Complete Remission of Metastatic Melanoma of the Scalp Following Treatment With Nivolumab Plus Relatlimab.

Melanoma is an aggressive malignancy accounting for approximately 1% of all skin cancers. The standard of care for distant melanoma of the skin is immunotherapy with PD-1 inhibitors (nivolumab) or CTLA-4 inhibitors. In March 2022, the FDA approved the combination of nivolumab with relatlimab, a lymphocyte-activation gene 3 antibody. There are few reports on the efficacy of treating widespread multivisceral metastatic melanoma with nivolumab plus relatlimab with a complete clinical response. We describe the diagnosis and management of a patient with metastatic nodular melanoma treated with palliative resection of the primary tumor followed by immunotherapy with nivolumab and relatlimab. Four months after his first treatment, he had no evidence of disease on PET scan. He continued to show no evidence of disease at recent follow-up. Treatment of metastatic melanoma of the skin with nivolumab and relatlimab is an effective approach showing greater benefit to patients than nivolumab alone.

Robotic Cytoreductive Surgery With Heated Intraperitoneal Chemotherapy.

Cytoreductive surgery with heated intraperitoneal chemotherapy (CRS-HIPEC) is traditionally an open operation given the dissection required during cytoreduction. There are reports of minimally invasive HIPECs, but CRS to an accepted completeness of cytoreduction (CCR) has been described less frequently. We report a patient with metastatic low-grade mucinous appendiceal neoplasm (LAMN) to the peritoneum treated with robotic CRS-HIPEC. A 49-year-old male presented to our center following a laparoscopic appendectomy at an outside facility with final pathology showing LAMN. He had a peritoneal cancer index (PCI) score of 5 determined by diagnostic laparoscopy. Given the small amount of peritoneal disease, he was deemed a candidate for robotic CRS-HIPEC. Cytoreduction was completed robotically with a CCR score of 0. He then received HIPEC with mitomycin C. This case shows the feasibility of robotic-assisted CRS-HIPEC for select LAMNs. When appropriately selected, we advocate for the continued use of this minimally invasive approach.

Rosai-Dorfman Disease of the Chest Wall Following Mastectomy for Breast Cancer.

Rosai-Dorfman disease (RDD) is a rare benign proliferative histiocytic disorder generally affecting the cervical lymph nodes as sinus histiocytosis with massive lymphadenopathy. We present a unique case of multifocal soft tissue RDD originating from previous mastectomy site and retroperitoneum. The patient is a 62-year-old African American female with a prior history of bilateral breast invasive ductal adenocarcinoma. 2 years following completion of therapy, our patient re-presented with an abdominal wall mass. The core biopsy was discordant, and the mass had rapid growth prompting excision. After the excision of the abdominal wall mass pathology confirmed RDD. A PET confirmed a solitary mass behind the left kidney this mass was biopsied and confirmed that it was RDD in the retroperitoneum. Due to the slow growth of this mass observation was deemed reasonable. We present this case to highlight the need for further research to improve treatment guidelines and expectations.

Late Diagnosis of Metastatic Leiomyosarcoma Originating in the Ureter.

This case report highlights a patient with a leiomyosarcoma originating in the ureter. A chart review was performed on a single patient who presented with a malignant retroperitoneal mass measuring 11.5 × 8.2 × 6.5 cm with subsequent metastasis sites to the breast, pancreas, liver, and lungs. The diagnosis of a leiomyosarcoma is uncommon, accounting for 0.1-0.4% of all cancer diagnoses in the United States. The diagnosis of a leiomyosarcoma originating from the ureter is extremely rare with fewer than 20 reported cases to date. Lack of typical urinary tract cancer signs and symptoms prevented an early presentation, allowing for considerable tumor growth and making complete surgical resection unlikely. We present this case as an example of a rare presentation of a very rare disease and to emphasize the necessity for further research of leiomyosarcoma and early diagnosis.

Multiple Intraabdominal and Pelvic Cystadenomas From Ovarian Remnant Syndrome.

Serous cystadenomas are benign epithelial neoplasms of the ovary, and they typically have an average size of around 10 cm. Our patient is a 68-year-old female who originally presented with abdominal page. Our patient's prior surgical history includes a bilateral salpingo-oophorectomy. Computed tomography scans showed five abdominal and pelvic masses of significant size. Our patient elected to undergo exploratory laparotomy and mass excision, and all five masses were able to be removed successfully. Final pathology confirmed the diagnosis of serous cystadenomas consistent with ovarian origin despite our patient undergoing a previous bilateral salpingo-oophorectomy. Our patient presented with a rare syndrome known as ovarian remnant syndrome that is thought to be caused by difficult hysterectomy procedures and prior abdominal surgeries that can unknowingly leave ovarian remnants. Second, the patient was found to have 5 abdominal and pelvic masses, and most of the masses were a very large size.

