Trends in specialized palliative care referrals at an oncology center from 2007 to 2019.

BACKGROUND: Early referral to palliative care, at least 3 months before death, should be a standard of care in oncological practice. Real life data in this setting are invaluable since they provide a picture of everyday practice and serve as the basis for future improvements. METHODS: We conducted a retrospective cohort assessment of all patients referred to our specialized palliative care (SPC) services at the Institute of Oncology, Ljubljana, Slovenia. Our analysis includes patient referrals between 2007 and 2019. RESULTS: During the above-specified time period of 13 years, 3234 patients were referred for SPC services at our institution. The median age at SPC referral was 67 years. The majority of patients (63%) were assessed only once, while 31% of patients were seen on more than one occasion. Median time from SPC referral to death was 25 days for the whole group. 1693 patients (52.7%) were referred to SPC in the last 30 days before death, 785 (25.8%) patients between 31 and 90 days and 652 (21.4%) patients more than 3 months before death. Neither age nor sex correlated with the duration of referral time. However, there was a strong correlation between the year of referral to palliative care and the duration of palliative care service (ρ = 0.19, p < 0.001). The median referral to death interval for lymphoma patients and breast cancer patients were 15 and 18 days, respectively, and the median referral to death interval for colorectal cancer and lung tumor patients were 34 and 26 days before death, respectively. CONCLUSION: Throughout the existence of our SPC services we have observed a positive trend in the number of referrals, a lengthening of time between referral and death, as well as an increase in the proportion of patients with an early referral to SPC (more than 3 months before death). Neither age nor sex correlated with the length of referral time.

An interesting case of likely BRCA2 related bilateral breast cancer with metastasis in the fimbrial part of fallopian tube.

BACKGROUND: In a patient with a germline BRCA2 pathogenic variant with breast cancer, an adnexal mass can represent either a metachronous primary tumor or a metastasis of the breast cancer. A clear distinction between those two possibilities is crucial since treatments differ substantially and so does survival of the patient. CASE PRESENTATION: We present a case of a 47-year-old patient with bilateral breast carcinoma with a germline BRCA2 pathogenic variant. The first manifestation of the disease was a lump in her left breast in 1998, histological report was invasive ductal carcinoma, triple-negative. She was treated with surgery, chemotherapy and radiotherapy. In 2011 a new occult carcinoma was found in her right axilla, however the specimen was estrogen receptor (ER) and progesterone receptor (PgR) positive. She was treated as a new primary occult carcinoma of the right breast with surgery, radiotherapy and adjuvant hormonal treatment. In 2016 a mass in the left adnexa was found with imaging techniques. She underwent surgery as if it was primary ovarian cancer, yet histology revealed it was a metastasis of a triple-negative breast carcinoma in the fimbrial part of the left Fallopian tube. She received adjuvant chemotherapy after surgery and is now in complete remission. CONCLUSION: We present an interesting and quite rare case of two primary breast carcinomas in a patient with a known BRCA2 pathogenic variant with metastasis in the fimbrial part of the left Fallopian tube. We conclude that there were two primary breast tumours and the one from 2011 spread into the fimbrial part of the left Fallopian tube in 2016. Despite the fact that molecular analyses could not confirm the joint tumour origin, we believe that there was a receptor status conversion over time explaining different receptor status. The possibility of a triple-negative metastasis from the tumour treated in 1998 is less probable. With both of aforementioned possibilities being prognostically unfavourable, the patients' outcome is so far excellent and she was in complete remission at the time of writing this article.

Long-term outcomes of high dose treatment and autologous stem cell transplantation in follicular and mantle cell lymphomas - a single centre experience.

