Dosimetry of soft tissue sarcoma of the calf using the 3D interstitial
brachytherapy technique
Ancuţa Elena Baciu1,2, Mădălina Croitoriu1, Simona Lupu1, Diana Cipu1, Amalia Constantinescu1, Mircea Savu1, Şerban Marinescu1,
Ana-Maria Galca1, Costina Diaconu1, Georgiana Chirt1, Bogdan Cosmin Tănase1,3, Andreea Ionescu2
1. “Prof. Dr. Alexandru Trestioreanu” Institute of Oncology, Bucharest, Romania
2. Faculty of Physics, University of Bucharest, Romania
3. “Carol Davila” University of Medicine and Pharmacy, Bucharest, Romania
Purpose of the work. To evaluate the efficacy of temporary interstitial brachytherapy (TIBT) for patients undergoing combined treatment of soft tissue sarcomas (STS). Clinical case. We present the case of a 62-year-old female patient diagnosed with sarcoma of soft tissue and other parts of the leg. She has been operated three times, the last surgery in August 2022 in the “Prof. Dr. Alexandru Trestioreanu” Institute of Oncology (IOB). Evaluation, diagnosis and treatment were carried out with the efforts of a multidisciplinary team, including radiotherapist, radiologist, surgeon, anesthesiologist, nurses and medical physicists for the planning and treatment part. After the surgical steps and subsequent assessments, the patient was transferred to the radiotherapy ward for further irradiation treatment. Materials and working methods for brachytherapy treatment technique. 1) Patient preparation before the treatment plan was carried out by using: interstitial catheters, recognition markers, ruler, radiopaque markers, all sterile. 2) For reconstruction and delineation of target volume and organs at risk: scanning of the region of interest with the help of the CT-simulator computer in the radiotherapy department. 3) Making the 3D computerized treatment plan and applying daily treatment. The dedicated menu of the Eclipse software was used to perform the treatment plan, with the prescribed dose and the evaluation of the doses received by the organs at risk. Treatment application was performed with the GammaMed Plus HDR brachytherapy machine, using the radioactive source of Iridium-192. Clinical case description. The surgical treatment included wide local excision of the primary tumor in the operating theatre of the IOB, followed by insertion of six interstitial catheters 1 cm apart. Interstitial brachytherapy treatment was delivered over for days, two times per day, with 4 Gy per fraction. CT simulation was used to obtain information on the position of the catheters, target volume to be treated and organs at risk. Image acquisition, with the aid of simulator CT, allowed a three-dimensional dosimetry of the implant. Radiopaque markers or clips placed at the time of surgery helped the physician to delineate the target volume. Clinical dosimetry results. The presentation of axial isodose curves, dose-volume histogram (DVH) data and virtual images facilitated the understanding of target doses and allowed the placement of dose constraints on normal tissue. Implant quality can be measured in terms of D90 (dose at 90% of CTV), V100 (percentage of CTV receiving 100% isodose), V150 (percentage of CTV receiving 150% isodose). Normal tissue dose constraints are derived from DVH data, which are represented as doses at different volumes, such as D0.1cc, D1cc and D2cc. Dosimetry for HDR based on CT images of the volume to be treated is optimally based on the prescribed dose in the target volume or it can be calculated, at a point of 5 mm from the catheters. Preliminary conclusions. Intraoperatively, the steps went according to plan, with a medical physicist taking part. Throughout the radiotherapeutic treatment, the patient was properly cared for in septic conditions and sterile dressings after each treatment session. Prior to the administration of HDR treatment, the patency, position and integrity of the implant catheters should be checked daily as part of the radiological safety process in the transfer of the radioactive source through the catheters. Temporary postoperative interstitial brachytherapy with Ir192 with or without EBRT after function-preserving surgery results in a satisfactory outcome in patients with STS. High dose-rate interstitial BT has an optimal response in terms of disease control and complications when used alone or in combination with EBRT. BT results in fewer complications compared to the combination of BT and EBRT. It is important to have regular assessment of the patient by the surgeon and radiotherapist. Multidisciplinary team collaboration is the key to the success of interstitial brachytherapy throughout the medical procedures and in subsequent evaluations. There are limited data in the literature to equate DVH parameters with local control or toxicity outcomes.
