Identification of two theranostic biomarker panels for epithelial ovarian cancer.

BACKGROUND: Epithelial Ovarian cancer (EOC) is the leading cause of death associated with gynecologic tumors. Because the disease is asymptomatic in early-stage, the majority of patients are not diagnosed until late stages, highlighting the need for the development of novel diagnostic biomarkers. Mediators of tumoral microenvironment may affect EOC progression and resistance to treatment. AIM OF THE STUDY: Analysis of serum proteins to identify a panel of theranostic biomarkers for EOC. PATIENTS AND METHODS: Serum levels of 65 analytes were determined in EOC patients, and healthy controls with the ProcartaPlex Human Immune Monitoring 65-Plex Panel. RESULTS: Twenty-one analytes: 7 cytokines (IFN-γ, IL-12p70, IL-13, IL-18 and TSLP), 7 chemokines (Eotaxin, eotaxin-2, IP-10, BLC, I-TAC, SDF-1α, and fractalkine), 2 growth factors (MMP-1, VEGF-α), and 5 soluble receptors (APRIL, CD40L, TWEAK, CD30 and TNFRII; were significantly differentially expressed between the two groups. ROC curves showed that only seven of them (IL-9, TNF-α, Eotaxin, IP-10, BLC, Fractalkine, and Tweak) had AUC values greater than 0.70 and thus had potential clinical utility. Moreover, five cytokines: IFN-γ, IL-1 ß, IL-8, MIP-1ß, and TNF-α are positively associated with patients who developed resistance to taxol-platinum-based chemotherapy (CT). CONCLUSION: This study has revealed a first panel of 7 analytes (IL-9, TNF-α, Eotaxin, IP-10, BLC, Fractalkine and Tweak) that can be used for early detection of EOC and a second panel of five cytokines (IFN-γ, IL-1ß, IL-8, MIP-1ß, TNF-α) that can help clinicians to identify EOC patients who are at higher risk to develop resistance to CT of EOC.

Development of a custom next-generation sequencing panel for the determination of bladder cancer risk in a Tunisian cohort.

BACKGOUND: Bladder cancer (BCa) is a heterogeneous disease caused by the interaction between environmental and genetic risk factors. The goal of this case-control study was to evaluate the implication of a selected SNP panel in the risk of BCa development in a Tunisian cohort. We were also interested in studying the interaction between this predictive panel and environmental risk factors. METHODS: The case/control cohort was composed with 249 BCa cases and 255 controls. The designed Bladder cancer hereditary panel (BCHP) was composed of 139 selected variants. These variants were genotyped by an amplification-based targeted Next-Generation Sequencing (NGS) on the Ion Torrent Proton sequencer (Life Technologies, Ion Torrent technology). RESULTS: We have found that rs162555, rs2228000, rs10936599, rs710521, rs3752645, rs804276, rs4639, rs4881400 and rs288980 were significantly associated with decreased risk of bladder cancer. However the homozygous genotypes for VPS37C (rs7104333, A/A), MPG (rs1013358, C/C) genes or the heterozygous genotype for ARNT gene (rs1889740, rs2228099, rs2256355, rs2864873), GSTA4 (rs17614751) and APOBR/IL27 (rs17855750) were significantly associated with increased risk of bladder cancer development compared to reference group (OR 2.53, 2.34, 1.99, 2.00, 2.00, 1.47, 1.96 and 2.27 respectively). We have also found that non-smokers patients harboring heterozygous genotypes for ARNT/rs2864873 (A > G), ARNT/ rs1889740 (C > T) or GSTA4/rs17614751 (G-A) were respectively at 2.775, 3.069 and 6.608-fold increased risk of Bca development compared to non-smokers controls with wild genotypes. Moreover the ARNT CT (rs1889740), ARNT CG (rs2228099), ARNT TC (rs2864873) and GSS GA genotypes were associated with an increased risk of BCa even in absence of professional risk factors. Finally the decision-tree analysis produced a three major BCa classes. These three classes were essentially characterized by an intensity of tobacco use more than 20 pack years (PY) and the CYP1A2 (rs762551) genotype. CONCLUSIONS: The determined association between environmental factors, genetic variations and the risk of Bca development may provide additional information to urologists that may help them for clinical assessment and treatment decisions. Nevertheless, the underlying mechanisms through which these genes or SNPs affect the clinical behavior of BCas require further studies.

