The translational gap for gene therapies in low- and middle-income countries.

Gene therapies are designed to address the root cause of disease. As scientific understanding of disease prevention, diagnosis, and treatment improves in tandem with technological innovation, gene therapies have the potential to become safe and effective treatment options for a wide range of genetic and nongenetic diseases. However, as the medical scope of gene therapies expands, consideration must be given to those who will benefit and what proactive steps must be taken to widen development and access potential, particularly in regions carrying a high disease burden.

Redefining informed consent form in cell and gene therapy trials.

Informed consent is a foundation of the ethical conduct of research involving human participants. Based on the ethical principle of respect for persons, the goal of informed consent is to ensure that participants are aware of the risks and potential benefits and make a voluntary decision about participating in clinical trial research. The extraordinary scientific advances happening globally, have demonstrated the potential of regenerative therapies in transforming the health of the nation by providing a therapeutic option for diseases that were previously considered incurable. These therapies, which include cells and gene therapy (GT) labeled as Advanced Therapeutic Medicinal Products globally, have complex mechanisms of action. Owing to their highly personalized and intricate nature of these therapies, developing the latter often presents unique challenges above and beyond those encountered for small molecule drugs. We recently looked through some cell and GT clinical trials and realized the lacunae in the informed consent form (ICF) provided by the investigators. Especially in a country like India, where the general understanding and perception of patients is limited regarding clinical trials, it is felt that any lapses in the consent process may jeopardize the informed decision-making and safety of the participants and tarnish the reputation of India globally. The present article highlights the need for appropriate patient and public education on the various aspects of cell and gene therapies and aims to address all the elements of ICF in light of the challenges associated with these innovative therapies.

Regulation of Clinical Research for Cellular and Gene Therapy Products in India.

The understanding of disease biology and advances in cellular and molecular biology platforms have ushered in a new era of cell and gene based therapeutic products. The US-FDA refers to this category of products as Cellular and Gene Therapy Products (CGTPs), while the European Medicines Agency, Europe, refers to them as Advanced Therapy Medicinal Products (ATMPs). The research and development (R&D) and final commercialization of these products have thus picked up pace, especially in the last decade. This emerging scenario necessitates framing regulations and guidelines that take into consideration the unique biological nature of these products. Regulators and government agencies of different countries across the globe have come up with regulations and guidance documents to guide, monitor, and regulate the research and development in this field. India, given its powerful resources of skilled scientific manpower and infrastructure, is also contributing to development of these innovative therapeutic products. Keeping in line with the international counterparts, the Indian regulators and government agencies have developed regulations and guidelines for stakeholders. This chapter summarizes the regulatory landscape for research and development of CGTP in India. It provides an overview of the government agencies and committees overseeing this field and their roles that a stakeholder working in this field needs to have knowledge of. Furthermore, the chapter outlines the salient features of rules, regulations, and guidelines relevant to CGTP, the approval process, the current approved products in Indian market, and finally, the challenges and way forward for CGTP in India.

Papillary Pattern in Acinic Cell Carcinoma of Parotid Gland: A Potential Diagnostic Pitfall on FNAC.

Fine needle aspiration cytology (FNAC) is often the first investigation in the work up of salivary gland lesions. However, its diagnostic accuracy is limited by the high rates of false positives and false negatives. Usually, acinic cell carcinoma is prone to be underdiagnosed because of the cytological similarity of the tumor cells to normal acinar cells, however rarely, a predominant papillary architecture on cytology may cause confusion with adenocarcinomas. We present a case of a 45-year-old male with a painful swelling of the right parotid region. FNA smears revealed a predominant papillary architecture and focal acinar pattern. A provisional diagnosis of acinic cell carcinoma was given, which was confirmed on histopathology. Familiarity with the cytomorphologic features of acinic cell carcinoma is cardinal for an accurate diagnosis and appropriate management.

Primary Leiomyosarcoma of the Mesentery: A Case Report.

Mesenteric masses are infrequent lesions ranging from benign cysts to aggressive malignancies and often present a diagnostic and therapeutic challenge. The mesentery is a frequent recipient of metastases from the gastrointestinal tract, pancreas, and biliary cancers. Primary mesenteric tumors are relatively rare, mostly mesenchymal in origin and benign in nature. Examples include gastrointestinal stromal tumors and smooth muscle tumors. We describe a 50-year-old woman, who presented with a lump in the left hypochondrium along with altered bowel habits of 2 years' duration. Imaging revealed a cystic lesion, raising the differentials of a benign lesion. Exploratory laparotomy revealed a large cystic mass in the mesentery closely abutting the jejunal loops. This was followed by mass resection along with a segment of the jejunum. Histopathological examination revealed features of a leiomyosarcoma. Postoperatively, the patient developed a colocutaneous fistula, which was re-excised. At 6 months' follow-up, the patient is doing well. Our case demonstrates the diagnostic challenge posed by the atypical clinical and imaging features of this tumor at an unusual site.