Keywords: 3D brachytherapy, interstitial, leg sarcoma
Managing perioperative bleeding in surgical patients: the power of thrombelastography
Adriana Bene, Alexandra Chirvase, Liliana Coman, Costina Diaconu, Leonard Dobre, Elena Moisescu, Dayana Nechita, Monica Olaru, Carmen Pantiş, Sorela Rădoi, Marilena Moroşan, Luminiţa Udrea, Jeanina Vâlcea, Carmen Zamfir
“Prof. Dr. Alexandru Trestioreanu” Institute of Oncology, Bucharest, Romania
Perioperative bleeding is a common complication in surgical patients and can have significant consequences if not managed effectively. Viscoelastic and conventional coagulation tests are commonly used to assess coagulation status and guide the use of blood products and pharmacological coagulation products. In this study, we aimed to analyze our management of difficult hemostasis situations in surgical patients by reviewing current guidelines and evaluating our use of coagulation tests and hemostatic interventions in major surgery cases. We analyzed our management of difficult hemostasis situations in our practice. Our findings suggest that the use of viscoelastic coagulation tests (VCT) in oncologic patients, despite not being supported by current guidelines, is helpful in guiding our therapeutic approach. Additionally, the use of VCT may have economic benefits by reducing the need for unnecessary blood transfusions and other interventions. Further studies are needed to establish clear indications for the potential use of VCT in this patients’ population. Our study highlights the importance of individualized patient management and the potential benefits of incorporating VCT into the management of perioperative bleeding in surgical patients.
Keywords: perioperative bleeding, viscoelastic coagulation tests, oncologic surgery, hemostatic interventions, coagulation status
Dynamic variation of the T lymphocyte’s subsets, B lymphocytes and NK cells during nivolumab therapy in cutaneous melanoma patients
Lucica Mădălina Bolovan1, Laurenţia Nicoleta Galeş1, Adina Elena Stanciu1, Antonela Buşcă1, Marieta Elena Panait1,
Lorelei Irina Braşoveanu2
1. “Prof. Dr. Alexandru Trestioreanu” Institute of Oncology, Bucharest, Romania
2. “Ştefan S. Nicolau” Institute of Virology, Bucharest, Romania
Introduction. Cutaneous melanoma (CM) is one of the most immunologic malignancies. Immune checkpoint inhibitors (ICI), such as nivolumab, are specific monoclonal anti-PD-1 antibodies used to block the interaction of the PD-1 receptor with the PD-L1 ligand, in metastatic melanoma therapy. The aim of the study was to evaluate the peripheral blood lymphocytes, respectively: T (CD3+) lymphocytes, B (CD19+) lymphocytes, helper/inducer T (CD3+CD4+) lymphocytes, suppressor/cytotoxic T (CD3+CD8+) lymphocytes, helper/suppressor T-lymphocyte ratio (CD3+CD4+/CD3+CD8+) and natural killer (NK) (CD3-CD16+CD56+) as potential predictors of ICI treatment response in advanced stages in CM patients. Methodology. In the study group, there were included 20 patients treated with nivolumab for advanced cutaneous melanoma. The samples were collected in an interval of one month to a maximum of three months between collection, at least four blood samples for each monitored patient. A total of 96 samples of peripheral blood were collected for all study groups. Also, there were constituted the baseline and control groups. The immune cells lymphocytes subsets were quantified by flow cytometry analysis, using BD Simultest TM IMK Plus Kit (BD Bioscience, USA). Results. Our findings revealed that, during immunotherapy with nivolumab, CD3+ T cells and CD16+CD56+ NK cells registered a moderate increase in 65% of cases and 92.30% of cases, respectively. Conversely, the percentage for CD19+ B cells decreased in 76.92% of cases, the decreasing of the CD19+ B lymphocytes being compensated by the increase of NK cells. Also, CD4/CD8 ratio decreased in 85% of cases, this descendent trend being explained by the increasing of CD8 cells expression. It was noticed that for those patients who registered positive response to the nivolumab therapy, the T lymphocyte CD3+ subset tended to increase in 71.42% of cases, while 86% of patients had CD4+/CD8+ ratios >1. Also, in all those patients with a favorable evolution, CD16+CD56+ NK had an increasing trend. Conclusions. The dynamic follow-up of lymphocyte parameters during nivolumab therapy could provide reliable information regarding the therapy outcomes.
