A physical tug-of-war and the evolution of immune cells.

Antibodies form an important component of our immune response to pathogens. A robust antibody response can lead to the swift clearance of infection. The protection offered by COVID-19 vaccines has been attributed in large measure to the antibodies they elicit (Padmanabhan et al. 2022). Yet, with other pathogens like HIV-1, vaccines that elicit potent antibodies have remained elusive despite intense efforts over decades (Burton 2019). It is important, therefore, to understand how our body mounts a robust antibody response specific to an invading pathogen or vaccine. A remarkable manifestation of Darwinian evolution happens to be at the heart of such a response.

Correlation NKX2.2 IHC and EWSR1 break-apart FISH in the diagnosis of Ewing sarcoma: Can combined NKX2.2 and CD99 immunoexpression obviate or minimize the need of FISH testing? First assessment study from Indian tertiary cancer care center.

Context: Ewing sarcoma (ES) are malignant small round cell tumors (MSRCT) characterized by rearrangements of EWSR1 gene. Although gold standard for diagnosis is detection of specific fusion genes by molecular testing, these ancillary tests are costly and only available in limited number of settings. There is a persuasive evidence for reliability of NKX2.2 immunohistochemistry (IHC) as a surrogate marker for EWSR1 gene rearrangement in ES. Aims: The aim of this study is to correlate the NKX2.2 immuno-expression with genetically confirmed ES cases and also to assess the reliability and accuracy of NKX2.2 along with combined positivity of NXX2.2 and CD99 in diagnosing ES and differentiating it from other relevant histological mimics. Settings and Design: The present study is a retrospective study conducted over a period of 6-year duration in a tertiary cancer care center. Methods and Material: We evaluated NKX2.2 immunoexpression in 35 genetically confirmed cases of ES and also in pertaining differential entities (n = 58) of ES including rhabdomyosarcoma (n = 20), lymphoblastic lymphoma (n = 14), Wilms tumor (n = 10), poorly differentiated synovial sarcoma (n = 4), small-cell osteosarcoma (n = 4), neuroblastoma (n = 5), and mesenchymal chondrosarcoma (n = 1). CD99 was performed in the category of MSRCTs showing NKX2.2 positivity to evaluate combined specificity for the diagnosis of ES. Results: Of the 35 genetically confirmed cases of ES, 29 cases (83%) showed NKX2.2-positive expression (83% sensitivity). Compared to ES, NKX2.2 was positive in only 05% cases (3/58 cases) of non-ES MSRCT. Only two of five cases of neuroblastomas and one case of mesenchymal chondrosarcoma showed NKX2.2 positivity. CD99 positivity was seen in 100% of ES and in the single case of mesenchymal chondrosarcoma. All five cases (100%) of neuroblastoma were negative for CD99. Conclusions: The presented study, which is the first from an Indian oncology center, showed NKX2.2 IHC is quite reliable in diagnosis of ES in the right clinicopathological context. With remarkable sensitivity and specificity of NKX2.2 IHC for diagnosis of ES, we propose that combined positivity of CD99 and NKX2.2 IHC can obviate or minimize the need of EWSR1 gene rearrangement molecular testing for diagnosis of ES.

Analysis of Clinical Outcomes of Patients with Soft Tissue Sarcoma.

The aim of this study was to evaluate the outcome of patients with soft tissue sarcoma of the extremity and abdominal wall. This is the retrospective analysis of patients from a prospectively maintained data base from a single institute. We identified 79 patients with intermediate- to high-grade soft tissue sarcomas who were treated at our institute between Jan 2015 and July 2018. Low-grade tumors were excluded. There were 60 males and 19 females with a mean age of 44.6 years. Of the 79 sarcomas, 50 were in the lower limb and 24 in the upper limb and 5 were in abdominal wall. The commonest subtypes were undifferentiated pleomorphic sarcoma (n = 21) and synovial sarcoma (n = 19). Only 9 patients had metastatic disease at presentation. All 79 patients underwent surgical resection with an intent to achieve clear margins. Amputation was done in 19 patients while wide excision of the tumor was done in 60 patients. Adjuvant radiotherapy was given in 49 patients while adjuvant chemotherapy was given in 35 patients. At last follow-up (73 patients), 48 patients are alive without disease, 9 are alive with disease, 12 patients had died of disease, and 4 patients died due to other causes. Overall survival (OS) for 3 year is 77.6%, and estimated mean survival is 55.05 months. Relapse-free surviva (RFS)l at 3 year is 74.3%, and estimated mean RFS is 51.78. The only independent factor that affected the OS was the dimension of primary tumor (p = 0.02). For disease-free survival, the independent factors that affected outcome were stage at presentation (p = 0.04) and dimension of the tumor (p = 0.04). Short-term results shown by this study shows good outcome in patient with intermediate- to high-grade sarcomas when multidisciplinary approach is utilized for the management. Patients who had metastatic disease at presentation did worse than patients who did not.

