Sarcoma Research Articles

Extra-skeletal osteosarcoma (ESOS) is a rare neoplasm that represents less than 2% of all soft tissue sarcomas. Common reported sites of involvement include limbs, retroperitoneum, chest wall and buttocks. ESOS arising primarily in parenchymatous organs are extremely uncommon, with the involvement of the urinary bladder is even rarer. We herein report a case of primary ESOS of the urinary bladder in a 48 year-old male patient. J Med Cases. 2021;12(7):280-283 doi: https://doi.org/10.14740/jmc3613

BackgroundMesenchymal sarcomas are tumors that originate from mesenchymal tissue. Most mesenchymal sarcomas can be accurately classified, but some are unclassifiable in clinical practice. Molecular detection methods enable patients to benefit from molecular-targeted therapies for many cancers, including lung, breast, and bowel cancers. Further, even unclassified tumors can have therapeutic targets. NTRK gene fusions are sporadic genetic alterations that occur across tumor entities. If NTRK gene fusions are detected, TRK inhibitors can be used regardless of the tumor entity.Case presentationThis report describes a case with an unclassifiable mesenchymal sarcoma carrying a neurotrophic tyrosine receptor kinase NTRK1-KHDRBS1 gene fusion that was diagnosed and treated at multiple hospitals. Diagnostic work-up included pathological and immunohistochemical analysis, which excluded angiosarcoma, dendritic cell sarcoma, and pseudomyogenic hemangioendothelioma. The patient achieved a long-term survival without tumor relapse after treatment with crizotinib.ConclusionsThis case will be of significant interest to pathologists because, despite the tumor being unclassified, a molecular target was identified. Although the FDA does not currently approve crizotinib for treatment of patients harboring NTRK gene fusions, this case provides new insights for diagnosis and treatment of mesenchymal sarcomas with NTRK1 gene translocations. Similar to ALKomas, which can be successfully treated using NTRK molecular-targeted therapy, tumors with NTRK gene translocations can be classified as NTRKomas, even when they occur at different organ sites, and with varying histological morphologies, and immunophenotypes.

Background Majority of children with cancer live in low and middle-income countries (LMIC) where survival is disproportionately low compared to high-income countries (HIC). Among the challenges of managing childhood cancers in LMIC is late presentation, advanced disease, and the prevalence of severe malnutrition. Advanced disease and severe acute malnutrition are associated with poor treatment outcomes. Methodology This was a descriptive study conducted in Tanzania at Ocean Road Cancer Institute (ORCI) in 2010. Children and adolescents below 18 years were longitudinally enrolled in the study. Pathological diagnosis was made by examination of tissue biopsies, fine needle aspiration (FNAC) or bone marrow aspiration cytology (BMAC). Stage of disease at presentation was determined by physical examination and radiological investigations such as chest x-ray and ultrasonography. World Health Organization (WHO) anthropometric measurement chart was used to interpret measured Mid-upper arm circumference (MUAC) for age. Body mass index (BMI) is affected by tumour weight hence was not used to assess malnutrition in this study. Results One hundred and fifty-one (151) patients were enrolled in the study. The mean age at presentation was 5.8 years (range 3-17years), and 51.7% of participants were males. Three quarters (76.6%) of patients attended the first health facility within a month of onset of symptoms, but forty per cent (40%) of patients took six (6) months to reach ORCI for treatment. Eighty-six percent (86%) of patients presented with advanced disease (50.8% - locally advanced, 35.1% - metastatic disease). Metastatic disease was more frequent in patients with Neuroblastoma (NB) and Non Hodgikins Lymphoma (NHL) (66.6% each), Burkitt’s lymphoma (BL) (50%), Soft tissue sarcoma (STS) (40%) and Wilm’s tumour (WT) (35.3%). Severe wasting was seen in 12.6% of patients, and more prevalent among patients with BL (31.3%) and WT (25%). Conclusion Even though most patients sought health care early, they reached ORCI late with advanced disease (86%), and 12.6% had severe acute malnutrition. Keywords: Children, Cancer, Advanced Disease, Malnutrition.