Skin toxicity after Filgrastim treatment for an Ewing's sarcoma patient.

INTRODUCTION: Filgrastim is a granulocyte colony-stimulating factor (GSCF) used in some chemotherapy regimen to prevent febrile neutropenia. Most common reaction of filgrastim are aches and pain including headaches, nausea and skin rash. CASE REPORT: We report the case of a patient who developed unusual, non-commonly reported adverse toxidermy to filgrastim. At first the eruption was limited to the lower members and genetics organs. Then it slowly spread across the whole body presenting as a polymorphic exanthematous-pustulosis lesions. MANAGEMENT & OUTCOME: A cutaneous biopsy was done, identifying a toxidermy modified by systemic treatment. A pharmacological study linked the role of filgrastim to these lesions. After switching from filgrastim to lénograstim, his lesions are completely gone and haven't flared up again. Thus, clearly imputing the use of filgrastim. DISCUSSION: The cutaneous reaction that has reported with use of GSCF are sweet syndrome, erythema nodosum, pyoderma nodosum and pyoderma gangrenosum. As far as we know, no acute generalized exanthematous pustulosis due to GSCF has been reported.

Uncovering the expression patterns and the clinical significance of miR-182, miR-205, miR-27a and miR-369 in patients with urinary bladder cancer.

BACKGROUND: Given the high recurrence and progression rates and the absence of reliable markers for early detection and prognosis prediction of patients with urothelial bladder cancer (BCa), the exploration of new biomarkers with high specificity is imperative. Mainly, microRNAs (miRNAs), which are involved in the initiation and the progression of BCa. Herein, the expression patterns of miR-182, miR-205, miR-27a and miR-369 were evaluated in patients with urothelial BCa. METHODS AND RESULTS: The expression levels of the miRNAs were investigated in 90 FFPE tissue samples (23 LG NMIBC, 44 HG NMIBC, 23 MIBC) and 10 non tumoral bladder tissues using TaqMan based RT-qPCR. Data analysis was performed using 2-ΔΔCT method. Correlation to clinical characteristics of the patients was performed using descriptive statistics and the receiver operating characteristic (ROC) curve was performed to evaluate the diagnostic value of all miRNAs. MiR-27a, miR-205 and miR-369 were down-regulated whereas miR-182 was up-regulated in patients compared to controls (p < 0.001). MiR-205 and miR-182 positively segregate between NMIBC and MIBC (p = 0.002 and p = 0.000 respectively) whereas the distribution of miR-27a's expression among these tumor groups was almost significant (p = 0.05) and that of miR-369's expression was irrelevant (p = 0.618). Interestingly, miR-182 was discriminative between LG NMIBC and HG NMIBC (p < 0.001) and Ta/T1 tumors (p = 0.000). Furthermore, high levels of miR-182 were potentially predictive of progression in NMIBC patients (p = 0.01). CONCLUSION: Collectively, a selection of miRNAs was found to be aberrantly expressed in BCa suggesting a potential diagnostic value in BCa. In addition, the clinical value of miR-182 and miR-205 as potential prognosis biomarkers was highlighted. Indeed, our data provide additional insights into cancer biology. Further functional or target studies are mandatory to strengthen these findings.

Target therapy for metastatic breast cancer.

Breast cancer is the first cancer in women worldwide. Since the previous estimates of WHO in 2008, incidence is increasing and it is estimated that 30% of women will develop immediately a metastatic form. However, advances in molecular biology and the discovery of new therapies have extended significantly the survival of patients and improved the quality of life of patients with metastatic breast cancer. The study of gene expression and protein profile has resulted in a finer classification of breast cancer and adapt the treatment of patients according to their molecular profiles. The purpose of our work is to describe the different targeted therapies used in the MBC and their action's mechanism   referring to various therapeutic trials described in the literature.

