Cholangiocarcinoma: Recent Advances in Molecular Pathobiology and Therapeutic Approaches.

Cholangiocarcinomas (CCA) pose a complex challenge in oncology due to diverse etiologies, necessitating tailored therapeutic approaches. This review discusses the risk factors, molecular pathology, and current therapeutic options for CCA and explores the emerging strategies encompassing targeted therapies, immunotherapy, novel compounds from natural sources, and modulation of gut microbiota. CCA are driven by an intricate landscape of genetic mutations, epigenetic dysregulation, and post-transcriptional modification, which differs based on geography (e.g., for liver fluke versus non-liver fluke-driven CCA) and exposure to environmental carcinogens (e.g., exposure to aristolochic acid). Liquid biopsy, including circulating cell-free DNA, is a potential diagnostic tool for CCA, which warrants further investigations. Currently, surgical resection is the primary curative treatment for CCA despite the technical challenges. Adjuvant chemotherapy, including cisplatin and gemcitabine, is standard for advanced, unresectable, or recurrent CCA. Second-line therapy options, such as FOLFOX (oxaliplatin and 5-FU), and the significance of radiation therapy in adjuvant, neoadjuvant, and palliative settings are also discussed. This review underscores the need for personalized therapies and demonstrates the shift towards precision medicine in CCA treatment. The development of targeted therapies, including FDA-approved drugs inhibiting FGFR2 gene fusions and IDH1 mutations, is of major research focus. Investigations into immune checkpoint inhibitors have also revealed potential clinical benefits, although improvements in survival remain elusive, especially across patient demographics. Novel compounds from natural sources exhibit anti-CCA activity, while microbiota dysbiosis emerges as a potential contributor to CCA progression, necessitating further exploration of their direct impact and mechanisms through in-depth research and clinical studies. In the future, extensive translational research efforts are imperative to bridge existing gaps and optimize therapeutic strategies to improve therapeutic outcomes for this complex malignancy.

Periprosthetic metastases in carcinoma of unknown primary: A rare association.

ABSTRACT: Septic or aseptic loosening may cause bone loss around artificial prosthesis leading to prosthesis failure. This occurrence due to metastatic infiltration of bone or surrounding soft tissues is rare but has been occasionally reported. We report a case of an elderly lady presenting with swelling and pain at the site of previous hemiarthroplasty performed for traumatic injury. On evaluation, she was found to have a lytic femur lesion with a large soft-tissue component around the prosthetic joint. Biopsy suggested a metastatic carcinoma of renal origin, but screening of kidneys did not reveal any primary lesion. She had additional skeletal metastatic lesions but no other primary site was detected either. She was given palliative radiotherapy and systemic therapy (sunitinib) based on the histologic diagnosis of renal cell origin but did not tolerate it. Thereafter, she is continuing on zoledronate every 4 weeks and best supportive management since 4 months from diagnosis.

Simultaneous Integrated Boost (SIB) Versus Sequential Boost in Anal Cancer Patients: A Single-Center Experience.