Background Majority of children with cancer live in low- and middle-income countries. The data is scarce on the epidemiology of childhood cancer in these countries. In this study, we enrolled children and adolescents with cancer at the only cancer hospital in Tanzania and determined the epidemiology and HIV infection among this population. Methodology This was a descriptive hospital-based study conducted at Ocean Road Cancer Institute in Dar es salaam, Tanzania. Data were collected for eight months (May to December 2010). Participants were enrolled consecutively as they presented to the hospital. Demographic data, HIV status and clinical diagnosis were determined and recorded. Each patient was followed up until a final diagnosis was reached, and investigations for disease staging were completed. Results One hundred and fifty-one (151) patients were enrolled in the study. Mean age at presentation was 5.8 years (range 3-17years), and 51.7% of participants were males. Sixty-three per cent (63%) of patients had their diagnoses confirmed by histology or cytology. Retinoblastoma was the most common malignancy (29.1%) followed by Nephroblastoma (11.3%), Burkitt lymphoma (10.6%) and Acute Lymphoblastic Leukemias (10.6%). More than half (58.2%) of patients aged three years or younger had Retinoblastoma. Four patients (2.8%) had HIV infection; three of them with Kaposi’s sarcoma and one with Burkitt lymphoma. Conclusion Retinoblastoma was the most typical malignancy followed by Wilms tumour, Burkitt lymphoma and acute lymphoblastic leukaemia. The prevalence of HIV infection was very low among patients with the described malignancies. Key Words: Childhood Malignancies, Tanzania.

ObjectivesDeoxyribonuclease 1 like 3 (DNASE1L3) is critically involved in apoptosis and immune response, however, its role in cancer has yet to be deciphered. We aimed to explore the prognostic value of DNASE1L3 across a series of malignancies.MethodsBased on Oncomine database and Tumor Immune Estimation Resource (TIMER), expression profiling of DNASE1L3 was detailed in malignancies. Using PrognoScan, Kaplan-Meier Plotter, GEPIA2, and bc-GenEcMiner v4.5, prognostic value of DNASE1L3 was estimated in diverse cancers. Based on TIMER, association between DNASEL13 expression and immune infiltration was examined in various cancers. Then, mRNA level of DNASE1L3 in hepatocellular carcinoma (HCC) samples (n=22) and stomach adenocarcinoma (STAD) samples (n=17) was measured with qRT-PCR. Immunohistochemistry was performed to confirm expression of DNASE1L3 in paraffin-embedded tissues of HCC (n=9) and lung adenocarcinoma (n=20).ResultsDNASE1L3 was downregulated in multiple cancers, including breast invasive carcinoma (BRCA), cholangiocarcinoma (CHOL), liver hepatocellular carcinoma (LIHC), and lung adenocarcinoma (LUAD). A lower level of DNASE1L3 correlated with poorer prognosis in various cancers, especially in breast, liver, kidney, stomach, lung adenocarcinoma and sarcoma (SARC). Moreover, DNASE1L3 was positively related to immune cell infiltration in many cancers, including BRCA, LIHC, STAD, LUAD, and SARC. DNASE1L3 was significantly associated with CCR7/CCL19 in cancers. DNASE1L3 was downregulated in HCC and STAD tissues as demonstrated by qRT-PCR, as well as in HCC and LUAD samples, as shown by immunohistochemistry.ConclusionDNASE1L3 has potential to serve as a prognostic biomarker in cancer of the breast, kidney, liver, stomach, lung adenocarcinoma and sarcoma. Down-regulation of DNASE1L3 may participate in immune escape via CCR7/CCL19 axis.

Unique features and treatment effects of trabectedin are presented in consideration of soft tissue sarcoma management. A prolonged time on trabectedin through 59 cycles is shown. This is one of the longer reported uses of trabectedin successfully to control disease. Adjunctive cytoreduction options with surgery, radiation or ablation are presented. Future studies would be helpful to investigate treatment holidays, the impact of multi-modality care and assessment of genetics of clonal metastases. This may assist in guiding and selecting patients for priority treatment with trabectedin. J Med Cases. 2021;12(4):160-163 doi: https://doi.org/10.14740/jmc3655