Perioperative chemotherapy in locally advanced gastric cancer. A retrospective study about 25 cases.

BACKGROUND: Perioperative chemotherapy containing 5FU, Cisplatin ± Docetaxel is one of the most active regimens in advanced gastric cancer. OBJECTIVE: To report epidemiological and clinical profile and therapeutic results of perioperative chemotherapy in locally advanced gastric cancer in Tunisia. METHODS: Our retrospective study concerned patients with histologically confirmed advanced gastric cancer treated at the institute Salah Azaiez of Tunis. They received 2-3 cycles / 3 weeks of neoadjuvant chemotherapy based on FP (5FU and Cisplatin) or TPF (Docetaxel-Cisplatin-5FU). RESULTS: From 2010 to 2012, 25 patients with a median age of 60 years and 7.3 sex-ratio received neoadjuvant chemotherapy. Protocols used were TFP in 20 and FP in 5 patients, 17 patients receiving more than 2 cycles. Side effects were represented by mucositis grade 3 in 2 patients, neutropenia grade ¾ in 3 patients and renal failure in 5 patients. After neoadjuvant chemotherapy, we observed 40% of partial response and 20% of stable disease. Six patients (24%) underwent surgery, curative in 4 (R0 in 3 cases) by total gastrectomy and D2 lymphadenectomy and palliative in 2 cases due to peritoneal carcinomatosis. With a median follow up of 16 months, median overall survival was 16 months (2-21 months). CONCLUSION: Probably due to the very bulky and advanced stages of our gastric cancer cases, neoadjuvant chemotherapy using FP±T showed no benefit in the treatment of locally advanced gastric cancer in Tunisian patients.

Adherence to guidelines in curative treatment of venous thromboembolism in cancer patients: Insights from a retrospective Tunisian study.

AIM: To describe the management and treatment practices of venous thromboembolism (VTE) in cancer patients, assess compliance with the 2023 European Society for Medical Oncology recommendations, and identify factors that may limit or influence their application. METHODS: We conducted, in a Tunisian center, a retrospective study that included patients treated for cancer or hematologic malignancies and diagnosed with deep vein thrombosis (DVT) and/or pulmonary embolism between January 1, 2022, and August 1, 2023. RESULTS: The study involved 90 patients. DVTs were significantly predominant (81.1%). VTE mostly occurred within 3 months of the cancer diagnosis (41.1%). All patients received anticoagulant treatment. The most frequently prescribed class of anticoagulants was direct oral anticoagulants (42.2%), followed by low molecular weight heparin (36.7%), and finally vitamin K antagonists (21.1%). Financial constraints and/or refusal of social security to provide the treatment were the main cause for changes in the anticoagulant therapy (16.7%). Deaths (25.5%) and repermeabilization of the initially thrombosed venous network on imaging (11.1%) were the two primary reasons for treatment discontinuation. Bleeding complication was the cause of treatment modification or discontinuation in 7.7% and 5.5% of patients, respectively. Overall, guidelines were fully followed in 49 patients (54.4%) concerning the choice of pharmacological class, dose and duration of treatment. Financial constraints experienced by patients were significantly and independently associated with lower adherence to recommendations (p = 0.032). CONCLUSION: Adherence to guidelines is insufficient. Measures must be implemented to enhance the management of VTE and to develop strategies for improving access to anticoagulants.

Gastrosplenic fistula due to splenic lymphoma: two case reports and review of the literature.