PURPOSE: Concurrent chemoradiation is the standard of care for the treatment of anal cancer. Radiation can be delivered by sequential or simultaneous integrated boost (SIB) approach. The present study was conducted to compare the treatment outcomes and toxicity profile of patients with anal cancer treated with sequential boost and SIB approach. METHODS: A single-institution retrospective analysis of patients with squamous cell carcinoma of the anal canal treated between 2019 and 2022 with radical chemoradiation was performed. The sequential boost schedule consisted of 45 Gy in 25 fractions (1.8 Gy daily) to the gross tumor, nodes, and elective nodal volume, followed by a 9 Gy in five fractions boost to the gross disease. Patients receiving SIB were treated as per RTOG 0529 protocol. In both the groups, patients were treated with volumetric modulated arc therapy (VMAT). The two groups were compared in terms of overall survival (OS), colostomy-free survival (CFS), relapse-free survival (RFS), and acute toxicity profile. p-values < 0.05 were considered statistically significant. RESULTS: The patient and disease characteristics in both treatment arms were comparable. The only difference was a significantly longer overall treatment time of ≥ 50 days in the sequential arm (77.8% vs 43.8%, p = 0.04). The median follow-up was 18 months. The 2-year CFS was 80% in sequential vs 87.5% at 2 years for the SIB arm, 2-year OS 83.3% vs 58.6%, and 2-year RFS was 38.9% vs 41.7%, respectively. A total of 14 (77.8%) in sequential and 8 (50%) in the SIB arm had disease relapse. On univariate analysis, the involved pelvic lymph node significantly affected OS (HR 10.45, p = 0.03) while inguinal lymph node involvement adversely affected RFS (HR 6.16, p = 0.02). The most common acute toxicity was radiation-induced dermatitis, 15 (83.4%; 5 grade II, 10 grade III) in sequential vs 7 (43.8%; 3 each grade II and III) in the SIB group followed by hematological (61.1% vs 68.75%). However, the incidence of overall acute toxicities was significantly less in the SIB arm (p = 0.006). CONCLUSION: Our study showed that concurrent chemoradiation with the SIB-VMAT approach is well tolerated in patients of anal carcinoma and resulted in lesser treatment interruptions and comparable outcomes as compared to the sequential approach. Our results warrant further evaluation in a prospective study.

Delineating and sparing the ileal conduit in adjuvant radiotherapy for bladder cancer with modulated radiotherapy.

Purpose: We undertook a prospective planning study to describe the delineation of ileal conduit (IC) loop on radiotherapy planning computed tomography (RTP CT) scan as an organ at risk (OAR) and its sparing using volumetric modulated arc therapy (VMAT) during adjuvant irradiation of bladder malignancies. Materials and Methods: Fifteen patients with bladder malignancy needing adjuvant radiotherapy postoperatively and having normal renal function underwent delayed phase RTP CT from June 2020 to March 2021, with certain modifications (Foley's catheter through stoma, additional delayed scans). We identified the course of ureters, external stoma, IC, and uretero-ileal (right and left) anastomotic sites. VMAT plans were generated. Results: A step-by-step description is given. Genitourinary OARs include kidneys, ureters, uretero-ileal anastomoses, and IC. The contrast on delayed scan opacifies ureters and IC. IC can be seen three-dimensionally as a structure with two fixed ends (blind proximal end anterior to the right sacroiliac joint and the open distal end over the right anterior abdominal wall in parasagittal location) and a 15-20 cm hanging intraabdominal loop that lies adjacent to the right iliac vessels. For prescription doses (PD) of 50.4 gray and 54 gray, respectively, VMAT plan achieved IC dose maximum to less than PD and V50 lower than 10 cc. Stoma sparing traditionally used as a surrogate for IC sparing is insufficient due to the variable intraabdominal location of IC loop. Conclusions: Delineation of IC as an OAR is feasible with slight modifications in the RTP protocols. VMAT (or other forms of intensity modulated radiation therapy) can help IC sparing and should be considered when it lies in close proximity to target volumes and the risk of additional morbidity is considerable.

Primary retroperitoneal squamous cell carcinoma: a literature review.

PURPOSE: Retroperitoneal squamous cell carcinoma is an extremely rare histological variant of retroperitoneal tumors. The exact etiology and origin of the same is still unknown. To date, only a few case reports have been published in the literature. Due to rarity, standard treatment protocol is not available. The article aims to review the literature and treatment options available for this uncommon entity, based on available data. METHODS: We searched the databases like PubMed, PubMed Central, Scopus, and Google Scholar with the keywords "Squamous cell carcinoma" and "retroperitoneal tumors". Peer-reviewed and recent articles were screened. RESULTS: Seven relevant articles comprising 14 cases were found. Due to the small number of reports, tabulation of treatment details and outcome was done. Like the sarcoma variant, these tumors also present with a large mass in the abdomen and abdominal discomfort. Association with human papillomavirus appears to be the most common factor that gives rise to squamous histology. CONCLUSION: Retroperitoneal SCC is an uncommonly diagnosed entity. Although no specific treatment guidelines exist for this uncommon malignancy; surgery followed by adjuvant or definitive radiotherapy with concurrent chemotherapy (in inoperable cases) seems a feasible option. Multicentre trials should be conducted for establishing definitive treatment strategies for this ailment.