Keywords: melanoma, lymphocytes, immunotherapy
ARS-CoV-2: a retrospective analysis of genetic and immunochromatographic testing
in the molecular biology laboratory
Daniela Chiriac1, Corina Elena Mihalcea1, Anita Cristina Ionescu1, Cristina Doina Niţu1, Daniela Frăţilă1, Daniela Glăvan1
“Prof. Dr. Alexandru Trestioreanu” Institute of Oncology, Bucharest, Romania
At the end of 2019, a new coronavirus was identified in the Southern region of China, later named Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). The disease generated by this virus spread very quickly throughout the world, and in March 2020 the World Health Organization declared the COVID-19 pandemic. The pandemic affected all areas of daily life, including medical care. The oncology departments were deeply affected by the pandemic, causing delays in the diagnosis of people with tumor suspicion and in the treatment of oncology patients. Thus, the mortality rate has increased. Objective. A brief statistical analysis of the COVID-19 cases tested in the Molecular Biology Department of the “Prof. Dr. Alexandru Trestioreanu” Institute of Oncology, Bucharest, during 2020-2022. Materials and method. A number of 46,921 tests to identify SARS-CoV-2 were performed. A high throughput extraction of viral RNA from the nasopharyngeal exudate was done using the KingFisher Flex instrument (ThermoFisher Scientific) and the MagMAX Viral/Pathogen II (MVP II) Nucleic Isolation kit (ThermoFisher Scientific). Manually viral RNA extractions were done with the NucleoSpin Dx Virus kit ( Mackerey-Nagel). The reaction mixture for amplifying the target sequences was made with the Allplex 2019-nCoV Assay (Seegene), GeneProof SARS-CoV-2 Screening PCR (GeneProof) and Allplex SARS-CoV-2 Assay (Seegene) kits. The plates with the RNA samples and the reaction mixture were amplified on CFX96 C1000 Touch Thermal Cycler (BioRad) and LightCycler 480 II (Roche) instruments. Rapid immunochromatographic SARS-CoV-2 antigen rapid kits (Roche SD Biosensor) were also used. Results and conclusions. Of the 46,921 tests, 45,367 (96.7%) were RT-PCR and 1554 (3.3%) were rapid antigen tests. 94.89% of the total RT-PCRs were performed on samples collected from our patients, and the remaining 5.11% were performed on request. A percentage of 4.06% (1843) of the samples were SARS-CoV-2 positive, 1.53% (696) results were inconclusive and 0.1% (44) tests were invalid. Most of the samples were negative (94.31%). The presence of the virus was detected in 1941 of the cases: 1843 confirmed by RT-PCR and 98 by rapid antigen test (rapid antigen tests were 100% correlated with RT-PCR). Of the 1941 positive results, 1271 were oncological patients and the rest were employees and individuals tested on requests. In our study, we observed the long COVID phenomenon in 12 patients, with a positive test between 4 and 12 weeks. Thirty-six of the patients were reinfected. We do not have a complete record regarding their vaccination status. The clinical and pathological features of the patients with tumor diseases tested positive included a median age of 58 years old (0-91 years old), and the gender distribution was 63.8% women and 36.2% men. Regarding the tumor incidence, the most common were breast tumors (25%), followed by genital tumors (13.8%), lung tumors (12.2%) and colorectal tumors (11.4%). The rest of the cases had other tumor localizations: thyroid, lymphoma, gastric, skin, central nervous system, as well as other non-tumoral diseases. At the time of diagnosis with SARS-CoV-2, 4.5% of the patients had metastases and 0.79% had multiple tumors. During the study, 103 (8.1%) of the oncologic patients who were diagnosed with COVID-19 died. It should be mentioned that we did not make a correlation between the cause of death and the date on which they were diagnosed. The mortality rate was 7.6% for women and 8.9% for men. The study showed that the highest incidence of deaths was observed in patients with lung tumors, followed by patients with breast cancer, gastric tumors, lymphomas, otorhinolaryngology and colorectal cancer. An increased number of deaths was also observed in patients with metastases, as well as in those with non-oncological conditions. Due to the fact that the number of tests is very large, the presented results are preliminary and require further studies.