AimImmune cells that infiltrate the tumor microenvironment (TME) are associated with cancer prognosis. The aim of the current study was to identify TME related gene signatures related to the prognosis of sarcoma (SARC) by using the data from The Cancer Genome Atlas (TCGA).MethodsImmune and stromal scores were calculated by estimation of stromal and immune cells in malignant tumor tissues using expression data algorithms. The least absolute shrinkage and selection operator (lasso) based cox model was then used to select hub survival genes. A risk score model and nomogram were used to predict the overall survival of patients with SARC.ResultsWe selected 255 patients with SARC for our analysis. The Kaplan–Meier method found that higher immune (p = 0.0018) or stromal scores (p = 0.0022) were associated with better prognosis of SARC. The estimated levels of CD4+ (p = 0.0012) and CD8+ T cells (p = 0.017) via the tumor immune estimation resource were higher in patients with SARC with better overall survival. We identified 393 upregulated genes and 108 downregulated genes (p < 0.05, fold change >4) intersecting between the immune and stromal scores based on differentially expressed gene (DEG) analysis. The univariate Cox analysis of each intersecting DEG and subsequent lasso-based Cox model identified 11 hub survival genes (MYOC, NNAT, MEDAG, TNFSF14, MYH11, NRXN1, P2RY13, CXCR3, IGLV3-25, IGHV1-46, and IGLV2-8). Then, a hub survival gene-based risk score gene signature was constructed; higher risk scores predicted worse SARC prognosis (p < 0.0001). A nomogram including the risk scores, immune/stromal scores and clinical factors showed a good prediction value for SARC overall survival (C-index = 0.716). Finally, connectivity mapping analysis identified that the histone deacetylase inhibitors trichostatin A and vorinostat might have the potential to reverse the harmful TME for patients with SARC.ConclusionThe current study provided new indications for the association between the TME and SARC. Lists of TME related survival genes and potential therapeutic drugs were identified for SARC.

CKLF-like MARVEL transmembrane domain-containing 6 (CMTM6) reportedly stabilizes programmed death-ligand 1 (PD-L1) and enhances the efficacy of immunotherapy. However, correlations between CMTM6 expression and the immune microenvironment and its prognostic value remain unknown in a variety of tumors. CMTM6 expression data were obtained from The Cancer Genome Atlas (TCGA) for 33 cancer types classified into high and low expression subgroups according to the median CMTM6 expression value. Pan-cancer analysis of CMTM6 protein expression in 20 tumor types was performed using a cohort from the Human Protein Atlas (HPA). PD-L1 protein expression data were obtained from The Cancer Proteome Atlas (TCPA) for 32 cancer types. Frequencies of CMTM6 copy number alterations and mutations were analyzed using cBioPortal. MANTIS was employed to estimate microsatellite instability in the TCGA cohort. CIBERSORT and the ESTIMATE algorithm were applied to estimate the relative fractions of infiltrating immune cell types and immune scores, respectively. Kaplan–Meier survival curve analysis was performed to assess the pan-cancer prognostic value of CMTM6.CMTM6 is heterogeneously expressed in diverse cancers. Further, the results revealed low CMTM6 mutation frequencies in multiple cancers. Among them, CMTM6 mutation frequency was the highest in uterine cancer. Additionally, CMTM6 expression was related to PD-L1 protein expression in breast invasive carcinoma, cervical squamous cell carcinoma and endocervical adenocarcinoma, cholangiocarcinoma, glioblastoma multiforme (GBM), head and neck squamous cell carcinoma, kidney renal papillary cell carcinoma, sarcoma (SARC), stomach adenocarcinoma, and uterine carcinosarcoma. Increased CMTM6 expression may be associated with increased infiltration of neutrophils in some types of cancer. Finally, pan-cancer analysis indicated that CMTM6 expression was closely related to overall survival in adrenocortical carcinoma, GBM, acute myeloid leukemia, liver hepatocellular carcinoma, mesothelioma, SARC, thymoma, and uveal melanoma. Taken together, these findings highlight that CMTM6 plays an important role in the tumor immune microenvironment, and CMTM6 has been identified to have prognostic value in some types of cancers. Thus, CMTM6 is a potential target for cancer immunotherapy and effective prognostic biomarker.