Treatment outcomes of adjuvant radiotherapy in adrenocortical carcinoma - A 13-years experience from a tertiary care centre.

Purpose: Adrenocortical carcinoma (ACC) is a rare and highly aggressive malignant neoplasm, usually diagnosed in advanced stage. Role and efficacy of adjuvant radiotherapy has not been well defined. The objective of this study is to describe the various clinical characteristics and prognostic factors affecting the survival of ACC along with the role radiotherapy on overall survival and relapse free survival. Methods: A retrospective analysis of 30 patients registered between 2007 and 2019 was carried out. The medical records containing clinical and treatment details were analysed. Data was analysed using SPSS 25.0. Survival curves were computed using Kaplan-Meier method. Univariate and multivariate analyses were performed to analyze the prognostic factors affecting the outcome. A p value of less than 0.05 was considered to be statistically significant. Results: The median age of patients was 37.5 years (range, 5-72 years). 20 patients were females. Twenty-six patients had advanced stage (III/IV) disease while only four patients presented in early stage. Twenty-six patients underwent total adrenalectomy. Eighty three percent patients received adjuvant radiation therapy. The median follow up was 35.5 months (range, 7 monthss-132months). The estimated three- and 5-years overall survival (OS) was 67.2% and 23.3%, respectively. Capsular invasion and positive margins were the independent prognostic factors influencing both OS and relapse free survival (RFS). Out of 25 patients who received adjuvant radiation, only three patients had local relapse. Conclusion: ACC is a rare and aggressive neoplasm with majority of patients presenting in advanced stage. Surgical resection with negative margins remains the mainstay of treatment. Capsular invasion and positive margins are independent prognostic factors for survival. Adjuvant radiation reduces the risk of local relapse and is well tolerated. Radiation can be used effectively in adjuvant and palliative settings in ACC.

Malignant Peripheral Nerve Sheath Tumor Arising from Small Bowel Mesentery: an Extremely Rare Case with Review of Literature.

PURPOSE: Malignant peripheral nerve sheath tumor (MPNST) of small bowel mesentery is a rare tumor. We report a rare case of MPNST of small bowel mesentery in a patient without neurofibromatosis (NF). METHODS: A 50-year-old male, with no features suggestive of NF1, presented to us with complaints of pain abdomen. Contrast-enhanced computed tomography (CECT) of the abdomen revealed a mass in the infrarenal region. On laparotomy, mass was seen to be arising from the mesentery of the jejunum. En-bloc resection of the tumor was done, and histopathological examination was suggestive of malignant peripheral nerve sheath tumor of the small bowel mesentery. RESULT: Patient received adjuvant external beam radiotherapy to a dose of 50.4 Gy to the tumor bed. The patient was planned for chemotherapy but absconded and later came with recurrence. The patient finally succumbed to disease. CONCLUSION: Surgery is the mainstay of treatment. Adjuvant treatment should be based on histopathological report.

Mucoepidermoid carcinoma of the trachea in a 9-year-old male child: case report and review of literature.

Mucoepidermoid carcinoma (MEC) is most common malignancy of minor salivary glands in adults. Pulmonary MEC is extremely uncommon comprising of only 0.1%-0.2% of the primary lung malignancies and <1% of primary bronchial tumors. It is even rarer in children and literature limited to few case reports only. Here we present a case report of a 9-year-old boy diagnosed with primary MEC of trachea along with review of the literature. A 9-year-old male child presented with complaint of dry cough for two years which was later associated with shortness of breath after one year. Bronchoscopic examination revealed a growth arising from right lateral wall of carina occluding 50% of the lumen and detailed histopathological examination revealed it to be a MEC of the trachea. Patient underwent local excision of the tumor with primary anastomosis. In view of positive margins adjuvant radiotherapy of 60 Gy in 30 fractions were given to the tumor bed. Patient tolerated the treatment well and is disease free at 6 months follow-up. Experience with MEC of the trachea in children is limited and optimal treatment protocols have not been defined, with current treatment mainly extrapolated from MEC of the salivary glands.

