Uncovering the Challenges of Rare Diseases: Insights From a Retrospective Cross-Sectional Study in Albania (2005-2022).

BACKGROUND: Diagnosing and treating rare diseases pose significant challenges within global healthcare systems due to their low prevalence and varying criteria for defining them. In Albania, the absence of a dedicated registry for rare diseases exacerbates these challenges. Recognising this gap, a retrospective cross-sectional study was conducted from January 2005 to December 2022 to analyse the incidence and prevalence of rare haematologic diseases in the country, diagnosed in the Hematology Service at the University Hospital Centre "Mother Teresa," which is the sole diagnostic center for blood diseases in Albania. This study aims to provide insights into the frequency of these diseases within the adult Albanian population and seeks to underscore the critical need for improved data collection and research in this field of healthcare. OBJECTIVE: The primary objective of this study is to assess the incidence and prevalence of rare hematologic diseases diagnosed at the Hematology Service of the University Hospital Centre "Mother Teresa" in Albania from January 2005 to December 2022. MATERIALS AND METHODS: This retrospective cross-sectional study employed a descriptive study design, focusing on the analysis of rare hematologic disease incidence and prevalence. The study was conducted exclusively at the University Hospital Centre "Mother Teresa" in Albania, the primary diagnostic center for blood-related disorders in the country. Data collection spanned a period of 18 years, from January 2005 to December 2022, encompassing patient records. Inclusion criteria encompassed adult patients aged 15 years and older who had received diagnoses of rare hematologic diseases during the specified timeframe, without specific operational definitions applied. Non-probability convenience sampling was used, including all eligible cases identified within the study's timeframe, obviating the need for formal sample size calculation. Data were extracted from the records of the Hematology Service at the University Hospital Centre "Mother Teresa," primarily using medical records containing essential patient information. Data analysis utilised software such as EXCEL 16.0 and SPSS (v. 25.0), applying descriptive statistical methods, including frequencies and percentages, to assess the incidence and prevalence of rare hematologic diseases. The study's findings were summarised and presented in a tabular format to provide a clear and concise overview of the results. RESULTS: Our study identified 64 cases of rare hematologic diseases among adults. Notably, primary myelofibrosis (MF) exhibited the highest incidence and prevalence rate, followed by Waldenström macroglobulinemia (WM) and Gaucher disease (GD) emerging as the most prevalent diagnoses after MF, with 16 and 10 cases, respectively. Several ultra-rare diseases, such as Fanconi anemia and chronic eosinophilic leukemia, were also detected, indicating a significant disease burden, while diseases such as Factor X deficiency and Niemann-Pick disease type C were exceptionally rare. CONCLUSION: Diagnosing and treating rare diseases remain formidable challenges in healthcare systems worldwide. This study underscores the need for enhanced awareness, research, and the pressing need for dedicated registries, collaborative research initiatives, and heightened attention to these conditions to enhance our understanding and management of rare hematological diseases, particularly within the Albanian healthcare context.

Bone Marrow Microenvironment Interplay and Current Clinical Practice in Multiple Myeloma: A Review of the Balkan Myeloma Study Group.

The course of multiple myeloma (MM) is influenced by a variety of factors, including the specificity of the tumour microenvironment (TME). The aim of this review is to provide insight into the interplay of treatment modalities used in the current clinical practice and TME. Bortezomib-based triplets are the standard for MM first-line treatment. Bortezomib is a proteasome inhibitor (PI) which inhibits the nuclear factor kappa B (NF-κB) pathway. However, bortezomib is decreasing the expression of chemokine receptor CXCR4 as well, possibly leading to the escape of extramedullary disease. Immunomodulatory drugs (IMiDs), lenalidomide, and pomalidomide downregulate regulatory T cells (Tregs). Daratumumab, anti-cluster of differentiation 38 (anti-CD38) monoclonal antibody (MoAb), downregulates Tregs CD38+. Bisphosphonates inhibit osteoclasts and angiogenesis. Sustained suppression of bone resorption characterises the activity of MoAb denosumab. The plerixafor, used in the process of stem cell mobilisation and harvesting, block the interaction of chemokine receptors CXCR4-CXCL12, leading to disruption of MM cells' interaction with the TME, and mobilisation into the circulation. The introduction of several T-cell-based immunotherapeutic modalities, such as chimeric-antigen-receptor-transduced T cells (CAR T cells) and bispecific antibodies, represents a new perspective in MM treatment affecting TME immune evasion. The optimal treatment approach to MM patients should be adjusted to all aspects of the individual profile including the TME niche.