Background.Undifferentiated embryonal cell sarcoma (UESL) of the liver is the third most common malignant liver disease of childhood presenting as a rapidly enlarging intraabdominal mass. This systematic review explores the practicality of liver transplantation as a viable option in the treatment armamentarium for locally advanced undifferentiated embryonal cell sarcoma.Methods.A systematic review of the literature was performed using Medline and Embase, from inception of databases to December 31, 2018. Keywords and MeSH headings used were embryonal sarcoma, mesenchymal sarcoma, and liver transplant. Reviews and manuscripts with incomplete data were excluded.Results.Twenty-eight patients had orthotopic liver transplantation (OLT) as a curative treatment option. The median age at presentation was 8 and 27 years in the pediatric and adult population, respectively, with a similar male to female ratio. A majority of the patients presented with abdominal pain, palpable mass, and a normal alpha-feto-protein. The median tumor size was 15 cm mainly affecting the right lobe (62%) of the liver. Eighty-two percent of the patients underwent primary OLT and 5 patients had salvage OLT. One death (3.6%) was due to initial misdiagnosis and management for hepatoblastoma. Recurrence was noted in 7.1% of the population. The median follow-up was noted to be 28.5 months. The documented survival rate post-liver transplant for UESL was 96%.Conclusions.Based on available data and the very positive results therein, liver transplantation is a practical and justifiable use of a scarce resource as a treatment option for locally unresectable, undifferentiated embryonal cell sarcoma. The authors propose (accepting existence of different proposals) neoadjuvant therapy before curative resection, and if not achievable, then liver transplantation followed by adjuvant chemotherapy is an option for suitable candidates. For recurrent tumors after surgical resection, adjuvant therapy with salvage liver transplantation is an option.

Advances in the Study of Kaposi’s Sarcoma in Human

Cisplatin, cisplatinum, or cis-diamminedichloroplatinum (II) a well-known chemotherapeutic drug. It has been used for treatment of numerous human cancers including testicular cancer, ovarian cancer, cervical cancer, breast cancer, bladder cancer, head and neck cancer, esophageal cancer, lung cancer, mesothelioma, brain tumors and neuroblastoma. It is given intravenous. It is effective against various types of cancers, including carcinomas, germ cell tumors, lymphomas, and sarcomas. This compound is used as chemotherapeutic agent to inhibit otherwise rapid division of tumor cells (i.e., Proliferation). Chemotherapy is the use of anticancer drugs designed to inhibit growth of rapidly dividing cancer cells in the body. The exact action of this complex is not known. Since the trans-isomer is inactive, therefore chelation or at least co-ordination to donor atoms at cis-positions (i.e., in close proximity) is an essential part of the activity. Its mode of action has been linked to its ability to crosslink with the guanine base on the DNA; interfering with DNA repair mechanisms, causing DNA damage, and subsequently inducing apoptosis in cancer cells. However, because of drug resistance and numerous undesirable side effects such as severe kidney problems, allergic reactions, decrease immunity to infections, gastrointestinal disorders, hemorrhage, and hearing loss especially in younger patients, other platinum- containing anti-cancer drugs such as Carboplatin, Oxaliplatin and others, have also been used. Furthermore, combination therapies of cisplatin with other drugs have been highly considered to overcome drug-resistance and reduce toxicity. This comprehensive article highlights the physicochemical properties of cisplatin and related platinum-based drugs, and discusses its uses for the treatment of different human cancers. A special attention is given to clinical uses, and its side effects.

Ewing’s sarcoma was first distinguished as “diffuse endothelioma of bone”. The cause is still unknown the but mostly theories suggest that these tumors arise from a primitive cell obtained either from an embryologic tissue which is called the neural crest, or from mesenchymal stem cells that are capable to become one of a variety of tissue types. Pathologists have studied that Ewing sarcoma is almost alike to an even rarer soft tissue tumor called primitive neuroectodermal tumor (PNET).ES and PNET were having similar features when observed under microscope, in more than 95% of cases also had a similar genetic abnormality called as translocation. Hence they were grouped into class of cancers entitled Ewing’s Sarcoma Family of Tumor (ESFT).This family includes, Ewing’s sarcoma of the bone, Extraosseus Ewing’s sarcoma, Primitive neuroectodermal tumor (PNET),Peripheral neuroepithelioma, Askin’s tumor and Atypical Ewing’s sarcoma. The translocation in ESFT is between chromosomes 11 and 22 and is referred to as t (11;22). The gene from chromosome 22 encodes the Ewing sarcoma gene (EWS) whose function is not well-understood. The gene FLI1 from chromosome 11, is involved in turning other genes on and off. EWS/FLI is a fused gene, which encodes an altered fusion protein which controls the regulation of other genes that can give rise to cancers when inappropriately expressed.