Calcific Myonecrosis: Solving the Diagnostic Dilemma.

We report the clinico radiological presentation of an unusual case of an ossified soft tissue mass in the leg in a 74-year-old man. Calcific myonecrosis is a rare soft tissue condition characterized by calcified mass within a compartment. Differential diagnosis of myonecrosis include myositis ossificans and sarcomas with propensity for extra-osseous calcification like extra-skeletal osteosarcoma, Ewing's sarcoma and epithelioid sarcoma. This entity is a late complication to trauma and prolonged high pressure state within the leg compartments. With imaging alone, the differential of soft tissue sarcoma could be ruled out but typical natural history of disease and radiopathological features aided in the diagnosis.

Salvaging the Unsalvageable Giant Cell Tumors of Bone: The 'Longitudinal Sandwich Technique'.

Management of Campanacci Grade III Giant Cell Tumors of bone (GCT) is challenging. Although selected cases of Grade III GCTs can still be managed with intralesional extended curettage, wide excision of the lesion is usually recommended when there is extensive cortical destruction. This study describes the outcome of 'longitudinal sandwich technique' for extended curettage of Grade III GCTs with more than 50% cortical destruction. Here, the deficiency of cortex was made up for by using bone graft/graft substitute, used alongside cement placed in a longitudinal fashion. Twelve patients operated with this technique between Jan 2012 and Jan 2018 were reviewed. Majority of the lesions involved the lower limbs. Bone graft was used in eight whereas commercial bone graft substitute was used in the remaining four, along with bone cement in all. On follow-up ranging from 38 to 84 months (median follow-up 59 months), there were 4 local recurrences (33.33%). All recurrences were managed successfully with repeat surgery without the need for bony resection. Mean MSTS score during the last follow-up was 25.08 ± 2.31 and all patients were disease-free during the last follow-up. 'Longitudinal sandwich technique' helps to expand the indications of extended curettage even for aggressive Grade III GCTs, with satisfactory outcomes.

Epithelioid haemangioma of bone: A series of four cases with a revision of this contentious entity.

Epithelioid hemangioma of bone is a rare and locally aggressive vascular neoplasm of bone associated with a good prognosis. Because of its worrisome histomorphologic features and aggressive clinicoradiologic findings, at times with multifocal presentation, they tend to simulate malignant tumors. We report a series of four cases of epithelioid hemangioma of bone with their clinicopathologic characteristics. All had adjacent soft tissue involvement and two had multifocal bone disease. Microscopically, all cases had a tumor in lobular configuration, composed of epithelioid endothelial cells with the formation of well-formed vessels or grew in solid sheets. The tumor cells lacked significant cytologic atypia, necrosis, and increased mitosis. All cases were immunohistochemically positive for vascular markers CD34, CD31, ERG1, whereas negative for CK. Two of the cases were treated with excision, and the other two underwent curettage. None had local recurrence or metastasis on follow-up. This study highlights the importance of recognizing histomorphological and clinicoradiological features for distinguishing epithelioid hemangiomas from malignant vascular neoplasms of bone because of their distinct therapeutic implications and clinical outcomes.

Reliability and Role of Mutation-specific H3F3A (Histone 3-3) G34W Immunohistochemistry to Differentiate Giant Cell Tumor of Bone From its Clinicoradiologic and Histologic Mimics: An Institutional Study.