BACKGROUND: Advanced follicular lymphoma (FL) and mantle cell lymphoma (MCL) are incurable diseases with conventional treatment. The high dose treatment (HDT) with autologous stem cell transplantation (ASCT), however, offers a certain proportion of these patients the prospect of a prolonged disease-free and overall survival. The aim of this study was to investigate the event free survival (EFS) and overall survival (OS) in patients with FL and MCL treated with ASCT. PATIENTS AND METHODS: Seventeen patients with FL and 29 patients with MCL were included, 15 of them were transplanted to consolidate the response to second line treatment and 24 to consolidate their first remission, respectively. All were conditioned with total body irradiation (TBI) and high dose cyclophosphamide between 2006 and 2014 and all were transplanted with peripheral blood stem cells. RESULTS: The estimated 5-year OS for FL was 87.8% (95% confidence interval [CI] 59.5%-96.8%) and for MCL 79.3% (95% CI 56.1%-91.1%), respectively. The estimated 5-year EFS for FL was 76.0% (95% CI 48.0%-90.3%) and for MCL 69.8% (95% CI 45.5%-84.8%), respectively. There were no secondary hematological malignancies observed in either group. CONCLUSIONS: Based on above results, the ASCT with TBI is a good treatment option in terms of long-term survival for patients with follicular and mantle cell lymphoma demonstrating a relatively low rate of late toxicities and secondary malignancies.

Fertility in young patients following treatment for Hodgkin's lymphoma: a single center survey.

PURPOSE: The purpose of this study was to determine the fertility rates following treatment by means of the BEACOPP regimen (regular and escalated) (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, prednisone) as compared to the ABVD regimen (doxorubicin, vinblastine, dacarbazine, bleomycin) in Hodgkin lymphoma patients under the age of 40 at the time of treatment. METHODS: A questionnaire was sent to 180 Hodgkin lymphoma (HL) patients. The questionnaire was composed of questions concerning reproduction and also menopausal and aging symptoms in females and males. The analyses were made using data collected from 123 patients (76 females and 47 males) who returned the questionnaire. All of the patients were treated between 1999 and 2012. RESULTS: In comparing the ABVD and BEACOPP groups of female patients, the frequency of the therapy-induced amenorrhea and the restored menses following treatment were found to be significantly different statistically (p = 0.002 and p = 0.012, respectively). The secondary amenorrhea statistically appeared more often in the BEACOPP group (p = 0.003) while the cases of achieving pregnancy and having children after chemotherapy were not significantly different (p = 0.630, p = 0.070, respectively). In comparing the ABVD and BEACOPP treatments in male patients, the only significant difference was in the number of artificially inseminated or in vitro pregnancies achieved in the BEACOPP and escalated BEACOPP group, p = 0.008 and p = 0.002, respectively. In total, 45.2% of patients in the ABVD female group, 34.6% in the BEACOPP female group, 52.6% in the ABVD male group, and 33.3% in the male BEACOPP group, respectively, of patients attempting conception post-therapy, had children after chemotherapy. CONCLUSIONS: Based on these high rates of childbirth following BEACOPP chemotherapy, we have concluded that intensified chemotherapy is not a definite predictor of reduced fertility in young HL patients.

Granulomatosis after autologous stem cell transplantation in nonHodgkin lymphoma - experience of single institution and a review of literature.

BACKGROUND: Sarcoidosis before and after treatment of malignancy is an important differential diagnosis that has to be distinguished from lymphoma. PATIENTS AND METHODS: Hodgkin lymphoma, diffuse large B-cell lymphoma and aggressive follicular lymphoma are being staged and treatment effect is evaluated with PET-CT. We report three cases of aggressive lymphoma after high dose therapy and autologous stem cell transplantation with positive lymph nodes on PET-CT, which were histologically diagnosed as sarcoidosis/granulomatosis. In the literature, we found that false positive lymph nodes were more common after allogeneic than after autologous transplantation. CONCLUSIONS: Post-treatment PET-CT positive lymph nodes should always be examined histologically prior to any further treatment decision to avoid unnecessary toxic procedures.

Long-term outcome of multilayer flow modulator in aortic aneurysms.

