN ineligible for intensive chemotherapy treated in the front-line with AZA.

Patients And Methods: We retrospectively collected clinical data from consecutive patients with t-MN treated in the front-line with AZA at five Haematology Centers. Response to therapy, overall survival (OS) and safety were considered.

Results: The overall response rate was of 35.7% with a median OS of 9.6 months. Patients who were heavily pre-treated for their primary malignancy (more than 3 lines of chemotherapy) presented a significant inferior OS (4.9 months). The principal reported toxicity was haematological with severe infections occurring in a minority of patients. Fatigue was the most common extra-haematological toxicity.

Conclusion: New aspects emerged on the management of t-MN. AZA may represent a reasonable choice for patients ineligible for intensive treatment, with the exception of heavily pre-treated patients who presented -anyway- a worse outcome.
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January 2015

Bendamustine plus rituximab for relapsed or refractory diffuse large B cell lymphoma: a retrospective analysis.

Leuk Res 2014 Dec 22;38(12):1446-50. Epub 2014 Oct 22.

Hematology and Bone Marrow Transplantation Unit, Antonio Perrino Hospital, Brindisi, Italy.

For patients with relapsed or refractory diffuse large B cell lymphoma (DLBCL) who are not eligible for intensive chemotherapy because of comorbidities, advanced age, or relapse after heavy salvage regimens, treatment options are very limited and prognosis is poor. We retrospectively analyzed 29 patients with relapsed/refractory DLBCL treated with combination bendamustine plus rituximab (BR) between July 2010 and January 2014 to evaluate overall response rate (ORR), progression-free survival (PFS), duration of response (DOR) and treatment safety. Twenty-eight patients were available for this analysis. ORR was 50% (14 patients), with 39.3% CR (11 patients), and 10.7% PR (3 patients). SD was reported in 2 patients (7.2%) and PD in 12 patients (42.8%). At the median follow up of 8 months (range 1-37.4 months), the median PFS was 8 months for all patients (95% CI 5.5-26.6). The median DOR was 24.7 months (95% CI 3.2-24.7). Grade 3/4 toxicity observed included hematologic events: lymphopenia (42.8%), neutropenia (32.1%), anemia (17.2%), and thrombocytopenia (14.2%). BR can be considered to have a role in the treatment of patients with relapsed/refractory DLBCL with limited therapeutic options, in that it can induce long-term remission in some patients with an acceptable toxicity profile.
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http://dx.doi.org/10.1016/j.leukres.2014.10.001DOI Listing
December 2014

Challenges and opportunities of microRNAs in lymphomas.

Molecules 2014 Sep 17;19(9):14723-81. Epub 2014 Sep 17.

Haematology Unit, National Cancer Research Centre, Istituto Tumori "Giovanni Paolo II", Bari 70124, Italy.

MicroRNAs (miRNAs) are small non-coding RNAs that control the expression of many target messenger RNAs (mRNAs) involved in normal cell functions (differentiation, proliferation and apoptosis). Consequently their aberrant expression and/or functions are related to pathogenesis of many human diseases including cancers. Haematopoiesis is a highly regulated process controlled by a complex network of molecular mechanisms that simultaneously regulate commitment, differentiation, proliferation, and apoptosis of hematopoietic stem cells (HSC). Alterations on this network could affect the normal haematopoiesis, leading to the development of haematological malignancies such as lymphomas. The incidence of lymphomas is rising and a significant proportion of patients are refractory to standard therapies. Accurate diagnosis, prognosis and therapy still require additional markers to be used for diagnostic and prognostic purpose and evaluation of clinical outcome. The dysregulated expression or function of miRNAs in various types of lymphomas has been associated with lymphoma pathogenesis. Indeed, many recent findings suggest that almost all lymphomas seem to have a distinct and specific miRNA profile and some miRNAs are related to therapy resistance or have a distinct kinetics during therapy. MiRNAs are easily detectable in fresh or paraffin-embedded diagnostic tissue and serum where they are highly stable and quantifiable within the diagnostic laboratory at each consultation. Accordingly they could be specific biomarkers for lymphoma diagnosis, as well as useful for evaluating prognosis or disease response to the therapy, especially for evaluation of early relapse detection and for greatly assisting clinical decisions making. Here we summarize the current knowledge on the role of miRNAs in normal and aberrant lymphopoiesis in order to highlight their clinical value as specific diagnosis and prognosis markers of lymphoid malignancies or for prediction of therapy response. Finally, we discuss their controversial therapeutic role and future applications in therapy by modulating miRNA.
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http://dx.doi.org/10.3390/molecules190914723DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6271734PMC
September 2014

FOXP1 and TP63 involvement in the progression of myelodysplastic syndrome with 5q- and additional cytogenetic abnormalities.

BMC Cancer 2014 Jun 3;14:396. Epub 2014 Jun 3.