BACKGROUND: Gastrosplenic fistula is a rare and potentially fatal complication of various conditions. Lymphoma is the most common cause. It can occur spontaneously or after chemotherapy. Gastrosplenic fistula diagnosis can be confused with a splenic abscess because of the presence of air into the mass. The computed tomography identification of the fistulous tract is the key to a right diagnosis. Treatment modalities include surgical resection, chemotherapy, or a combination of both. CASE PRESENTATION: Here we report two patients with gastrosplenic fistula due to diffuse large B cell lymphoma. The first patient was a 54-year-old Caucasian woman with an enormous primary splenic diffuse large B cell lymphoma leading to the development of a spontaneous fistula in the stomach. The second patient was a 48-year-old Caucasian male patient with an enormous splenic diffuse large B cell lymphoma complicated by fistula after chemotherapy. Both patients died of septic shock several days after surgery. CONCLUSION: Gastrosplenic fistula is a rare complication with a poor-prognosis, for which surgery is currently the preferred treatment.

Carcinoma of unknown primary: retrospective study of 437 patients treated at Salah Azaiez Institute.

BACKGROUND: Carcinoma of unknown primary (CUP) origin is defined as histologically confirmed metastatic carcinoma in the absence of a detectable primary site at the time of making therapeutic decision. AIM: To report epidemiological, clinical, histopathological, therapeutic, and prognostic features of CUP's patients collected at the Salah Azaiez institute (SAI). METHODS: We reviewed retrospectively the files of 437 CUP-patients in SAI between January 1994 and December 2006. We analyzed their epidemiological, clinical, histological and therapeutic features and classify patients in favourable and unfavourable subsets. Statistical analysis was performed with R software. Survival curves were made with the method of Kaplan-Meier. RESULTS: We collected 437 patients with a median age of 60 years and a sex-ratio of 1.8. CUP are metastatic to lymph nodes (56.5%), bones (29.7%) and liver (28%). 33% of patients had a unique site of metastases. Adenocarcinoma represented 50.5% of cases while 10.5% are classified in the favourable subgroup. 141 out 437 patients received palliative chemotherapy, 83% of them by cisplatin-based regimens obtaining 13% (58 patients) of objective response. Median survival was 7 months. 24 out 58 patients (41%) relapsed. Poor prognostic factors for survival were: multiple metastases (p=0.00033), >3 sites (p=0.03), undifferentiated carcinoma and adenocarcinoma (p>0.0001), liver metastases (p=0.0137), bone (p=0.00653) and adrenal gland (p=0.0334) metastatic sites. Patients who underwent chemotherapy (p>0.001) and who received cisplatbased regimen had better survival (p=0.01). CONCLUSION: Our retrospective study done in the context of a minimal and biological work-up confirmed the difficulty to find the primary in CUP.

Immune checkpoints as potential theragnostic biomarkers for epithelial ovarian cancer.

BACKGROUND: Epithelial ovarian cancer (EOC) is the leading cause of death associated with gynecologic tumors. EOC is asymptomatic in early stages, so most patients are not diagnosed until late stages, highlighting the need to develop new diagnostic biomarkers. Mediators of the tumoral microenvironment may influence EOC progression and resistance to treatment. AIM: To analyze immune checkpoints to evaluate them as theranostic biomarkers for EOC. PATIENTS AND METHODS: Serum levels of 16 immune checkpoints were determined in EOC patients and healthy controls using the MILLIPLEX MAP® Human Immuno-Oncology Checkpoint Protein Magnetic Bead Panel. RESULTS: Seven receptors: BTLA, CD40, CD80/B7-1, GITRL, LAG-3, TIM-3, TLR-2 are differentially expressed between EOC and healthy controls. Serum levels of immune checkpoints in EOC patients are positively significantly correlated with levels of their ligands, with a higher significant correlation between CD80 and CTLA4 than between CD28 and CD80. Four receptors, CD40, HVEM, PD-1, and PD-L1, are positively associated with the development of resistance to Taxol-platinum-based chemotherapy. All of them have an acceptable area under the curve (>0.7). CONCLUSION: This study has yielded a first panel of seven immune checkpoints (BTLA, CD40, CD80/B7-1, GITRL, LAG-3, TIM-3, TLR-2) associated with a higher risk of EOC and a second panel of four immune checkpoints (CD40, HVEM, PD-1, PD-L1) that may help physicians to identify EOC patients who are at high risk of developing resistance to EOC chemotherapy.