Keywords: SARS-CoV-2, COVID-19, RT-PCR, cancer
All for one – a cluster of four malignant cell types in a primary lung cancer
Anca-Pati Cucu1, Oana Adriana Porumbiţă1, Adrian Ciuche1,2, Claudiu-Eduard Nistor1,2
1. Thoracic Surgery Clinical Department, “Dr. Carol Davila” Central Emergency University Military Hospital, Bucharest, Romania
2. “Carol Davila” University of Medicine and Pharmacy, Bucharest, Romania
Introduction. Along with the new classification of lung tumors, World Health Organization (WHO) has been successful in providing a better insight into the molecular profile of lung cancer, allowing for more precise diagnosis and targeted treatment. Emerging oncological therapies have gained attention in recent decades and allowed for a better management and improved quality of life in lung cancer patients. Materials and method. We present the case of a 70-year-old man with a solitary lung tumor who underwent lung wedge resection. The pathology report confirmed the malignant nature of the tumor which displayed no less than four different malignant cell types: small cell neuroendocrine carcinoma, large cell neuroendocrine carcinoma, lung adenocarcinoma, and lung pleomorphic carcinoma. Results. We discuss the new data from the 2021 WHO classification of lung tumors, as well as the management options in such cases. The scarce literature data on combined neuroendocrine lung cancer shows that single-cell lung cancers have longer survival. Nevertheless, there are two types of combined neuroendocrine lung carcinoma – small cell and large cell – with the latter having a better prognosis. Usually, there is an association between large cell neuroendocrine lung carcinoma and another histological type. In such patients, oncological treatment targeting the predominant cell type is beneficial after surgery. The specificity of this case is the coexistence of four different histological types within a solitary lung tumor. Conclusions. Although there are no guidelines for combined lung cancer cell types, they are found in up to 25% of cases. For these patients, the key to effective oncological management is to recognize the presence of multiple cell types, ideally increasing the chances of improved response.
Keywords: combined large cell lung neuroendocrine lung cancer (combined LGNEC), combined small cell neuroendocrine lung cancer (combined SCNEC), lung adenocarcinoma, lung pleomorphic carcinoma
Software-aided gene expression analysis
Iolanda Dumitrescu
“Prof. Dr. Alexandru Trestioreanu” Institute of Oncology, Bucharest, Romania
Objective. The determination of the expression level of a gene in one tissue over another may be critical in the context of evaluating its importance in normal function or disease processes, in highlighting whether a particular gene product might have potential as a future drug target. In the conditions of high-throughput experiments, software-aided gene expression analysis is mandatory. Methodology. We considered some techniques for the determination of the pattern of genes expressed: sequencing-based approaches, allowing profiling of all active genes; microarrays-based approaches, measuring the relative activity of previously identified target genes; text mining approaches, considering biomedical repositories. Results. Serial analysis of gene expression (SAGE) was analyzed in the first case. As bioinformatic resources and software tools we find a public repository for high-throughput molecular abundance data, which are primarily gene expression data, at the National Center for Biotechnology Information (NCBI, NIH, USA) and one at the EMBL’s European Bioinformatics Institute (EMBL-EBI). For microarrays-based approaches, repositories and software tools from the National Human Genome Research Institute (NHGRI, NIH, USA) and EMBL-EBI were considered. The main steps in software analysis are: image processing; normalization; dimensionality reduction; statistical analysis to identify differentially expressed genes; microarray data classification. The text mining repositories considered – one at NLM, USA, and the other one at his European partner – revealed a preference for reporting differentially expressed genes that are overexpressed rather than underexpressed, are overexpressed in multiple diseases, or are popular in the biomedical resources at large. Conclusions. Experimental techniques for gene expression measurements must be combined with informatic tools and mathematical-modeling tools.