Poorly Differentiated Metastatic Carcinoma of Possible Eccrine Sweat Gland Origin.

Sweat gland carcinomas are a rare group of cancer, representing less than .01% of all diagnosed skin malignancies. We report the case of a 32-year-old male who presented with a fungating lesion on the posterolateral side of his left knee. Immunohistochemical results were positive for cytokeratin 5/6 and cytokeratin 7, consistent with possible eccrine gland origin. Our patient underwent wide local excision of the mass with lymph node dissection. Pathology confirmed the diagnosis of poorly differentiated carcinoma of possible adnexal, eccrine gland origin. He completed taxol/cisplatin-based chemotherapy and radiation. Surveillance imaging showed bilateral lung nodules, a right pleural effusion, and peritoneal carcinomatosis, which were diagnostic of metastatic carcinoma. He started carboplatin and epirubicin chemotherapy and has been doing well. Because standard of care treatment options for metastatic eccrine carcinoma have not been developed, it is imperative to report these cases to better understand these complex tumors and their treatment.

Curcumin potentiates rhabdomyosarcoma radiosensitivity by suppressing NF-κB activity.

Ionizing radiation (IR) is an essential component of therapy for alveolar rhabdomyosarcoma. Nuclear factor-kappaB (NF-κΒ) transcription factors are upregulated by IR and have been implicated in radioresistance. We evaluated the ability of curcumin, a putative NF-κΒ inhibitor, and cells expressing genetic NF- κΒ inhibitors (IκBα and p100 super-repressor constructs) to function as a radiosensitizer. Ionizing radiation induced NF-κΒ activity in the ARMS cells in vitro in a dose- and time-dependent manner, and upregulated expression of NF-κΒ target proteins. Pretreatment of the cells with curcumin inhibited radiation-induced NF-κΒ activity and target protein expression. In vivo, the combination of curcumin and IR had synergistic antitumor activity against Rh30 and Rh41 ARMS xenografts. The greatest effect occurred when tumor-bearing mice were treated with curcumin prior to IR. Immunohistochemistry revealed that combination therapy significantly decreased tumor cell proliferation and endothelial cell count, and increased tumor cell apoptosis. Stable expression of the super-repressor, SR-IκBα, that blocks the classical NF-κB pathway, increased sensitivity to IR, while expression of SR-p100, that blocks the alternative pathway, did not. Our results demonstrate that curcumin can potentiate the antitumor activity of IR in ARMS xenografts by suppressing a classical NF-κΒ activation pathway induced by ionizing radiation. These data support testing of curcumin as a radiosensitizer for the clinical treatment of alveolar rhabdomyosarcoma. IMPACT OF WORK: The NF-κΒ protein complex has been linked to radioresistance in several cancers. In this study, we have demonstrated that inhibiting radiation-induced NF-κΒ activity by either pharmacologic (curcumin) or genetic (SR-IκBα) means significantly enhanced the efficacy of radiation therapy in the treatment of alveolar rhabdomyosarcoma cells and xenografts. These data suggest that preventing the radiation-induced activation of the NF-κΒ pathway is a promising way to improve the antitumor efficacy of ionizing radiation and warrants clinical trials.

HIF-1α activation mediates resistance to anti-angiogenic therapy in neuroblastoma xenografts.

INTRODUCTION: The anti-tumor activity of angiogenesis inhibitors is often limited by the development of resistance to these drugs. Here we establish HIF-1α as a major factor in the development of this resistance in neuroblastoma xenografts. METHODS: Neuroblastoma xenografts were established by injecting unmodified SKNAS or NB-1691 cells (2 × 10(6) cells), or cells in which HIF-1α expression had been knocked down with shRNA, into the retroperitoneal space of SCID mice. Treatment of established tumors included bevacizumab (5mg/kg q2wk), sunitinib (40 mg/kg qd), or topotecan (0.5mg/kg qd) alone or in combination for a total of two weeks. RESULTS: NB-1691 xenografts showed no difference in relative growth in HIF-1α knockdowns compared to control tumors (73.33 ± 7.90 vs 79.94 ± 6.15, p=0.528). However, HIF-1α knockdowns demonstrated relative final volumes that were significantly lower than unmodified tumors when both were treated with bevacizumab (35.88 ± 4.24 vs 53.57 ± 6.61, p=0.0544) or sunitinib (12.46 ± 2.59 vs 36.36 ± 4.82, p=0.0024). Monotherapy of unmodified xenografts with bevacizumab, sunitinib, or topotecan was largely ineffective. Relative final volumes of NB-1691 xenografts were significantly less in cohorts treated with sunitinib+topotecan (4.78 ± 0.77 vs 39.17 ± 2.44 [sunitinib alone], p=0.011) and bevacizumab+topotecan (13.63 ± 1.55 vs 48.16 ± 9.94 [bevacizumab alone], p=0.014). CONCLUSION: Upregulation of HIF-1α appears to be a significant mechanism of resistance to antiangiogenic therapies in neuroblastoma. Suppressing HIF-1α with low-dose topotecan potentiates the effects of the antiangiogenic drugs in a mouse model.