Giant cell tumor of bone (GCTB) is a benign neoplasm, which can sometimes be a diagnostic challenge, especially in small biopsies, due to its histologic benign and malignant mimics. We evaluated the role of H3.3 G34W immunohistochemistry (IHC) antibody in diagnosing GCTB and its role in differentiating it from its close histologic mimics. A total of 120 cases (80 cases of GCTB and 40 cases of histologic mimics) were retrieved and subjected to IHC. Of 80 cases of GCTB, 72 cases showed a positive nuclear immunoexpression, while all 40 cases of histologic mimics of GCTB showed a negative staining for H3.3 G34W IHC. Sensitivity and specificity of this mutation-specific antibody for diagnosis of GCTB was 90% and 100%, respectively, while, the positive predictive value and the negative predictive value were 100% and 83.3%, respectively. A positive expression of H3.3 G34W was seen in all 5 cases of GCTB, postdenosumab therapy, as well as, in all 3 cases of malignant giant cell tumor. The presented study showed that H3.3 G34W mutation-specific IHC is a reliable and specific marker for GCTB and can help distinguish it from the histologic mimics due to distinct therapeutic implications.

Primary Fibular Sarcomas: Do They Behave Differently? An Institutional Review of 14 Patients.

Surgical resection with wide margins is pivotal for sarcoma treatment but achieving the same for fibular sarcomas is a surgical challenge. Thus, we decided to evaluate our own institutional database of primary fibular sarcomas for surgical treatment, margins and pattern of relapse. From July 2014 to October 2018, we identified fourteen patients with histologically confirmed fibular sarcomas. Limb salvage surgery (LSS) was performed in thirteen patients included in our study. One patient treated with definitive radiotherapy was excluded from final survival and functional analyses. The proximal third fibula was the most common site of involvement (85.7%). Osteosarcoma was the histological diagnosis in eight (57.1%) and Ewing's in the remaining six (42.9%). All patients with proximal fibular tumours underwent Malawer type II resection. Margins were reported as free in twelve and involved in one case. The mean follow-up period was 37.15 months. In the operated group (n = 13), distant relapse occurred in 3 patients, combined relapse in 1 patient and 10 patients are alive and disease free until the last follow-up. The Kaplan-Meier survival analyses revealed the EFS (event-free survival-local/distant relapse) probability as 72.7% at 24 months and 53% at the end of 42 months. The OS (overall survival) probability at 24 months was 75.5% and 57.5% at the end of 42 months. Although it is difficult to achieve conventional wide margins in fibular sarcomas, our results suggest no increased incidence of local recurrence rates as compared to sarcomas at other common sites as reported in literature. Our series helps in understanding site-specific behaviour of sarcomas while contributing to the available data.

Clinical outcome of a conservative approach to giant cell tumor of ankle and foot bones.

Giant cell tumor of the bone (GCTB) affecting foot and ankle is rare, and the literature available on their clinical behavior and reconstructive options is scarce. Many authors consider these sites a special subset with high rates of local recurrence. Eighteen patients with GCTB of foot and ankle were treated from (March 2014 to February 2020). Extended curettage was offered wherever feasible. Twelve patients underwent extended curettage, three underwent resection and reconstruction, one patient had ray amputation, one had below knee amputation. One patient with multifocal disease was treated conservatively with denosumab. There were 11 females and the mean age was 31.7 years. Distal tibia (11 patients) was the commonest location, followed by the first metatarsal (four patients). At a median follow up of 46 months, two patients out of the 17 operated had a local recurrence. GCTB affecting the foot and ankle have a clinical course comparable to those at other locations. They should be treated with a conservative approach, where radical resection and amputation are reserved for only the non-curettable tumors.

Computer navigation assisted tumor surgery for internal hemipelvectomy - Early experience.

Internal hemipelvectomy is a surgically challenging entity, owing, among other reasons, to a complex anatomy. The apprehension of an inadequate margin or injury to critical structures adds to the complexity of these major surgical procedures. Computer assisted tumor surgery (CATS) has been increasingly used to improve outcomes of internal hemipelvectomy over the last decade. We analyzed the surgical and postoperative details of first four patients undergoing internal hemipelvectomy with CATS assistance at our institute, the first ever report in an Indian setting. The patients were analyzed for blood loss (mean 1300 ml), operative time (mean 306 min) and hospital stay (mean 7 days). The histopathological margins were free of disease in all the patients, even as the average closest bony margin was 0.9 cm. Sparing of sacral nerve root was made possible by the close yet free margins in two patients. In this retrospective analysis of a small series of patients with computer navigation assisted internal hemipelvectomy, we found this technique to be feasible and effective in achieving the oncological aim of negative margins with preservation of critical structures.