Keywords: gene expression, SAGE, microarray, bioinformatic software, biomedical text mining
A rare benign soft-tissue tumor with an unusual localization
Adina Ene1, Ariana Neicu1, Roxana Pridie1, Cristina Guti1, Mădălina Radu1, Constanţa Ioniţă1, Luiza Tomescu1,2, Mihai Ceauşu1,2
1. “Prof. Dr. Alexandru Trestioreanu” Institute of Oncology, Bucharest, Romania
2. “Carol Davila” University of Medicine and Pharmacy, Bucharest, Romania
Objective. Hibernoma is a rare, slowly-growing benign tumor derived from brown fat, with an incidence of less than 2% of all benign lipomatous tumors, frequently involving the thigh, shoulder, back, neck and the chest wall. This report describes the case of a 66-year-old female who presented with a palpable but painless mass in the left axillary region. MRI revealed a well-defined tumor consistent with a lipoma, measuring 11 cm in diameter. Materials and method. Left axillary wide local excision was performed. The tumor was lobulated and well demarcated, with a homogenous yellow-brown cut surface and soft consistence. The specimen was processed and examined by standard H&E. Results. The H&E slides showed a well-defined neoplastic proliferation of large polygonal brown fat cells with abundant eosinophilic, granular and multivacuolated cytoplasm and small nuclei centrally and peripherally located, admixed with a variable amount of mature adipocytic cells. The tumor cells were arranged in a diffuse pattern and were associated with rich vascularization, thin fibrous septa and focal hemorrhage. The surgical margins were negative. Conclusions. The histological aspects were consistent with the diagnosis of a hibernoma – a rare benign adipocytic tumor. The particularity of this case is the presence of a brown fat tumor in an old female, with atypical localization in the axillary region.
Keywords: hibernoma, benign tumor, brown adipose tissue, atypical localization
Adenomatoid tumor of the uterus: an incidental finding worth being aware of
Ioana Eliza Găianu1, Robert Roşca1, Luiza Tomescu1, Ariana Neicu2, Adina Ene2, Cristina Guti2, Roxana Pridie2, Mădălina Radu2, Constanţa Ioniţă2, Mihai Ceauşu2
1. University Emergency Hospital Bucharest, Romania
2. “Prof. Dr. Alexandru Trestioreanu” Institute of Oncology, Bucharest, Romania
Objective. Adenomatoid tumors are benign tumors of mesothelial origin. They can be found both in males and females. In males, they are usually located in testis and epididymis. In women of reproductive age, they can be found (with an incidence of 1% to 5%) within the uterus, fallopian tube and ovary, in the form of a small nodule, with usually less than 1 cm in diameter, often as an incidental finding. We present the case of a 54-year -old woman with an adenomatoid tumor found incidentally in a uterus resected for an endometrial adenocarcinoma. While adenomatoid tumors are benign entities, they can be a diagnostic challenge if one is not aware of their existence. Materials and method. The specimen (total hysterectomy with bilateral salpingo-oophorectomy) was received in our laboratory and fixed in 10% buffered formalin. Upon sectioning, the uterine cavity showed a tan white friable tumor mass that seemed to invade less than half of the myometrium. The presence of the adenomatoid tumor was not readily apparent on gross inspection. Results. The main diagnosis was well differentiated endometrioid carcinoma which was invading less than half of the myometrium. A second lesion was discovered nested in the uterine wall, a relatively well circumscribed nodule measuring 0.9/0.5 cm. The tumor consisted of vague, haphazardly arranged tubules and cords of varying size and shape, lined by cuboidal or flattened cells, occasionally creating cyst-like spaces. The cells had bland nuclei, pale eosinophilic or clear cytoplasm and no mitotic activity. The tumor was admixed with collagen fascicles and smooth muscle. The IHC panel revealed loss of MLH1 and PMS2 in the endometrioid carcinoma and preservation of MSH2 and