Rapamycin increases neuroblastoma xenograft and host stromal derived osteoprotegerin inhibiting osteolytic bone disease in a bone metastasis model.

PURPOSE: Osteoprotegerin (OPG) is a decoy receptor for the Receptor of NF-κB (RANK) ligand that can inhibit osteoclastogenesis. Previous studies have suggested that Mammalian Target of Rapamycin (mTOR) inhibition upregulates OPG production. We tested the hypothesis that the mTOR inhibitor rapamycin could inhibit neuroblastoma bone metastases through its action on OPG. EXPERIMENTAL DESIGN: An orthotopic model of bone metastasis was established. Mice with established disease were subsequently treated with rapamycin (5mg/kg IP daily) or vehicle control (DMSO 1:1000). X-rays were obtained twice a week to detect pathologic fractures. Serum OPG levels were measured by ELISA after two weeks of treatment. RESULTS: Mice with bone disease receiving rapamycin had increased serum levels of OPG in the CHLA-20 mice compared to controls (36.89 pg/mL ± 3.90 vs 18.4 pg/mL ± 1.67, p=0.004) and NB1691 tumor-bearing groups (46.03 ± 2.67 pg/mL vs 17.96 ± 1.84pg/mL, p=0.001), and a significantly longer median time to pathologic fractures with CHLA-20 (103 days vs 74.5 days, p=0.014) and NB1691 xenografts. CONCLUSION: In a xenograft model, increased OPG expression correlated with a delay to pathologic fracture suggesting a potential role for mTOR inhibitors in the treatment of neuroblastoma bone metastases.

Toward defining grade C pancreatic fistula following pancreaticoduodenectomy: incidence, risk factors, management and outcome.

BACKGROUND: In 2005 the International Study Group for Pancreatic Fistula (ISGPF) created a definition and grading system for pancreatic fistulae (PF) in which grade C denotes the most severe and potentially life-threatening type. Factors and outcomes associated with grade C fistulae have been ill defined. METHODS: Systematic searches of PubMed and EMBASE were conducted by two independent reviewers utilizing the keywords 'pancreaticoduodenectomy' (PD) and 'pancreatic fistula'. Inclusion criteria were: (i) a sample of ≥100 patients; (ii) consecutive accrual of all pathologies, and (iii) use of the ISGPF definition and grading system. Quality appraisal and data extraction were performed using pilot-tested templates. RESULTS: Fourteen articles describing a total of 2706 PDs met the study entrance criteria. Pancreatic fistulae occurred in 479 patients (18%) and included 71 grade C PF that were directly responsible for 25 deaths (35% mortality rate). Only two studies analysed risk factors; these found soft pancreatic texture and histology other than adenocarcinoma to be the most common risk factors. Ten studies reported management strategies and indicated that 51% of patients required reoperation. CONCLUSIONS: Grade C PF: (i) accounts for 15% of fistulae following PD and has an associated mortality rate of 35%; (ii) occurs most commonly in pathology associated with a soft remnant, and (iii) requires reoperation in approximately one half of patients. The published literature incompletely describes grade C PF.

Analysis of prognostic factors in extraosseous Ewing sarcoma family of tumors: review of St. Jude Children's Research Hospital experience.