Adapting Management of Sarcomas in COVID-19: An Evidence-Based Review.

With the novel coronavirus disease (COVID-19) being declared a global pandemic by the World Health Organization, the Indian healthcare sector is at the forefront to deliver optimal care. Patients with cancer especially are at serious risk for increased chances of morbidity and mortality due to their immunocompromised state. Currently there is a paucity of definitive guidelines for the management of sarcomas during the pandemic in a resource-constrained and diverse population setting like India. Health care professionals from various specialties involved in the management of sarcomas have collaborated to discuss various aspects of evidence-based sarcoma management during the COVID-19 pandemic. This article provides structured recommendations for HCP to adapt to the situation, optimize treatment protocols with judicious use of all resources while providing evidence-based treatment for sarcoma patients.

Sarcoma Care Practice in India During COVID Pandemic: A Nationwide Survey.

BACKGROUND: Amidst the COVID-19 pandemic, management of cancer has been one of the most intensely debated topics across the globe. We conducted an online survey to determine the consistency/or the lack of it, in the management of sarcoma patients between centres and the changes in policies. METHODS: A twenty-five question online survey was conducted among practicing physicians over a period of 10 days using online portal (surveymonkey.com). It was followed by a critical analysis based on responses to each question. RESULTS: Of 194 medical professionals who participated, 80% were surgeons and 53% were working in government institutes. Most respondents (81%) continued their practice with some modifications. In OP majority (67%) relied only on symptom, contact enquiry and temperature recording for screening. COVID-19 testing was done more (43%) in IP patients. Most of institutes (83%) followed rotational policy to reduce the number of staff at risk while 57% offered an alternate accommodation. 52.3% continued chemotherapy for all patients while radiotherapy for all was offered by 45%. In metastatic cases, majority preferred either no treatment or non-surgical intervention (71%).84.5% believed in adapting changes (42%-avoid supra major surgeries, 27%-Operating only emergency cases and 15.5%-High grade sarcomas with curative intent) in surgical management of sarcomas. For benign bone tumors, majority (71%) agreed on adapting changes while 25% agreed on deferring all cases. 69% preferred teleconsultations for follow-up. Complete PPE were being used for all aerosol generating procedures by 44%. Only two thirds agreed with their institutes policy of PPE usage and COVID-19 testing. CONCLUSION: This survey has highlighted disparity on COVID-19 screening and management in various institutes across the country. This will act as a reference point for tracking future trends in bone and soft tissue tumor management guidelines, as the COVID-19 scenario unfolds globally and particularly in India.

Vascularized fibula with and without extracorporeal radiotherapy for limb salvage surgery in Indian patients.

BACKGROUND: Reconstruction of segmental bone defects following resection of bone sarcomas is a challenging procedure. Vascularised fibula grafts alone or in combination with extracorporeal radiotherapy and reimplantation of tumor bone have long been established as a method of reconstruction of such defects, with satisfying results. Prompted by paucity of data on Indian patients, we report our experience with vascularised fibula graft for patients undergoing limb salvage surgery for sarcomas of bone. MATERIAL AND METHODS: A total of 25 patients underwent the procedure from December 2008 to December 2014. Femur was the commonest site and osteosarcoma was the commonest diagnosis. Intercalary resection was done in 19 patients and arthrodesis in 6 patients. Vascularised fibula was used in combination with extra corporeally irradiated bone in eight patients, and alone in 17 patients. RESULTS: All but one limb could be salvaged, and all but three patients had united at final follow up. Combination of extracorporeal radiotherapy and reimplantation with vascularised fibula fared better than vascularised fibula alone in terms of time to union (9.6 months vs 12.2 months) and rate of graft related complications (14.2% vs 62.5%). CONCLUSION: Reconstruction with VFG with or without ECRT has a good and predictable functional outcome. Though manageable with active intervention, complications were more commonly seen with vascularised fibula alone than a combination of the two techniques.