A real world multicenter retrospective study on extramedullary disease from Balkan Myeloma Study Group and Barcelona University: analysis of parameters that improve outcome.

Here, we report the outcome of 226 myeloma patients presenting with extramedullary plasmacytoma or paraosseous involvement in a retrospective study conducted in 19 centers from 11 countries. Extramedullary disease was detected at diagnosis or relapse between January 2010 and November 2017. Extramedullary plasmacytoma and paraosseous involvement were observed in 130 patients at diagnosis (92 of 38) and in 96 at relapse (84 of 12). The median time from multiple myeloma diagnosis to the development of extramedullary disease was 25.1 months (range 3.1-106.3 months) in the relapse group (median follow up: 15 months). Imaging approach for extramedullary disease was computed tomography (n=133), positron emission tomography combined with computed tomography (n=50), or magnetic resonance imaging (n=35). The entire group received a median two lines of treatment and autologous stem cell transplantation (44%) following the diagnosis of extramedullary disease. Complete response was higher for paraosseous involvement versus extramedullary plasmacytoma at diagnosis (34.2% vs 19.3%; P=NS.) and relapse (54.5% vs 9%; P=0.001). Also paraosseous involvement patients had a better progression-free survival (PFS) when recognized at initial diagnosis of myeloma than at relapse (51.7 vs 38.9 months). In addition, overall survival was better for paraosseous involvement compared to extramedullary plasmacytoma at diagnosis (not reached vs 46.5 months).Extramedullary plasmacytoma at relapse had the worst prognosis with a PFS of 9.1 months and overall survival of 11.4 months. In the multivariate analysis, paraosseous involvement, extramedullary disease at diagnosis, International Staging System (ISS-I), and undergoing autologous stem cell transplantation improved overall survival independently. This cohort demonstrated that extramedullary disease benefits from front-line autologous stem cell transplantation and extramedullary plasmacytoma differs from paraosseous involvement in terms of rate and duration of response, with even worse outcomes when detected at relapse, constituting an unmet clinical need.

Is extracapsular tumour spread a prognostic factor in patients with early breast cancer?

BACKGROUND: This study searched for extra capsular tumour spread (ECS) as a prognostic factor for recurrence in terms of Disease Free Survival (DFS) and Overall Survival (OS). PATIENTS AND METHODS: For this study, from a retrospective database of the Doubs cancer registry, 823 eligible women with node positive breast cancer treated from February 1984 to November 2000 were identified. The following factors were evaluated: ECS, numbers of involved nodes, histological tumour grade, tumour size, status of estrogen and progesterone receptors, and age of patient. A Cox proportional hazards method was used to search for significant factors related to OS and DFS length. RESULTS: In the multivariate analysis, factors related to DFS length were found to be: tumour grade (aHR 0.76, 95 % CI 0.61-0.96, p = 0.02), ECS status (aHR 0.7, 95 % CI 0.49-0.96, p = 0.03), progesterone (PgR) status (aHR 0.63, 95 % CI 0.44-0.85 p = 0.008), number of nodes involved (aHR 0.75, 95 % CI 0.56-1, p = 0.05). The multivariate analysis for OS found as significant factors: tumour grade (aHR 0.76, 95 % CI 0.61-0.95; p = 0.02) and PgR status (aHR 0.8, 95 % CI 0.56-0.99, p = 0.02). CONCLUSIONS: This study might suggest taking into account ECS status in the adjuvant decision-making process.

Impact of STAT3 phosphorylation on the clinical effectiveness of anti-EGFR-based therapy in patients with metastatic colorectal cancer.