Pathologic complete response to neoadjuvant imatinib of a gastric stromal tumor with concomitant mutations in KIT: A case report and literature review.

Key clinical message: We report the first case of pathologic complete response (pCR) to neoadjuvant imatinib in a gastric stromal tumor harboring KIT mutations in both exons 11 and 9. The significance of this co-occurrence is unknown and might increase the responsiveness of gastrointestinal stromal tumors (GISTs) to imatinib. Abstract: pCR of GIST to neoadjuvant imatinib is rare. We report a case of pCR to neoadjuvant imatinib in a gastric stromal tumor that harbored co-occurrence of multiple KIT mutations in exons 11 and 9. This co-occurrence in exons 9 and 11 is the first to be reported in the English literature.

Clinico-Epidemiological Profile, Prognostic Factors and Treatment Outcome of Refractory Hodgkin Lymphoma.

Approximately 5-10% of patients with Hodgkin lymphoma are refractory to initial treatment. The aim of our study was to assess the clinico-epidemiological profile, prognostic factors and treatment outcome. A retrospective study was conducted over a period of 12 years between June 2006 and January 2018 at the oncology department of Salah Azaïz Institute. Thirty-one patients were included. The median age was 27 years with a female predominance (sex ratio = 0.93).The majority had an advanced stage (61%). IGEV regimen was the most commonly used salvage chemotherapy (n = 14). Age above 30 years was predictive of treatment failure after salvage therapy (p = 0.003). IGEV regimen showed better results than ICE protocol in terms of response to salvage therapy (p = 0.048). Seven patients had salvage radiotherapy. Four patients had autologous stem cell transplant. Progressive disease (n = 12) was the main cause of non-eligibility of autologous stem cell tansplant. Overall survival and progression free survival at 3 years were 50% and 5% respectively. The prognostic factors influencing the overall survival were age above 30 years (p = 0.001), advanced Ann Arbor stage before progression (p = 0.02), advanced Ann Arbor stage of refractory Hodgkin lymphoma (p = 0.001), histological subtype (p = 0.001), CD20 expression (p = 0.027) and non-response to salvage therapy (p = 0.004). The prognostic factor influencing progression free survival was the non-response to salvage therapy (p = 0.045). The prognosis of refractory Hodgkin lymphoma remains poor. The current standard secondary treatment consists of combination therapy, usually followed by autologous stem cell transplantat. Innovative therapies are needed to improve the prognosis of refractory Hodgkin lymphoma. Supplementary Information: The online version contains supplementary material available at 10.1007/s12288-021-01463-4.

Intra-abdominal cystic lymphangioma in adults: A case series of 32 patients and literature review.

Introduction: Cystic lymphangioma (CL) is a benign tumor originating from the lymph vessels. Lymphangiomas in the abdominal cavity are extremely rare, particularly in adults.This article was designed to study the epidemiological, diagnostic difficulties, and therapeutic principles of intra-abdominal cystic lymphangioma (ACL) in adults. Material and methods: We conducted a single-center, retrospective study of 32 adult patients with ACL admitted to surgical department "A" in "La Rabta Hospital" in Tunis, from January 1998 through December 2020. The demographic, clinical, biological, radiological characteristics, histopathologic, and therapeutic data were collected, as well as the surgical intervention used and the postoperative immediate and late complications. Results: Thirty-two adult patients with ACL were recruited, including 20 females and 12 males. The median age at treatment was 47 (range 14-80) years. The most prevalent sites were the retroperitoneum (25%), the mesentery (21.9%), and the paracolic gutters (n = 18. 7%). Twenty patients underwent open surgery (62.5%), whereas 12 cases (37.5%) had laparoscopic surgery. Twenty-eight patients received total cystectomy (87%). Three recurrences were observed during follow-up (9.4%). Conclusion: The clinical features of CL in adults remain unclear. The diagnosis is only confirmed by histopathological examination after complete surgical resection. The laparoscopic approach is considered safe and feasible.