Department of Biology, University of Bari, Via G,Amendola 165/A, Bari 70126, Italy.

Background: The progression of low-risk del(5q) myelodysplastic syndrome to acute myeloid leukemia is increased when associated with mutations of TP53, or with additional chromosomal abnormalities. However, to date the prognostic impact and molecular consequences of these rearrangements were poorly investigated. Single additional alterations to del(5q) by balanced chromosome rearrangements were rarely found in myelodysplasia. In particular, balanced alterations involving TP63 and FOXP1 genes were never reported in the literature.

Case Presentation: Here we report on a 79-year woman with an aggressive form of myelodysplastic syndrome with del(5q), no TP53 mutation, and a novel complex rearrangement of chromosome 3 in bone marrow cells. Our results revealed that the FOXP1 and TP63 genes were both relocated along chromosome 3. Strikingly, immunohistochemistry analysis showed altered protein levels, disclosing that this rearrangement triggered the expression of FOXP1 and TP63 genes. FOXP1 was also found activated in other patients with myelodysplasia and acute myeloid leukemia, showing that it is an important, recurrent event.

Conclusions: We document an apparent role of FOXP1 and TP63, up to now poorly documented, in the progression of MDS in our patient who is lacking mutations in the TP53 tumor suppressor gene normally associated with poor outcome in myelodysplastic syndrome with 5q-. Finally, our results may suggest a possible broader role of FOXP1 in the pathogenesis and progression of myelodysplasia and acute myeloid leukemia.
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http://dx.doi.org/10.1186/1471-2407-14-396DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4059025PMC
June 2014

Whole body magnetic resonance with diffusion weighted sequence with body signal suppression compared to (18)F-FDG PET/CT in newly diagnosed lymphoma.

Hell J Nucl Med 2014 Jan-Apr;17 Suppl 1:40-9

D.I.M.- Diagnostic Imaging - Nuclear Medicine, University of Bari "Aldo Moro", Bari, Italy.

Lymphomas are a heterogeneous group of lymphoid malignancies, which can be broadly divided into non-Hodgkin Lymphomas (NHL) and Hodgkin lymphoma (HL) that display different patterns of biological behavior and response to treatment. Their incidence is still increasing and for this reason they require a lot of effort in scientific research. The management of both NHL and HL follows well-established guidelines based on the initial staging assessment. Therefore an accurate staging is the basis for the selection of an appropriate therapeutic approach in order to prevent over or under treatment as well as to minimize morbidity related to the radio-chemotherapy regimens given. (18)F-FDG-PET is currently regarded as the reference standard imaging modality in the staging of the majority of lymphoma type, for evaluation of distribution of the disease by providing both functional and anatomic information in a single whole body examination. In particular its role is established in HL and high-grade NHL, confirmed also in Follicular Lymphoma, but its impact on the other histotypes remains to be demonstrated. Among the diagnostic tools currently available for a bio-molecular imaging assessment, of great interest is the Whole Body-Magnetic Resonance with DWIBS sequence (WB-MR/DWIBS), an emerging and promising functional whole body imaging modality to evaluate oncologic and non-oncologic lesions, resulting in images that remarkably resemble (18)F-FDG PET/CT studies. In our research study we evaluated the role of WB-MR/DWIBS, compared with (18)F-FDG-PET/CT in the initial staging of lymphomas, considering its impact on the management of these patients and how it could influence the therapeutic choice. We prospectively enrolled 27 consecutive patients with newly diagnosed lymphoma (13 HL, 14 NHL) histologically proven, who underwent (18)F-FDG-PET/CT and WB-MR/DWIBS (coronal T1-weighted, coronal STIR, axial sequences DWIBS) within 10 days from the diagnosis and before start the treatment. We evaluated the overall agreement between the two methods, the general agreement in evaluating both nodal and extra-nodal involvement and a specific site agreement according to lymph nodal basins or extra-nodal sites involvement. The agreement between the two diagnostic tools in relation to histological types (HL/NHL) and in relation to indolent and aggressive forms, within NHL histotypes, as well as in relation to the Ann Arbor stage was also evaluated. We also analyzed the role of WB-MRI/DWIBS and (18)F-FDG-PET/CT in bone marrow involvement detection by calculating their sensitivity and specificity, with bone marrow biopsy as the reference standard, and comparing them with McNemar test. A total of 85 lesions, nodal (74) and extra-nodal (11), were detected by (18)F-FDG-PET/CT. WB-MRI/DWIBS showed a total of 91 sites involved, (81) nodal and (13) extra-nodal lesions. The overall agreement between the two imaging modalities was very good (k=0.815; IC:0.739-0.890); however considering histotypes, the agreement comes down to good in evaluating NHL for both nodal and extra-nodal involvement (k=0.763, IC: 0.627-0.898; k=0.629, IC:-0.021-1.278). Considering indolent or aggressive forms the agreement between WB-MR/DWIBS and (18)F-FDG PET/CT findings was very good in aggressive forms while it appeared to be lower in indolent forms. Sensitivity and specificity of WB-MRI/DWIBS and (18)F-FDG PET/CT in bone marrow involvement detection were respectively: 100%and 100% vs. 50% and 96%. The switch from (18)F-FDG PET/CT to WB-MR/DWIBS in the AA Staging System resulted in an over-staging in 1/27 patient. The two methods were concordant in the staging in 26/27 patients (96%). In conclusion, our initial results show a good overall agreement between the two diagnostic tools. (18)F-FDG-PET/CT remains the gold standard for lymphoma staging, however WB-MRI/DWIBS can be useful in histotypes not (18)F-FDG-avid or in the evaluation of "critical" organs for (18)F-FDG PET/CT. The integrated information provided by metabolic and tissutal functional imaging can be complementary to assist hematologic decision of tailored patient's treatment.
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September 2013