UNLABELLED: Half of patients with KRAS wild-type colorectal cancer do not benefit from adding anti-epithelial growth factor receptor (EGFR) to standard chemotherapy regimens. This retrospective study was performed in 94 patients with metastatic colorectal cancer (mCRC) treated in the second line with cetuximab and chemotherapy. Signal transducer and activator of transcription 3 (STAT3) phosphorylation in tumor cells was correlated with decreased median progression-free survival and overall survival (OS). These results highlight the potential role of STAT3 as a molecular target to optimize anti-EGFR therapies. BACKGROUND: Signal transducer and activator of transcription 3 (STAT3) is involved in epithelial growth factor receptor (EGFR) signaling in a KRAS-independent manner. Phosphorylated STAT3 (pSTAT3) expression in patients with metastatic colorectal cancer (mCRC) treated with anti-EGFR-containing salvage chemotherapy has never been investigated. PATIENTS AND METHODS: : The first endpoint of this retrospective study was to evaluate the impact of pSTAT3 on the time to progression (TTP) in 94 patients with mCRC treated with anti-EGFR-based therapies in the second- or third-line setting between July 2004 and November 2009. The influence of pSTAT3 on objective response rate and overall survival (OS) was also reported. Nuclear expression of pSTAT3 status was evaluated by immunohistochemical tests on formalin-fixed and paraffin-embedded tumor samples obtained before therapy. RESULTS: Positive expression of pSTAT3 was observed in 24.5% of the tumor samples. The probability of achieving an objective response was 13% among patients with positive nuclear expression of pSTAT3 compared with 41% for patients displaying pSTAT3-negative tumors (P = .02). In a multivariate logistic regression model, high-grade skin rash, wild-type KRAS status, and negative pSTAT3 status significantly improved TTP and OS. CONCLUSION: These results underscore an impact of pSTAT3 on the clinical efficacy of anti-EGFR-containing chemotherapy regimens and support the prospective assessment of this biomarker.

Duration: escalation study of oral etoposide with carboplatin in patients with varied solid tumors.

Prolonged fractionated oral administration of etoposide may present a theoretical advantage over intravenous administration of the bolus. This phase I trial was carried out to determine the recommended duration of oral etoposide in combination with a fixed dose of carboplatin. Nineteen patients with varied solid tumors, who were not candidates for standard chemotherapy, were administered an escalating duration (6, 9 or 12 consecutive days) of oral etoposide (a 25 mg capsule three times daily) combined with carboplatin AUC5 administered on day 1, by a 30 min intravenous infusion, to define the maximum tolerated dose on the basis of the acute toxicities that were reported. Etoposide was started on day 2; the cycles repeated every 28 days until disease progression or toxicity. Pharmacokinetics was carried out during the two first cycles. The maximum tolerated dose was determined to be the 12-day treatment level, with two cases of grade 4 neutropenia, grade 3 anemia and thrombocytopenia. As no severe toxicity occurred with the 9-day treatment level and in an attempt to explore an optimal combination, a new 10-day treatment plan was studied in three patients. As one patient presented dose-limiting toxicity at that level, five additional patients were included to establish the recommended regimen. Nonhematological toxicities among all patients were moderate, consisting of grade 2 nausea and asthenia. No treatment-related death occurred. Objective responses were observed in four patients and stabilization in three patients. Pharmacokinetics highlighted no interaction between etoposide and carboplatin. Fractionated oral etoposide (3×25 mg/day) for 10 days in combination with carboplatin AUC 5 presents acceptable toxicity and efficacy. The main toxicity remains hematological.

Peripheral neuropathy in association with an ovarian dysgerminoma.

BACKGROUND: Peripheral neuropathy among women with ovarian dysgerminoma has not been so far reported in the literature. CASE: We report a case of an 18-year-old woman with an association of an abdominal relapse of an ovarian dysgerminoma and a polyradiculoneuritis. The normality of neurologic investigations and the disappearance of all sensitive and muscular alterations after tumor ablation and one cycle of chemotherapy are in favor of a paraneoplastic syndrome. After 5 years this young woman is still in complete remission without any neurologic symptoms. CONCLUSION: We describe the first case of a polyradiculoneuritis associated with an ovarian dysgerminoma. The evolution of the paraneoplastic syndrome was favorable after treatment of the tumor.