MSH6. Estrogen and progesterone stains were diffusely and strongly positive, while p53 showed a wild-type phenotype. WT1 was negative and p16 showed patchy stain. The second tumor stained positive for mesothelial markers calretinin and WT1, being negative for hormone receptors. Conclusions. The final main diagnosis was that of a well differentiated endometroid carcinoma invading less than half of the myometrium, but with metastasis/occult extension into the Douglas uterine pouch, therefore the tumor was upstaged to Pt3a. The IHC panel showed microsatellite instability and prompted for further testing for methylation of MLH1 promoter. A second diagnosis was represented by a benign entity of mesothelial origin, an adenomatoid tumor of the uterus, confirmed by the stains for mesothelial markers calretinin and WT1. Although a benign neoplasm, this rare benign tumor can pose diagnostic challenges due to its appearance on HE. It can potentially mimic an adenocarcinoma or a vascular tumor, or it can mimic the extension of adenocarcinoma deep within the serosal flank of the uterine wall, due to its morphology (gland-like structures and tubules). Awareness of this lesion and mesothelial markers are helpful in this setting.
Keywords: adenomatoid tumor, benign, mesothelial, incidental
The molecular classification of endometrial carcinomas and its subsequent
clinical implications
Vlad Lupu1,2, Cristina Oprean1,2,3
1. ANAPATMOL Research Center, “Victor Babeş” University of Medicine and Pharmacy, Timişoara, Romania
2. Department of Oncology, OncoHelp Hospital, Timişoara, Romania
3. Department of Oncology, Oncomed Outpatient Unit, Timişoara, Romania
Objective. Currently, the 5th Edition of the WHO Classification of Female Genital Tumors (WHO-C), published in 2020, is the one used in pathological reports across the globe. This edition introduces the TCGA Molecular Classification of Endometrial Cancer (TCGA-CEC), with its four subtypes: POLE-mut, dMMR, no special molecular type (NSMT) and p53 aberrant, but only applies it to the endometrioid tumors. Our objective is to highlight the importance of expanding on the TCGA classification and its clinical importance. Materials and method. We conducted a systematic search on Web of Science and PubMed databases on the subject of the TCGA-CEC, its subtypes and the therapeutic implications, and we analyzed the data in conjunction with the NCCN and ESMO guidelines, and WHO-C. We identified areas that require further expansion in future editions of these guidelines, as well as the subsequent clinical implications. Results. While sequencing (either NGS or Sanger) is needed for identifying POLE mutations, the dMMR and p53 aberrant subtypes can be diagnosed through immunohistochemistry surrogates. POLE-mut tumors have an extremely low recurrence rate (below 4%) and do not benefit from any form of adjuvant therapy if completely resected. They benefit from anti-PD-L1 immunotherapy due to being TMB-high. However, while their prognosis is excellent, 53% of these tumors are G3, thus being at the risk of overtreatment if sequencing is not performed. dMMR tumors also benefit from anti-PD-L1 immunotherapy. p53 aberrant tumors have the worst prognosis and comprise the only subtype that benefit from adding chemotherapy to radiation therapy in the adjuvant setting. Conclusions. We conclude that the TCGA-CEC should be expanded to all endometrial carcinomas in the future edition of WHO-C. It can and should be used in adjuvant therapy decisions and brings important prognostic elements. We consider that the molecular subtyping brings important supplementary information and should be performed whenever available. We expect a decrease in NGS cost in the coming years, further helping with the implementation. Meanwhile, we suggest performing IHC for identifying at least dMMR and p53 aberrant tumors.
Keywords: endometrial carcinoma, molecular classification, TCGA, POLE-mutated, p53 aberrant, adjuvant treatment, recurrence, immunotherapy