Comparative analyses of paclitaxel/carboplatin with cisplatin/5-fluorouracil-based chemoradiation in locally advanced inoperable upper and middle third esophageal cancer: A randomized prospective pilot study.

Introduction: Chemoradiation therapy (CRT) remains the treatment of choice for inoperable locally advanced esophageal cancer (LAEC). Several CRT regimens are existent in esophageal cancer, but definitive conclusions are lacking. We performed a pilot study to compare treatment outcome, survival, and toxicities in inoperable upper and middle third esophageal cancer patients undergoing CRT using either paclitaxel/carboplatin or cisplatin/5FU based regimen. Methods: Patients were randomised in two arms (arm A and arm B). In Arm A, taxane-based (Paclitaxel+carboplatin) and in arm B non-taxane-based (cisplatin+5FU) doublet chemotherapy drugs were given concurrently with external beam radiation therapy (EBRT). EBRT in two phases up to a total dose of 54 Gy/27#@2Gy/# was given. Response was subsequently assessed using Response evaluation criteria in solid tumors (RECIST v1.1) and toxicities utilizing Common Terminology Criteria for Adverse Events (CTCAE v 4.0). Result: The overall response rate (ORR) in the taxane-based group was higher than the non-taxane-based group, but was not significantly different (p=0.851). Regarding hematological toxicities, anaemia and reduced cell counts were more in the taxane group compared to the non-taxane group while non-hematological toxicities were comparable. Similarly, better survival with late toxicities were seen with taxane-based arm when compared to non-taxane-based arm, though it was not statistically significant. Conclusion: Our pilot analysis highlights the fact that paclitaxel/carboplatin CRT shows better response, survival, and comparable toxicities when compared to cisplatin/5FU, though statistically nonsignificant. Further randomised prospective trials with large sample size are warranted.

Sequential small cell transformation and T790M mutation in an epidermal growth factor-mutant lung adenocarcinoma: A rare occurrence with significant management implications.

BACKGROUND: Epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) resistance may be acquired via genotypic and/or phenotypic transformations. Herein, we report an extremely uncommon case with sequential small cell transformation and EGFR T790M mutation, in an elderly female with EGFR exon 21 L858R-mutant lung adenocarcinoma, following treatment with a first-generation EGFR-TKI. CASE: A 67-year-old female never-smoker presented with a cough and dyspnoea of 2 months' duration. Computerised tomography revealed a 39 mm lesion in the upper lobe of the right lung with pleural effusion. Pleural fluid cytology revealed metastatic lung adenocarcinoma, and EGFR testing revealed exon 21 L858R mutation. She was started on gefitinib. After a progression-free survival of 31 months, she presented with disease progression and multiple extra-thoracic metastases. Fine needle aspiration cytology of a chest wall lesion revealed metastatic small cell carcinoma. EGFR testing on this aspirate revealed persistent L858R mutation only. In view of small cell transformation, chemotherapy (etoposide and carboplatin) was administered. After 4 months, ascitic fluid cytology revealed metastatic adenocarcinoma with persistent L858R mutation and an acquired T790M mutation (both detected on liquid biopsy as well) indicating amplification of the adenocarcinoma clone and regression of the small cell carcinoma clone. She was then initiated on osimertinib. CONCLUSIONS: The index case highlights the significance of serial EGFR genotyping along with repeated tissue and/or blood sampling in the prompt detection of genetic and phenotypic resistance mechanisms to EGFR-TKIs. Furthermore, it lends evidence in support of the upfront treatment approaches targeting the heterogeneity of acquired EGFR-TKI resistance mechanisms.