HIF-1α of bone marrow endothelial cells implies relapse and drug resistance in patients with multiple myeloma and may act as a therapeutic target.

Clin Cancer Res 2014 Feb 2;20(4):847-58. Epub 2013 Dec 2.

Authors' Affiliations: Section of Internal Medicine, Department of Biomedical Sciences and Human Oncology; Department of Basic Medical Sciences, Neurosciences and Sensory Organs, University of Bari Medical School, Bari, Italy, National Cancer Institute "Giovanni Paolo II", Bari, Italy; Department of Human Anatomy, Histology and Embryology, and Pathological Anatomy, University of Bari Medical School; Hematology Unit, Istituto di Ricerca e Cura a Carattere Scientifico (IRCCS) Oncologic Hospital; Laboratory of Preclinical and Translational Research, IRCCS Basilicata Cancer Reference Centre, Potenza; Department of Clinical and Experimental Medicine, University of Foggia Medical School, Foggia; Hematology Unit, Ospedale Di Venere, Carbonara di Bari, Bari; and Department of Haematology, Businco Hospital, Cagliari, Italy.

Purpose: To investigate the role of hypoxia-inducible factor-1α (HIF-1α) in angiogenesis and drug resistance of bone marrow endothelial cells of patients with multiple myeloma.

Experimental Design: HIF-1α mRNA and protein were evaluated in patients with multiple myeloma endothelial cells (MMEC) at diagnosis, at relapse after bortezomib- or lenalidomide-based therapies or on refractory phase to these drugs, at remission; in endothelial cells of patients with monoclonal gammapathies of undetermined significance (MGUS; MGECs), and of those with benign anemia (controls). The effects of HIF-1α inhibition by siRNA or panobinostat (an indirect HIF-1α inhibitor) on the expression of HIF-1α proangiogenic targets, on MMEC angiogenic activities in vitro and in vivo, and on overcoming MMEC resistance to bortezomib and lenalidomide were studied. The overall survival of the patients was also observed.

Results: Compared with the other endothelial cell types, only MMECs from 45% of relapsed/refractory patients showed a normoxic HIF-1α protein stabilization and activation that were induced by reactive oxygen species (ROS). The HIF-1α protein correlated with the expression of its proangiogenic targets. The HIF-1α inhibition by either siRNA or panobinostat impaired the MMECs angiogenesis-related functions both in vitro and in vivo and restored MMEC sensitivity to bortezomib and lenalidomide. Patients with MMECs expressing the HIF-1α protein had shorter overall survival.

Conclusions: The HIF-1α protein in MMECs may induce angiogenesis and resistance to bortezomib and lenalidomide and may be a plausible target for the antiangiogenic management of patients with well-defined relapsed/refractory multiple myeloma. It may also have prognostic significance.
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http://dx.doi.org/10.1158/1078-0432.CCR-13-1950DOI Listing
February 2014

Changes in angiogenesis and hypoxia-inducible factor-1α protein expression in relapsed/refractory indolent non-Hodgkin lymphomas.

Br J Haematol 2013 Dec 13;163(5):640-5. Epub 2013 Sep 13.

Haematology Unit, Department of Medical and Experimetal Oncology, IRCCS National Cancer Research Centre "Giovanni Paolo II", Bari, Italy.

Angiogenesis is involved in the pathogenesis and progression of non-Hodgkin lymphomas (NHL), and hypoxia-inducible factor-1α (HIF-1α, also termed HIF1A) might contribute to this process. Currently, there is no direct evidence that the clinical progression of indolent NHL is associated with angiogenesis, and the expression of HIF-1α at recurrence is unknown. Matched lymph node biopsies at diagnosis and recurrence of relapsed/refractory indolent NHL patients were analysed by immunohistochemical and morphometric analysis. We observed an increased vascular network and HIF-1α protein expression in the second biopsy, providing direct evidence that angiogenesis is an essential process for disease progression.
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http://dx.doi.org/10.1111/bjh.12560DOI Listing
December 2013