Prognostic Factors in Indian Patients Operated for Soft Tissue Sarcomas-a Retrospective Cross-sectional Analysis.

Soft tissue sarcomas are a rare entity. While surgery is established as the mainstay of treatment, the exact role and sequencing of adjuvant therapy is not well defined. Literature on Indian patients with soft tissue sarcoma with respect to clinical profile and prognostic factors is scarce. We retrospectively analysed the data of 112 patients operated for soft tissue sarcoma of extremity or trunk (excluding retroperitoneal and mediastinal sarcomas, round cell histology) at our institute from 1 January 2009 to 31 December 2013. Around half the patients were less than 50 years of age and around a third had size more than 10 cm. Oncological outcome was correlated with various demographic, tumour-related and treatment-related factors using SPSS 22. Overall survival at 5 years was 73.2 % and event-free survival at 5 years was 42.2 %. At final follow-up (mean of 44.85 ± 4.64 months), local recurrence was seen in 31.9 % and distant metastasis was seen in 30.1 % of the patients. Using both univariate and multivariate analysis, younger age (<50 years), larger size (>10 cm, but not >5 cm) and pathologically positive lymph nodes were the only factors found significantly affecting overall survival. The clinical profile and prognosis of Indian patients with soft tissue sarcoma were found to be different from that reported in Western literature. The impact of established prognostic indicators for soft tissue sarcoma also differed in Indian patients, which may have both prognostic and therapeutic implications.

Limb salvage surgery for osteosarcoma: Early results in Indian patients.

BACKGROUND: While limb salvage surgery has long been established as the standard of care for osteosarcoma, large studies from Indian centers are few. Given the diverse socio economic milieu of our patients, it becomes significant to determine the feasibility and outcome of management of osteosarcoma in our population. We analyzed the early outcome of limb salvage surgery with multimodality treatment of osteosarcoma of the extremity/girdle bones at a tertiary North Indian Cancer Centre. MATERIALS AND METHODS: A total of 51 limb salvage surgeries performed during the months between November 2008 and November 2012 were studied. Neoadjuvant/adjuvant chemotherapy was given by the pediatric/adult medical oncology teams as applicable. The mean followup was 19.45 months (range 2-50 months). The oncological outcome was correlated with age, sex, size of tumor, stage at presentation, site, histological subtype, type of chemotherapy protocol followed and necrosis seen on postoperative examination of resected specimen. The functional outcome of the patients was evaluated using the musculoskeletal tumor society (MSTS) scoring system. RESULTS: Out of a total of 37 males and 14 females with an average age of 18.8 years, the 3 year overall survival was 66% and 3 year event free survival was 61.8%. In this group of patients with a short followup, a better oncological outcome was associated with good postoperative tumor necrosis, nonchondroblastic histology and age <14 years. The average MSTS score was highest in patients with proximal or distal femur prosthesis and the lowest in patients undergoing a knee arthrodesis. CONCLUSION: The present study shows oncological and functional outcomes of limb salvage combined with chemotherapy in Indian patients with osteosarcoma comparable to those in world literature. Larger studies on Indian population with longer followup are recommended.

Current concepts in surgical treatment of osteosarcoma.

Osteosarcoma is the most common malignant primary neoplasm of bone. For an optimal oncological outcome, surgical removal of tumor is an essential component of its multidisciplinary treatment. Limb salvage surgery has long been established as the standard of care for osteosarcoma. While limb-salvaging techniques have acceptable rates of disease control, amputation remains a valid procedure in selected cases. In current orthopedic oncology practice, the focus is on optimizing the balance between preservation of form and function of the limb and adequate oncological clearance at the same time. Improving the functional outcome and longevity of reconstructive procedures also remains a challenge.

Evolution of surgical treatment for sarcomas of proximal humerus in children: retrospective review at a single institute over 30 years.