Role of intraluminal brachytherapy in palliation of biliary obstruction in cholangiocarcinoma: A brief review.

Surgery is the only curative treatment for cholangiocarcinoma. However, most patients present with advanced disease, and hence are unresectable. Thus, the intent of treatment shifts from curative to palliative in the majority of cases. Biliary drainage with intraluminal brachytherapy is an effective means of relieving the malignant biliary obstruction. In this review, we discuss the role of brachytherapy in the palliation of obstructive symptoms in extrahepatic cholangiocarcinoma.

Reviewing the potential role of radiation therapy in gallbladder cancer: an update.

Gallbladder cancer is a highly malignant disease with a poor prognosis. It is the most common cancer of the biliary tract pathway. Although surgery remains the treatment of choice for early-stage disease, majority of the patients presents in locally advanced, unresectable and metastatic stage of the disease. Radiotherapy and chemotherapy thus form an integral part of management for these locally advanced staged patients. The role of radiation though has been advocated in gallbladder cancer, majorly in the adjuvant setting, its role in neoadjuvant and palliative settings remains in an evolving phase. The article thus aims to review and update the existing literature regarding the role of radiation therapy in gallbladder cancer.

Managing brain tumors in pregnancy: The oncologist's struggle with maternal-fetal conflict.

The diagnosis of malignancy, particularly brain tumors, in pregnancy is uncommon but poses a complex dilemma for the management of both the patient and her fetus, as the interplay of disease with the physiological state of pregnancy affects both outcomes. The routine evaluations (symptomatology, imaging, and hormonal assessments) and treatments (surgery, radiation therapy, and chemotherapy) that are commonplace in brain tumor management may need to be omitted or modified keeping in mind the risk to offspring. Multidisciplinary care and extensive prenatal and perinatal counseling and monitoring are essential. In this review, we discuss the available data addressing these issues and factors which may affect considerations of therapeutic abortions, changes in surgical or medical practices, and outcomes thereof.

Small bowel adenocarcinoma: An overview.

Small bowel adenocarcinoma (SBA) is a rare malignancy of the gastrointestinal tract. However, these tumors are among those with worst prognosis. Vague clinical signs and symptoms and radiological diagnostic challenges often delay treatment, which negatively impacts the prognosis of the patients. However, recent advances in imaging technology, like multidetector computed tomography, magnetic resonance imaging, and capsule endoscopy, have made earlier and accurate diagnosis possible. Surgery is the treatment of choice followed by adjuvant therapy. However, there are no strict treatment guidelines available for the management of SBA. Most of the available evidence from colorectal and gastric carcinoma has been extrapolated to adequately manage SBA. Prognosis for SBA is better than gastric carcinoma but worse than colorectal carcinoma. Currently, there is not enough information on the molecular characteristics and tumor pathogenesis. Because the incidence of SBA is very low, there is a need for further studies to evaluate the possible application of newer investigative agents and strategies to obtain a better outcome within the framework of international collaborations.

Subclinical Hypothyroidism After 225Ac-DOTATATE Therapy in a Case of Metastatic Neuroendocrine Tumor: Unknown Adverse Effect of PRRT.

ABSTRACT: Radiation-induced thyroid dysfunction is very rarely associated with peptide receptor radionuclide therapy (PRRT) for neuroendocrine tumors using ß-emitting radionuclides. With the emergence of α radionuclide such as 225Ac, PRRT using these radionuclides has shown better results; however, data on the toxicity profile are limited. This is a case report describing the thyroid dysfunction developed in a patient with inoperable metastatic neuroendocrine tumor with unknown primary after PRRT using 225Ac-DOTATATE, which has never been reported previously.

Hematological Markers as Predictors of Treatment Outcomes with Lutetium 177 (177Lu)-DOTATATE in Patients with Advanced Neuroendocrine Tumors.