BACKGROUND: Advances in the treatment of Ewing sarcoma family of tumors (ESFT) are the result of improvements in systemic and local therapies. Clinical data of extraosseous ESFT are scarce. METHODS: A retrospective analysis of all patients with extraosseous ESFT treated at St. Jude Children's Research Hospital (SJCRH) from June 1982 to August 2009. RESULTS: Forty-six patients with extraosseous ESFT were identified. The mean age at diagnosis was 13.8 years. The majority of patients were male and white. The most common site of primary tumor was the trunk. Twelve patients had subcutaneous tumors. The median tumor size was 8 cm. Six patients (13 %) had metastatic disease at diagnosis. A total of 59 % of patients were alive at the time of analysis, with a median follow-up from diagnosis of 15.3 years. Fifteen-year estimates of survival and event-free survival (EFS) for all patients were 53.3 ± 9.4 and 50 ± 9.1 %, respectively. Fifteen-year estimates of survival and EFS with localized disease were 61.4 ± 9.8 and 57.6 ± 9.7 %, respectively. Stage and subcutaneous ESFT were significant predictors of outcome. There was no significant difference in patient's demographics and tumor characteristics between patients with skeletal ESFT and extraosseous Ewing sarcoma. The outcome for patients with localized extraosseous Ewing sarcoma was similar to that reported for all localized ESFT patients treated at SJCRH. CONCLUSIONS: The outcome for localized patients treated with extraosseous ESFT was similar to that reported for all ESFT patients treated on protocols at SJCRH. Patients with subcutaneous ESFT had a favorable prognosis when compared to their counterparts.

Rapamycin-induced tumor vasculature remodeling in rhabdomyosarcoma xenografts increases the effectiveness of adjuvant ionizing radiation.

PURPOSE: Rapamycin inhibits vascular endothelial growth factor expression. Vascular endothelial growth factor is a tumor-elaborated protein that stimulates neovascularization. This inhibition can cause transient "normalization" of the generally dysfunctional tumor vasculature, resulting in improved tumor perfusion and oxygenation. We hypothesized that this may potentiate the antitumor effects of adjuvant ionizing radiation. METHODS: Mice bearing orthotopic Rh30 alveolar rhabdomyosarcomas were treated with rapamycin (5 mg/kg intraperitoneally daily ×5). Tumors were then evaluated for changes in intratumoral oxygenation, perfusion, vessel permeability, and microvessel density. Additional tumor-bearing mice were treated with 5 doses of rapamycin, irradiation (4 Gy), or 5 doses of rapamycin with irradiation administered on the first or sixth day of rapamycin treatment. RESULTS: Although tumor vessel permeability changed only minimally, microvessel density decreased (3153 ± 932 vs 20,477 ± 3717.9 pixels per high-power field), whereas intratumoral oxygenation increased significantly (0.0385 ± 0.0141 vs 0.0043 ± 0.0023 mm Hg/mm(3)) after 5 doses of rapamycin. Contrast-enhanced ultrasound demonstrated a significantly increased rate of change of signal intensity after 5 days of rapamycin, suggesting improved intratumoral perfusion. Tumor volume 14 days after treatment was smallest in mice treated with the combination of rapamycin given before irradiation. CONCLUSION: Combination therapy with rapamycin given before irradiation to normalize the tumor vasculature, thereby improving tumor oxygenation, increased the sensitivity of alveolar rhabdomyosarcoma xenografts to adjuvant irradiation.

Continuous local delivery of interferon-ß stabilizes tumor vasculature in an orthotopic glioblastoma xenograft resection model.

BACKGROUND: High-grade glioblastomas have immature, leaky tumor blood vessels that impede the efficacy of adjuvant therapy. We assessed the ability of human interferon (hIFN)-ß delivered locally via gene transfer to effect vascular stabilization in an orthotopic model of glioblastoma xenograft resection. METHODS: Xenografts were established by injecting 3 grade IV glioblastoma cell lines (GBM6-luc, MT330-luc, and SJG2-luc) into the cerebral cortex of nude rats. Tumors underwent subtotal resection, and then had gel foam containing an adeno-associated virus vector encoding either hIFN-ß or green fluorescence protein (control) placed in the resection cavity. The primary endpoint was stabilization of tumor vasculature, as evidenced by CD34, α-SMA, and CA IX staining. Overall survival was a secondary endpoint. RESULTS: hIFN-ß treatment altered the tumor vasculature of GBM6-luc and SJG2-luc xenografts, decreasing the density of endothelial cells, stabilizing vessels with pericytes, and decreasing tumor hypoxia. The mean survival for rats with these neoplasms was not improved, however. In rats with MT330-luc xenografts, hIFN-ß resulted in tumor regression with a 6-month survival of 55% (INF-ß group) and 9% (control group). CONCLUSION: The use of AAV hIFN-ß in our orthotopic model of glioblastoma resection stabilized tumor vasculature and improved survival in rats with MT330 xenografts.