Periampullary Carcinoma: Unusual Sites of Metastasis.

BACKGROUND: Periampullary neoplasms include carcinomas of the duodenum, ampulla of Vater, distal common bile duct, and pancreas. The aggressive course of these neoplasms is attributable to the delay in diagnosis, as patients have no symptoms until advanced stages of the disease. More than half of patients have distant metastasis at the time of diagnosis. The most frequent sites of metastasis are the liver, lymph nodes, peritoneum, lung, bone, kidney, and, rarely the skin. CASE REPORT: We report the case of a 45-year-old female patient with adenocarcinoma of the ampulla of Vater metastasizing to the right parietal skull with overlying cutaneous involvement 1 year after a Whipple procedure. CONCLUSION: Cutaneous and skull metastasis of periampullary neoplasms is unusual, but early recognition of such metastatic disease is important because it indicates a poor prognosis for the patient.

Inflammatory Myofibroblastic Tumor of the Breast Mimicking Malignancy in an Elderly Male.

BACKGROUND: Inflammatory myofibroblastic tumor (IMT) is a rare, distinctive lesion composed of a proliferation of myofibroblastic spindle cells accompanied by an inflammatory infiltrate. It was first described in the lung, but its occurrence at various extrapulmonary sites has also been reported. The literature mentions only a handful of cases of IMT in the breast and only 1 case in the male breast. We report the second case of IMT in the male breast. CASE REPORT: A 60-year-old male presented with a large, lobulated lump in the left breast that had progressively increased in size during the past year. The lump measured 15 × 10 cm. Ultrasonography revealed a solid mass lesion with regular borders in the subcutaneous plane of the left anterior chest wall. Fine-needle aspiration cytology showed a cellular mesenchymal tumor. Macroscopically, the nodule was firm, circumscribed, and yellow. On microscopic examination, the tumor was composed of bland spindle cells arranged in sheets and short fascicles along with a rich inflammatory infiltrate comprising predominantly plasma cells, admixed with lymphocytes, neutrophils, and eosinophils. On immunohistochemistry, the tumor cells were positive for vimentin, focally positive for smooth muscle antigen, and negative for anaplastic lymphoma kinase, CD34, S100, ß-catenin, and cytokeratin. Thus, a final diagnosis of IMT was rendered. CONCLUSION: IMT is a rare entity with intermediate clinical behavior. Knowledge of this entity and its recurrence and metastatic potential is of paramount significance to guide appropriate treatment and follow-up.

Bilateral rhabdoid meningioma mimicking glioma: an unusual occurrence.

Rhabdoid meningioma is an infrequent variant of meningioma, introduced for the first time in the 2000 World Health Organization's classification of tumors of the nervous system. Owing to its aggressive clinical course and high proliferative index, it has been classified as a grade III neoplasm. We describe a fifty-year-old male with headache, weakness of limbs, and altered sensorium. CT showed hetero-dense enhancing mass lesions in both right and left parietal areas raising suspicion of high grade glioma. Histopathologic and immunohistochemical examination revealed a tumor with features of rhabdoid meningioma. A review of literature did not reveal any bilateral occurrence of this tumor.

Pleomorphic Sarcoma of Breast: A Report of Two Cases and Review of Literature.

Sarcomas account for less than 1% of all primary breast malignancies, pleomorphic sarcoma of the breast being even rarer. We present two cases of pleomorphic sarcoma of the breast in a 35-year-old and a 43-year-old female. An extensive review of the available literature with evaluation of the etiology, changing terminologies and histopathologic features of pleomorphic sarcoma of the breast are discussed. The prognostic factors and treatment modalities have also been reviewed.

Papillary carcinoma thyroid with anastomosing channels: An unusual morphology.

Papillary thyroid carcinoma (PTC) is the most common thyroid malignancy, accounting for 70%-80% of all thyroid malignancies. It is biologically indolent and has an excellent prognosis. Variations in histopathologic patterns are known to influence prognosis and often result in a diagnostic dilemma. We report an unusual case of a 35-year-old female with papillary carcinoma of a thyroid isthmus showing anastomosing channels on histopathology, a distinctive pattern that has not been described in PTC. Similar to tumor cells, the lining cells of these channels were also positive for thyroid transcription factor 1, thyroglobulin, and cytokeratin-19 and negative for CD34 and CD31. The diagnosis of PTC should rely on nuclear morphology rather than architecture. Pathologists should be aware of different variants because some of these variants show aggressive behavior and poor outcome. The present report highlights the distinctive pattern of PTC, recognition of which is important to avoid any diagnostic pitfall.