BackgroundTelomere length is an important indicator of tumor progression and survival for cancer patients. Previous work investigated the associations between genetically predicted telomere length and cancers; however, the types of cancers investigated in those studies were relatively limited or the telomere length-associated genetic variants employed often came from genome-wide association studies (GWASs) with small sample sizes.MethodsWe constructed the genetic risk score (GRS) for leukocyte telomere length based on 17 associated genetic variants available from the largest telomere length GWAS up to 78,592 individuals. Then, a comprehensive analysis was undertaken to evaluate the association between the constructed GRS and the risk or mortality of a wide range of cancers [i.e., 37 cancers in the UK Biobank and 33 cancers in The Cancer Genome Atlas (TCGA)]. We further applied the two-sample Mendelian randomization (MR) to estimate the causal effect of leukocyte telomere length on UK Biobank cancers via summary statistics.ResultsIn the UK Biobank dataset, we found that the GRS of leukocyte telomere length was associated with a decreased risk of nine types of cancer (i.e., significant association with multiple myeloma, chronic lymphocytic leukemia, kidney/renal cell cancer, bladder cancer, malignant melanoma, basal cell carcinoma, and prostate cancer and suggestive association with sarcoma/fibrosarcoma and Hodgkin’s lymphoma/Hodgkin’s disease). In addition, we found that the GRS was suggestively associated with an increased risk of leukemia. In the TCGA dataset, we observed suggestive evidence that the GRS was associated with a high death hazard of rectum adenocarcinoma (READ), sarcoma (SARC), and skin cutaneous melanoma (SKCM), while the GRS was associated with a low death hazard of kidney renal papillary cell carcinoma (KIRP). The results of MR further supported the association for leukocyte telomere length on the risk of malignant melanoma, Hodgkin’s lymphoma/Hodgkin’s disease, chronic lymphocytic leukemia and multiple myeloma.ConclusionOur study reveals that telomere played diverse roles in different types of cancers. However, further validations in large-scale prospective studies and deeper investigations of the biologic mechanisms are warranted.

Ewing sarcoma is typically seen in children involving long bones. Although well described, its presentation in extraskeletal tissues is relatively rare and is classified as an Ewing sarcoma family of tumors. They are mostly curable when they occur in children. An extraskeletal Ewing sarcoma in adults is uncommon, limiting the experience in adult oncologists. The biopsy is essential for definitive diagnosis, which shows small round blue cells that must be differentiated from lymphoma, embryonal rhabdomyosarcoma, and small cell carcinoma. Management is multimodal, involving surgery, radiation for local treatment of primary tumor, and systemic chemotherapy. A multidisciplinary approach, coupled with risk-adapted intensive neoadjuvant and adjuvant multi-agent chemotherapies and other modalities such as radiation and surgery for control of the primary site and metastatic disease, is needed. The primary multidrug chemotherapy regimen consists of alternating cycles of vincristine/doxorubicin/cyclophosphamide (VDC) and ifosfamide/etoposide (IE) given every 2 weeks with growth factor support. Prognosis and the 5-year survival rate are better for localized than the metastatic disease, and in metastatic disease, it is better for patients with lung metastasis than other metastatic disease sites. We describe a rare extraskeletal tumor arising from a lung that tested positive for Ewing sarcoma, also known as Askin’s tumor in a young adult. In our case, the tumor rapidly metastasized locally to involve the thoracic spine causing paraparesis. Timely diagnosis and early management are essential to improve outcomes. We also present how treatment can be delayed due to sepsis and emphasize the careful multispecialty approach’s importance. J Med Cases. 2020;11(12):388-393 doi: https://doi.org/10.14740/jmc3582

Chemoradiotherapy of spinal extradural Ewing sarcoma after the Fontan procedure.

Identification of a survival-related signature for sarcoma patients through integrated transcriptomic and proteomic profiling analyses.