BACKGROUND: This retrospective study investigated the efficacy of endovascular treatment with multilayer flow modulators (MFMs) for treating aortic aneurysms in high-risk patients unsuitable for conventional treatments. PATIENTS AND METHODS: Conducted from 2011 to 2019 at a single center, this retrospective observational study included 17 patients who underwent endovascular treatment with MFMs. These patients were selected based on their unsuitability for traditional surgical or endovascular procedures. The study involved meticulous pre-procedural planning, precise implantation of MFMs, and follow-up using CT angiography. The primary focus was on volumetric and flow volume changes in aneurysms, along with traditional diameter measurements. Moreover, the technical success and post-procedural complications were also registered. RESULTS: The technical success rate was 100%, and 30-day procedural complication rate was 17.6%. Post-treatment assessments revealed that 11 out of 17 patients showed a decrease in flow volume within the aneurysm sac, indicative of a favorable hemodynamic response. The median decrease in flow volume was 12 ml, with a median relative decrease of 8%. However, there was no consistent reduction in aneurysm size; most aneurysms demonstrated a median increase in volume for 46 ml and median increase in diameter for 18 mm. CONCLUSIONS: While MFMs offer a potential alternative for high-risk aortic aneurysm patients, their effectiveness in preventing aneurysm expansion is limited. The results suggest that MFMs can provide a stable hemodynamic environment but do not reliably reduce aneurysm size. This underscores the need for ongoing vigilance and long-term monitoring in patients treated with this technology.

Do Double-Expressor High-Grade B-Cell Lymphomas Really Need Intensified Treatment? A Report from the Real-Life Series of High-Grade B-Cell Lymphomas Treated with Different Therapeutic Protocols at the Institute of Oncology Ljubljana.

High-grade B-cell lymphomas with MYC and BCL2 and/or BCL6 rearrangements are known for their aggressive clinical course and so are the ones with MYC and BCL2 protein overexpression. The optimal therapy for these lymphomas remains to be elucidated. A retrospective analysis of all diffuse large B-cell lymphomas and high-grade B-cell lymphomas with MYC and BCL2 and/or BCL6 rearrangements diagnosed between 2017 and 2021 at the Institute of Oncology Ljubljana, Slovenia, has been performed. Only patients with double-expressor lymphoma (DEL), double-hit lymphoma (DHL), or triple-hit lymphoma (THL) were included. Demographic and clinical parameters were assessed, as well as progression-free survival (PFS) and overall survival (OS). In total, 161 cases out of 309 (161/309; 52,1%) were classified as DEL. Sixteen patients had DHL, MYC/BCL2 rearrangement was observed in eleven patients, and MYC/BCL6 rearrangement was observed in five patients. Five patients were diagnosed with THL. Out of 154 patients (according to inclusion/exclusion criteria) included in further evaluation, one-hundred and thirty-five patients had double-expressor lymphoma (DEL), sixteen patients had DHL, and three patients had THL. In total, 169 patients were treated with R-CHOP, 10 with R-CHOP and intermediate-dose methotrexate, 19 with R-DA-EPOCH, and 16 with other regimens. The median follow-up was 22 months. The 5-year OS for the whole DEL group was 57.1% (95% CI 45.9-68.3%) and the 5-year PFS was 76.5% (95% CI 72.6-80.4%). The log-rank test disclosed no differences in survival between treatment groups (p = 0.712) while the high-risk international prognostic index (IPI) carried a significantly higher risk of death (HR 7.68, 95% CI 2.32-25.49, p = 0.001). The 5-year OS for DHL patients was 32.4% (95% CI 16.6-48.2%) while all three TH patients were deceased or lost to follow-up. Our analyses of real-life data disclose that the R-CHOP protocol with CNS prophylaxis is a successful and curative treatment for a substantial proportion of DEL patients.

The prognostic significance of programmed cell death protein 1 and its ligand on lymphoma cells and tumor-immune cells in diffuse large B-cell lymphoma, not otherwise specified.