Myeloid sarcoma: a report of four cases at unusual sites.

Background: Myeloid sarcoma (MS) or granulocytic sarcoma is a rare tumor consisting of myeloid blasts with or without maturation occurring at anatomic sites other than the bone marrow. MS can involve any organ system but shows a predilection for skin, bone, and soft tissues of head and neck region. Case report: We report four cases of MS occurring at unusual sites, out of which three were de novo and one was associated with acute myeloid leukemia (AML). Conclusion: Although MS is associated with AML, it can rarely present without any existent hematologic disease. Differential diagnosis of a soft tissue mass should include MS even in the absence of leukemia. Establishment of the correct diagnosis depends on morphologic, histochemical, and immunohistochemical examination.

Pancreatic Tuberculosis with Markedly Elevated CA 19-9 Levels: A Diagnostic Pitfall.

Despite the high prevalence of tuberculosis (TB) in developing countries, isolated pancreatic TB is rare and is usually seen in immunocompromised patients. It presents with non-specific signs and symptoms and may mimic malignancy both clinically and radiologically. Cytologic and histologic confirmation is required to establish the definitive diagnosis. We present a case of a 25-year-old male with a pancreatic mass and markedly elevated serum cancer antigen (CA) 19-9 levels raising the suspicion of malignancy but with a histopathologic picture of TB. This case suggests that clinicians should have a heightened suspicion of pancreatic TB when faced with discrete pancreatic lesions even though elevated tumor markers may indicate malignancy. It is important to perform appropriate diagnostic testing and initiate antitubercular therapy early.

Radiation-induced Leiomyosarcoma of the Oral Cavity: A Rare Occurrence Detected on 18F-FDG PET/CT.

Radiation-induced sarcomas (RIS) or postirradiation sarcomas have been reported as a rare long-term complication of radiation therapy (RT). The survival benefit offered by radiotherapy has been masked by an increase in the incidence of these sarcomas, thus making radiotherapy a double-edged sword. RIS generally develop with a mean latency period of 10-15 years and encompass different histological types. We report a case of oral leiomyosarcoma with a rather short latency period of 4 years after the radiotherapy of the prior oral squamous cell carcinoma (OSCC) detected on fluorine-18 (18F)-fluoro-2-deoxy-D-glucose (FDG) positron emission tomography/computed tomography (PET/CT). The rarity of occurrence of leiomyosarcoma in the oral cavity is also highlighted.

Hepatosplenic T-cell lymphoma with coexistent hepatitis B infection: a rare clinicopathologic entity.

BACKGROUND: Hepatosplenic T-cell lymphoma (HSTL) is a rare extranodal and systemic lymphoma derived from cytotoxic T cells usually of γδ T cell receptor type. It is characterized by primary extranodal disease with typical sinusoidal infiltration of liver, spleen, and bone marrow by medium-sized lymphoid cells. CASE REPORT: A 29-year-old man, with no significant prior medical history, presented with fever and massive splenomegaly. A diagnosis of HSTL was established by histologic examination and immunohistochemistry. Staging workup demonstrated bone marrow involvement by lymphoma. In addition, the patient was found to have hepatitis B infection. The association of these 2 entities has been described rarely. CONCLUSIONS: Hepatosplenic T-cell lymphoma is a distinct T cell lymphoma associated with an aggressive clinical course, a poor response to conventional treatment, and an exceedingly high mortality rate. An association of HSTL with hepatitis B as seen in the present case is exceedingly rare, with few cases reported in the literature.

Primary testicular lymphoma with solitary cutaneous nodule as the initial presentation.

Primary testicular lymphoma (PTL) is an uncommon disease, and accounts for about 1% to 2% of non-Hodgkin's lymphomas and less than 5% of all testicular malignancies. Of all testicular malignances, primary testicular diffuse large B-cell lymphoma is the most common type, whose incidence is estimated at 0.26/100 000 per year. At presentation or relapse, PTL tends to spread to several extranodal sites, such as the contralateral testis, the central nervous system, skin, lung, pleura, Waldeyer's ring, and soft tissues. Orchiectomy and chemotherapy are the preferred treatment. We report a case of a 40-year-old male presenting with a nodule on the anterior abdominal wall and with right scrotal swelling on physical examination. Histopathologic examination led to the diagnosis of cutaneous metastasis of testicular lymphoma.