Background: Chronic inflammation has been linked to the development and prognosis of neuroendocrine tumors (NETs). The current study intended to evaluate the role of peripheral hematological inflammatory markers, viz. the platelet-lymphocyte ratio (PLR), neutrophil-lymphocyte ratio, and monocyte-lymphocyte ratio, as predictors of treatment outcomes in patients with advanced NETs after Lutetium-177(177Lu)-DOTATATE therapy. Materials and Methods: Data of consecutive patients with advanced metastatic and/or inoperable NETs treated with 177Lu-DOTATATE from the year 2012 to 2019 at the authors' center were retrospectively analyzed. Results: Forty-two NET patients (median age: 49.5 years) received a median cumulative activity of 29.6 GBq of 177Lu-DOTATATE over 2-5 cycles at 8-12-week intervals. The median progression-free survival (PFS) of the study cohort was 30 months (95% confidence interval, CI: 18.2-41.9 months). A baseline PLR ≥173.1 was found to be a significant predictor of poor PFS with a univariate hazard ratio of 3.82 (95% CI: 1.21-12.03); however, the association was not significant on multivariate analysis. The median overall survival was not reached and none of the parameters were significantly associated with it. Conclusions: A higher baseline PLR was shown to be associated with a negative outcome on PFS after 177Lu-DOTATATE therapy and is a promising marker for future larger studies.

Expanding role of radiotherapy in adenoid cystic carcinoma of the tracheobronchial tree: a new horizon.

BACKGROUND: Primary adenoid cystic carcinomas (ACCs) of central trachea-bronchi system are rare and heterogeneous tumors. Definitive radiotherapy (RT) is the recommended treatment in surgically unresectable or incomplete resection or in the presence of severe comorbidities. OBJECTIVE: To evaluate the clinical features and outcomes of patients with ACC of trachea-bronchi treated with radiotherapy. METHODS: Retrospective medical records review was done in all patients with histologically confirmed ACC of trachea-bronchi between January 2010 and December 2019. Patient disease and treatment characteristics and toxicity data were analyzed. Overall survival (OS), local recurrence-free survival (LRFS), and distant metastasis-free survival (DMFS) were computed using Kaplan-Meier method (log-rank test). RESULTS: Nineteen patients (10 women and 9 men) were included in this analysis with median age of 40 years (range, 14-70). Of these patients, 63.2% (n = 12) presented in stage IV disease. Twelve and three patients received definitive (median dose 67.8 Gy) and adjuvant (median dose 50 Gy) RT, respectively. The median follow-up was 42.5 months (range, 4-120); 15 patients were alive and 4 were dead at that time. Local recurrence or progression was observed in 52.6% and distant metastasis found in 47.3% of patients. The 5-year OS, LRFS, and DMFS for all patients were 81.2%, 52.8%, and 39.6%, respectively. Baseline lymph node involvement showed significant impact on OS (56.3% vs 100%, p = 0.011). Among patients receiving definitive RT, patients with higher RT dose (⩾66 Gy) had significantly better survival outcomes (5-year LRFS: 75% vs 16.7%, p = 0.013). CONCLUSION: Definitive RT is an exemplary treatment for unresectable disease. Higher dose is recommended to improve long-term outcomes.

Primary angiosarcoma of the seminal vesicle.

Angiosarcomas are rare but highly aggressive malignancies originating from lymphatic or vascular endothelial cells and may arise from any site in the body. Angiosarcomas of the genitourinary tract, especially of seminal vesicle origin, are extremely rare with only five reported cases. Surgery forms the mainstay of therapy in localised disease while adjuvant therapies are still being refined. We present the case of a 40-year old gentleman who presented with lower urinary tract symptoms and, on evaluation, was found to have a localised angiosarcoma originating in right seminal vesicle and offered laparoscopic resection, adjuvant paclitaxel (12 weekly cycles) and adjuvant radiation therapy (66 gray in 30 fractions). He developed a peritoneal nodular recurrence after 6 months of radiotherapy that was successfully salvaged with excision and metronomic chemotherapy, which he is currently receiving. Localised angiosarcomas need multimodality management despite small size. Attempts should be made for surgical salvage of limited recurrences whenever feasible.