BACKGROUND: Diffuse large B-cell lymphoma, not otherwise specified (DLBCL, NOS) is the most common type non-Hodgkin's lymphoma, where the treatment of relapsed/refractory cases is the major challenge. Programmed cell death protein 1 (PD-1) and its ligand PD-L1 play a crucial role in the negative regulation of the immune response against the disease. The aim of the study was to analyze the expression of PD-1 and PD-L1 on lymphoma cells (LCs) and tumor-immune cells (TICs) and to investigate their correlation with outcome. PATIENTS AND METHODS: Samples from 283 patients diagnosed with DLBCL, NOS (both germinal center B cell like [GCB] and non-GCB subtypes) were included in the study. Expression of PD-1 and PD-L1 was determined using double immunohistochemical staining (D-IHC) for PD-1/PAX5 and PD-L1/PAX5 on tissue microarrays. LCs were highlighted by D-IHC to obtain more accurate results. Clinical data and histologic diagnoses were obtained from electronic data records. We correlated clinical characteristics, and PD-1 and PD-L1 expression on LCs and TICs with progression-free survival (PFS) and overall survival (OS). RESULTS: Expression of PD-1 on TICs was observed in 38.4% and on LCs in 8.8% of cases, while PD-L1 was expressed on TICs in 46.8% and on LCs in 6.5% of cases. PD-L1 expression on LCs was more frequent in non-GCB subtype (p = 0.047). In addition, patients with PD-L1 expression on LCs had significantly shorter PFS (p = 0.015), and the expression retained significant in the multivariate model (p = 0.034). CONCLUSIONS: PD-L1 was more frequently expressed in LCs of the non-GCB subtype. Additionally, PD-L1 in LCs may predict shorter PFS time. D-IHC staining for PD-L1/PAX5 is a feasible method to assess PD-L1 expression on LCs of DLBCL, NOS patients and can be used to identify patients who may benefit from targeted immunotherapy with checkpoint inhibitors.

Correlation of t(14;18) translocation breakpoint site with clinical characteristics in follicular lymphoma.

BACKGROUND: t(14;18)(q32;q21) translocation is an important genetic feature of follicular lymphoma resulting in antiapoptotic B-cell lymphoma 2 (BCL2) protein overexpression. On chromosome 18 breakpoint-site variation is high but does not affect BCL2. Breakpoint most commonly occurs at major breakpoint region (MBR) but may happen at minor cluster region (mcr) and between MBR and mcr at 3'MBR and 5'mcr. The aim of this study was to analyze the correlation of t(14;18)(q32;q21) breakpoint site with clinical characteristics in follicular lymphoma. PATIENTS AND METHODS: We included patients diagnosed with follicular lymphoma who received at least 1 cycle of systemic treatment and had the t(14;18)(q32;q21) translocation detected by polymerase chain reaction (PCR) at MBR, mcr or 3'MBR prior to first treatment. Among patients with different breakpoints, sex, age, disease grade, stage, B-symptoms, follicular lymphoma international prognostic index (FLIPI), presence of bulky disease, progression free survival and overall survival were compared. RESULTS: Of 84 patients, 63 had breakpoint at MBR, 17 at mcr and 4 at 3'MBR. At diagnosis, the MBR group had a significantly lower disease stage than the mcr group. Although not significant, in the MBR group we found a higher progression-free survival (PFS) and overall survival (OS), lower grade, age, FLIPI, and less B-symptoms. CONCLUSIONS: Compared to patients with mcr breakpoint, those with MBR breakpoint seem to be characterised by more favourable clinical characteristics. However, a larger study would be required to support our observation.

CD56-positive diffuse large B-cell lymphoma: comprehensive analysis of clinical, pathological, and molecular characteristics with literature review.