Follicular dendritic cell sarcoma (FDCS) accounts for < 0.4% of soft tissue sarcomas. Only 35 cases of tonsillar FDCS have been reported, and majority had localized presentation. We present a case of FDCS of the tonsil, wherein a well-coordinated trimodality approach provided good disease control in advanced disease. A 53-year-old man presented with a painless and enlarging neck mass of 11-month duration, with no other symptoms. Close examination revealed a 10 × 5 cm mass at the left carotid triangle, and a 3.2 × 2.2 cm mass at the left tonsillar fossa. Imaging revealed the tumor to be unresectable due to its attachment to the great vessels. There were no distant metastases. Biopsy and immunohistochemistry were initially deemed consistent with an undifferentiated sarcoma. Palliative chemotherapy was given using single agent doxorubicin and subsequent dacarbazine, resulting in partial response and stable disease, respectively. Pathological re-evaluation was pursued because of the uncharacteristic slow progression of the tumor, revealing diffuse positivity for CD21 and negative for CD1A and CD34, consistent with FDCS. The patient underwent three cycles of gemcitabine plus docetaxel resulting in 50% regression. This allowed dissection of level IB-V lymph nodes and subsequent radiotherapy for the neck and tonsillar mass, with weekly gemcitabine as a radiosensitizer. Evaluation 8 months post-treatment showed no signs of disease progression. Treatment-related complications included radiation dermatitis and swallowing dysfunction, which both resolved on follow-up. This case highlights the multidisciplinary management of a rare type of sarcoma in an uncommon anatomic location. Precise pathologic diagnosis is important in soft tissue sarcoma because of its therapeutic implications. For FDCS, effective response may still be achieved in the third-line setting. J Med Cases. 2020;11(10):309-316 doi: https://doi.org/10.14740/jmc3551

Mesenchymal chondrosarcoma (MC) is a rare aggressive mesenchymal sarcoma. Specific markers for the differential diagnosis of MCs remain to be developed. OLIG2 expression has been reported only in neuroepithelial tumors. Recently, OLIG2 expression was found to be involved in the development of NCOA2 fusion-positive alveolar rhabdomyosarcomas. Therefore, we investigated whether OLIG2 expression could be used as a diagnostic marker for MC. We report the clinical pathological and immunohistochemical features of 14 MCs. All tumors showed typical pathological features including biphasic patterns with sheets of primitive round mesenchymal cells and interspersed islands of cartilage. These tumors expressed BCL2, SOX9, and CD99. OLIG2 was robustly expressed in 12/14 of MCs. NCOA2 rearrangement was found in 12 cases. OLIG2 expression was not found in the NCOA2 rearrangement-negative MCs. Notably, OLIG2 expression was not detected in 52 neoplasms (8 Ewing sarcomas, 23 hemangiopericytomas, and 21 chondrosarcomas) that are frequently misdiagnosed as MC. Our findings provide convincing evidence that OLIG2 can serve as a reliable marker in the differential diagnosis of MC and may be a unique neurodevelopmental gene expression signature for the NCOA2 rearranged MCs.

Granulocytic sarcoma is a rare solid malignant tumor that occurs in patients with acute myeloid leukemia. As such, granulocytic sarcoma without leukemia occurring in long bones is quite rare. This case report describes an isolated granulocytic sarcoma of the right humerus in an 82-year-old woman in the absence of acute myeloid leukemia. The patient was admitted to our hospital with a pathological fracture of the right humerus. An incisional biopsy was performed, and the pathological diagnosis was granulocytic sarcoma. Radiotherapy (45 Gy) to the humerus resulted in a good clinical outcome with no evidence of myeloid leukemia at 9.5 years of follow-up. Radiotherapy was effective for pain relief and maintenance of good quality of life in this patient. Although laboratory evaluation has not revealed any abnormalities 9.5 years after radiotherapy, periodic observation is required. J Med Cases. 2020;11(8):249-252 doi: https://doi.org/10.14740/jmc3526

Rhabdomyosarcoma (RMS) is a cancer of skeletal muscle origin, and the second most common soft tissue sarcoma encountered in childhood. The head and neck are common sites though the temporal bone is rare. Rhabdomyosarcoma represents 3.5% of all malignancies in children aged 0-14 years, with approximately 250 new cases diagnosed each year. Despite the more intensive management modalities including surgery and combination chemo-radiation, the outcome for patients with metastatic disease remains poor. Here, we report a case of temporal bone Embryonic RMS in a three and half year-old male who was seen at Mulago National Referral Hospital, Kampala in 2016 and describe the clinical, radiological and histopathological presentation of relevance to RMS. Key Words: rhabdomyosarcoma, temporal bone, mesenchymal tissue, parameningeal, chronic suppurative otitis media, multi-modality therapy, Kampala