Current Opinion and Practice on Peritoneal Carcinomatosis Management: The North African Perspective.

Background: The status of peritoneal surface malignancy (PSM) management in North Africa is undetermined. The aim of this study was to assess and compare current practice and knowledge regarding PSM and examine satisfaction with available treatment options and need for alternative therapies in North Africa. Methods: This is a qualitative study involving specialists participating in PSM management in North Africa. The survey analyzed demographic characteristics and current knowledge and opinions regarding PSM management in different institutions. We also looked at goals and priorities, satisfaction with treatment modalities and heated intraperitoneal chemotherapy (HIPEC) usefulness according to specialty, country, years of experience, and activity sector. Results: One-hundred and three participants responded to the survey (response rate of 57%), including oncologists and surgeons. 59.2% of respondents had more than 10 years experience and 45.6% treated 20-50 PSM cases annually. Participants satisfaction with PSM treatment modalities was mild for gastric cancer (3/10 [IQR 2-3]) and moderate for colorectal (5/10 [IQR 3-5]), ovarian (5/10 [IQR 3-5]), and pseudomyxoma peritonei (5/10 [IQR 3-5]) type of malignancies. Good quality of life and symptom relief were rated as main priorities for treatment and the need for new treatment modalities was rated 9/10 [IQR 8-9]. The perceived usefulness of systemic chemotherapy in first intention was described as high by 42.7 and 39.8% of respondents for PSM of colorectal and gastric origins, while HIPEC was described as highly useful for ovarian (49.5%) and PMP (73.8) malignancies. Conclusions: The management of PSM in the North African region has distinct differences in knowledge, treatments availability and priorities. Disparities are also noted according to specialty, country, years of expertise, and activity sector. The creation of referral structures and PSM networks could be a step forward to standardized PSM management in the region.

Polymorphisms in NQO1 and MPO genes and risk for bladder cancer in Tunisian population.

BACKGROUND: NAD (P) H: quinone oxidoreductase (1) (NQO1-HGNC: 2874) and myeloperoxidase (MPO-HGNC: 7218) are two enzymes involved in phase II of the xenobiotic metabolism pathway. METHODS: In this study, a case-control analysis was conducted to investigate the relationship between genetic variations in the NQO1 (C609T, rs1800566; IVS1-27 C >G, rs689452) and MPO (G463A, rs2333227) genes and the risk for bladder cancer among Tunisian population. RESULTS: We have found that the MPO 463GA genotype was associated with a decreased risk of developing bladder cancer (p = 0.049; OR = 0.696; 95% CI 0.484-0.999). In contrast, we have found that the NQO1 609CT genotype could increase the risk of bladder cancer patients (p = 0.0039; OR = 1.454; 95% CI = 1.017-2.078). Moreover, patients with "NQO1 609 CT/IVS1-27 CG" genotype show a 2.180-fold increasing risk for developing bladder cancer in comparison to the control group with wild genotype. This OR is estimated at 5.6-fold in smokers patients with "NQO1 609 CT/IVS1-27 CG" genotype. Lastly, study findings suggest that the NQO1 IVS-27 *CG genotype (rs689452) is associated with a risk of progression to muscle invasive bladder cancer. CONCLUSION: Our study suggests that environmental risk factors in association to NQO1 genotypes (NQO1 609 CT/IVS1-27 CG) play an important role in the development of bladder cancer in Tunisian population.

Pancreatic Metastasis of Renal Cell Carcinoma: A Surgical Indication for a Disseminated Disease.

Pancreatic metastasis (PM) of renal cancer is a rare condition. It is characterized by a long period after initial nephrectomy and a favorable prognosis compared to other pancreatic malignancies. Its diagnosis may confuse clinicians if the medical history is not known. In the era of targeted therapies for metastatic renal carcinoma, surgery stands as the best treatment option for PM of renal cancer. We report the case of a woman who underwent successfully left splenopancreatectomy for corporeal PM of renal cancer treated seven years ago. This case underlines the necessity of long-term follow-up of patients treated for kidney cancer.