BACKGROUND: Diffuse large B-cell lymphoma (DLBCL) is the most common non-Hodgkin lymphoma. The expression of CD56 in DLBCL is highly unusual. Little is known about its incidence and clinical importance. So far, no genetic profiling was performed in CD56 positive DLBCL. PATIENTS AND METHODS: Tissue microarrays have been constructed, sectioned, and stained by H&E and immunohistochemistry for 229 patients with DLBCL diagnosed 2008-2017. For CD56 positive cases, clinical data was collected including age at diagnosis, stage of the disease, International Prognostic Index (IPI) score, treatment scheme and number of chemotherapy cycles, radiation therapy, treatment outcome, and possible relapse of the disease. Overall survival (OS) and progression-free survival (PFS) were calculated. For four patients, RNA was extracted and targeted RNA (cDNA) sequencing of 125 genes was performed with the Archer FusionPlex Lymphoma kit. RESULTS: CD56 expression was found in 7 cases (3%). The intensity of expression varied from weak to moderate focal, to very intensive and diffuse. All patients had de novo DLBCL. The median age at the time of diagnosis was 54.5 years. Five of them were women and 2 males. According to the Hans algorithm, 6 patients had the germinal centre B cells (GBC) type and one non-GBC (activated B-cell [ABC]) type, double expressor. Genetic profiling of four patients according to Schmitz's classification showed that 1 case was of the BN2 subtype, 1 of EZB subtype, 2 were unclassified. The six treated patients reached a complete response and did not experience progression of the disease during the median follow-up period of 80.5 months. CONCLUSIONS: We report on one of the largest series of CD56+DLBCL with detailed clinicopathological data and for the first time described genetical findings in a limited number of patients. Our results show that CD56 expression is rare, but seems to be present in prognostic favourable subtypes of DLBCL not otherwise specified (NOS) as tested by immunohistochemical or genetic profiling.

Current Opinion on Pixantrone in the Treatment of Non-Hodgkin B-Cell Lymphoma.

Not many treatment options exist for patients with relapsed or refractory (R/R) B-cell non-Hodgkin lymphoma (NHL) in whom first- and second-line therapies were unsuccessful. This is especially true for patients with aggressive lymphomas. The innovative agent pixantrone has shown some promising results in terms of disease-free and overall survival, both in monotherapy as well as in combinations. However, recent trials (Phase III and real-world studies) reported unsatisfactory results, thereby raising the question about the role of pixantrone in the current treatment of R/R aggressive lymphomas. Nonetheless, there might still be a potential position for this drug in combinations, for use as first-line treatment of patients with cardiac dysfunction. This article summarizes the definition, structure, mechanism of action and reduced cardiotoxicity of pixantrone as well as efficacy and toxicity both in monotherapy and in combinations, as treatment for aggressive and indolent non-Hodgkin lymphomas.

Limited efficacy of pixantrone in refractory diffuse large B-cell lymphoma.

Relapsed or refractory diffuse large B-cell lymphoma (DLBCL) is an aggressive disease with poor outcomes in patients ineligible for autologous stem cell transplantation. In this setting, novel treatment approaches are urgently required and the innovative agent pixantrone has shown some promising results in terms of disease-free and overall survival (OS). The present study retrospectively analyzed 12 patients routinely treated with pixantrone in monotherapy or in combinations at the Institute of Oncology Ljubljana, Slovenia, between January 2016 and October 2018. All 12 patients had refractory lymphoma to last treatment and a large proportion of them had other high risk features (high proliferation index, high disease stage, high international prognostic index (IPI) score, high percentage of primary refractory disease and high percentage of refractoriness to anthracyclines) at initiation of pixantrone. All patients progressed during treatment and none of the patients were alive at the time of analysis due to progressive lymphoma. Pixantrone specific median OS was 3.5 months (range, 0.5-10 months). A somewhat superior median OS (P=0.065) was observed in patients primarily sensitive to anthracyclines. Pixantrone has shown only limited efficacy in the present real world study comparable to the results of another real world UK retrospective analysis and substantially worse than the efficacy observed in the PIX301 registration trial. Therefore, an appropriate selection of patients for this treatment is crucial. Despite the limited experience due to a small number of patients, it was recommended to consider only patients with relapsed (and not refractory) disease, patients with non-primary refractory disease and those with fewer lines of prior therapy.