BACKGROUND: Proximal humerus, although a common site for primary bone sarcomas, finds scant mention in literature as far as options and outcome of reconstruction in the skeletally immature skeleton are concerned. Reconstruction after resection of proximal humeral sarcomas in the immature skeleton poses specific challenges to the surgeon, and there has been a definite evolution of these techniques over the decades. We studied the evolution and compared the outcome of various techniques for such reconstruction over 3 decades at a single institution. METHODS: All 61 children younger than 13 years of age and treated for a primary sarcoma of the proximal humerus at Department of Musculoskeletal Oncology, Rizzoli Orthopedic Institute, from 1976 to 2006 were studied for techniques of resection and reconstruction, complications, surgical procedures needed during follow up, and functional and radiologic outcomes during and at final follow-up. The functional outcomes after various procedures were compared using the Musculoskeletal Tumor Society scoring system. RESULTS: A definite trend from amputation in the first decade, to the use of nonbiological reconstruction (endoprostheses, K nail cement spacer) in the second and biological reconstruction (vascular proximal fibula autograft, osteoarticular allograft, and allograft prosthesis composite) in the third decade was seen. There was a trend of improvement in the functional outcome over the 3 decades, although the complication rates and the need for repeated surgical procedures remained a major problem in all the techniques. CONCLUSIONS: Reconstruction of proximal humerus after resection for sarcomas is a challenging task. Although endoprostheses do have a definite role to play in reconstruction of proximal humerus in children, the use of biological techniques in well-selected patients is being carried out more often now than before, as is reflected in this series, with a potentially improved functional outcome. LEVEL OF EVIDENCE: Level III-Retrospective comparative study.

Outcome of multimodality treatment of Ewing's sarcoma of the extremities.

BACKGROUND: The management of Ewing's sarcoma family of tumors (ESFT, Ewing's sarcoma/primitive neuroectodermal tumor) has been established as a multimodality treatment. Advances in imaging and diagnostics, chemotherapy, surgical techniques, radiotherapy and prosthetic technology have resulted in drastic changes in the outcome of this disease, with most of the recent studies having 5-year survival rates of more than 60%. The Indian patients present at a more advanced stage and the compliance of treatment is suboptimal. While there is plenty of data in the world literature on the outcome of Ewing's sarcoma, there is paucity of data in Indian patients. Therefore, we conducted the present study to analyze the outcome of multimodality treatment of ESFT of the extremities at a tertiary nonprofit institute over a decade. MATERIALS AND METHODS: 34 patients who had histopathologically proven diagnosis of Ewing's sarcoma of the extremities and had received treatment at our institute from 1997 through 2007 were included for analysis. The majority of patients had involvement of the femur (35%), followed by tibia (17%), fibula and foot (15% each), humerus (12%) and soft tissue of thigh (6%). Twenty-nine patients presented with localized disease (Enneking stage II B) while five patients presented with metastases (Enneking stage III). All patients received Vincristine, Actinomycin D, Cyclofosfamide + Ifosfamide and Etoposide (VAC+IE)-based chemotherapy and local treatment was offered to all but three patients having multicentric disease. The local treatment offered were, radiation (n= 15), surgery (n= 12) both surgery and radiation (n=4). All patients were analyzed for oncological outcome (event-free and overall survival, local and systemic relapses) by clinical and imaging evaluation and functional outcome by using the musculoskeletal tumor society (MSTS) score. These outcomes were correlated with age, sex, size of tumor, stage at presentation, modality of local treatment and site of relapse. RESULTS: At the final follow-up (mean, 26 months; median, 17 months; range, 3-97 months), the overall and event-free survivals were 47 ± 12% and 34 ± 9%, respectively. Sixty-two percent of the patients presented with a tumor size more than 8 cm. On correlation with age, sex, size of tumor, stage at presentation, modality of local treatment and site of relapse, no correlation of survival was seen with any of the variables except event-free survival with size of the tumor. The functional outcome of all the patients was satisfactory (MSTS score >16 out of 30). No patient underwent amputation. CONCLUSION: Although the demographic profile, stage at presentation and the local and systemic treatment regimen followed in our study was similar to the world literature, the outcome of Ewing's sarcoma in Indian patients were found to be inferior to that reported in the western literature. Larger multicentric studies with longer follow-up are required to exactly determine the key areas crucial in improving this outcome.