Comparison of the algorithms classifying the ABC and GCB subtypes in diffuse large B-cell lymphoma.

Different immunohistochemical algorithms for the classification of the activated B-cell (ABC) and germinal center B-cell (GCB) subtypes of diffuse large B-cell lymphoma (DLBCL) are applied in different laboratories. In the present study, 127 patients with DLCBL were investigated, all treated with rituximab and cyclophosphamide, hydroxydaunorubicin, oncovin and prednisone (CHOP) or CHOP-like regimens between April 2004 and December 2010. Multi-tumor tissue microarrays were prepared and were tested according to 4 algorithms: Hans; modified Hans; Choi; and modified Choi. For 39 patients, the flow cytometric quantification of CD19 and CD20 antigen expression was performed and the level of expression presented as molecules of equivalent soluble fluorochrome units. The Choi algorithm was demonstrated to be prognostic for OS and classified patients into the GCB subgroup with an HR of 0.91. No difference in the expression of the CD19 antigen between the ABC and GCB groups was observed, but the ABC subtype exhibited a decreased expression of the CD20 antigen compared with the GCB subtype.

Diffuse large B-cell lymphoma: 10 years' real-world clinical experience with rituximab plus cyclophosphamide, doxorubicin, vincristine and prednisolone.

Treatment with rituximab plus a regimen of cyclophosphamide, doxorubicin, vincristine and prednisolone (CHOP) for patients with diffuse large B-cell lymphoma (DLBCL) has proven efficacy in clinical trials. The present study investigated its application in clinical practice. This single-center, retrospective database analysis included patients with DLBCL treated at the Slovenian Institute of Oncology Ljubljana between 2004 and 2013. Overall survival (OS) and progression-free survival (PFS) were assessed according to International Prognostic Index (IPI) and revised IPI (R-IPI) categories. Overall, 573 patients with DLBCL were included in the study (median follow-up, 45.3 months; range, 0.1-143.0). Patients were categorized as IPI 'low' (n=170; 30%), 'low-intermediate' (n=134; 23%), 'high-intermediate' (n=129; 23%) and 'high' (n=140; 24%) risk. R-IPI groups were indicated with 'very good' (n=59; 10%), 'good' (n=245; 43%) and 'poor' (n=269; 47%) prognosis. Ten-year OS and PFS rates were 51 and 72%, respectively; median OS was 124 months and median PFS was not reached. Ten-year OS rates were 80 and 87% in low-risk and 'very good' prognosis groups, respectively, and 30 and 37% in high-risk and poor prognosis patients, respectively. This analysis of patients with DLBCL indicated that many patients treated with R-CHOP and R-CHOP-like regimens in the real-world setting have excellent outcomes.

Voice Disorders in Occupations with Vocal Load in Slovenia.

AIM: The aim of this paper is to compare the prevalence of voice disorders and the risk factors for them in different occupations with a vocal load in Slovenia. METHODS: A meta-analysis of six different Slovenian studies involving teachers, physicians, salespeople, catholic priests, nurses and speech-and-language therapists (SLTs) was performed. In all six studies, similar questions about the prevalence of voice disorders and the causes for them were included. RESULTS: The comparison of the six studies showed that more than 82% of the 2347 included subjects had voice problems at some time during their career. The teachers were the most affected by voice problems. The prevalent cause of voice problems was the vocal load in teachers and salespeople and respiratory-tract infections in all the other occupational groups. When the occupational groups were compared, it was stated that the teachers had more voice problems and showed less care for their voices than the priests. The physicians had more voice problems and showed better consideration of vocal hygiene rules than the SLTs. The majority of all the included subjects did not receive instructions about voice care during education. CONCLUSIONS: In order to decrease the prevalence of voice disorders in vocal professionals, a screening program is recommended before the beginning of their studies. Regular courses on voice care and proper vocal technique should be obligatory for all professional voice users during their career. The inclusion of dysphonia in the list of occupational diseases should be considered in Slovenia as it is in some European countries.