Genomic characterization of an esthesioneuroblastoma with spinal metastases: illustrative case.

BACKGROUND: Esthesioneuroblastoma (ENB) is a rare neoplasm of the sinonasal tract. Currently, the optimal treatment includes maximal resection combined with radiotherapy and/or chemotherapy. Although ENBs often recur and have an aggressive clinical course, spinal metastases are extremely rare and the underlying molecular mechanisms are poorly understood. OBSERVATIONS: Here, the authors describe a 50-year-old male with an aggressive ENB, initially treated with resection and chemotherapy/radiation, who developed multiple thoracic and lumbar spinal metastases. The authors performed targeted exome sequencing on both the resected primary tumor and biopsied spinal metastases, which revealed 12 total variants of unknown clinical significance in genes associated with the PI3K/AKT/mTOR pathway, chromatin remodeling, DNA repair, and cell proliferation. Six of these variants were restricted to the metastatic lesion and included missense mutations with predicted functional effects in GRM3, DNMT3B, PLCG2, and SPEN. LESSONS: This report discusses the potential impact of these variants on tumor progression and metastasis, as well as the implications for identifying potential new biomarkers and therapies.

Association of advanced age and cancer history with autoimmune disease in melanoma patients: a cross-sectional study.

BACKGROUND: Immune-related adverse events (irAEs) are a major toxicity of immune checkpoint inhibitors. Studies have reported that pre-existing autoimmunity increases the risk of irAEs, but it remains unknown which clinical factors are linked to auto-immune disorders in cancer patients. This study aimed to evaluate if the prevalence of autoimmune diseases varied by specific cancer history and advanced age. METHODS: Our cross-sectional medical record review consisted of 291,333 patients (age, ≥18 years) treated between 2000 and 2018. Patients were classified into four study groups (melanoma only, non-cutaneous solid cancer only, melanoma and non-cutaneous cancer, and no cancer history). Dependent variable was the presence of ≥1 autoimmune disorders based on 98 conditions using 317 ICD codes. RESULTS: Non-cutaneous cancer, in the absence or presence of melanoma, was associated with a higher prevalence of autoimmunity (16.5, 95% CI 16.1-16.9; 20.0, 95% CI 18.3-21.7, respectively) compared to the rates in patients with melanoma only and those without cancer history (9.3, 95% CI 8.6-10.0; 6.2, 95% CI 6.1-6.3, respectively). Among patients with metastases at initial presentation, those in the melanoma and non-cutaneous cancer group had a prevalence of 24.0% (95% CI 20.1-27.9) compared to 19.1% (95% CI 17.2-21.0) in those without metastases. Multiple logistic regression demonstrated that patients > 75 years exhibited the highest odds of autoimmunity relative to other age groups, with age 18-34 as the referent (OR, 1.78, 95% CI 1.67-1.89). CONCLUSIONS: Among patients with melanoma, the greatest prevalence of autoimmunity occurred with advanced age and a history of non-cutaneous cancer.

Intracranial bleeding following soccer-related head trauma in a young student with occult factor VII deficiency.

It is important to obtain coagulation tests to assess bleeding risk in trauma patients undergoing emergency surgery when a bleeding disorder may be obscured. Identifying specific clotting factor defects is critical in successful patient management.

Current status of chimeric antigen receptor engineered T cell-based and immune checkpoint blockade-based cancer immunotherapies.

Adoptive cell therapies with chimeric antigen receptor (CAR) engineered T cells (CAR-T) and immune checkpoint inhibition (ICI)-based cancer immunotherapies have lately shown remarkable success in certain tumor types. CAR-T cell-based therapies targeting CD19 can now induce durable remissions as well as prolong disease-free survival of patients with CD19 positive treatment refractory B cell malignancies and ICI-based therapies with humanized monoclonal antibodies against the T cell inhibitory receptors CTLA-4 and PD-1 as well as against the PD-1 ligand, PD-L1, can now achieve durable remissions as well as prolongation of life of a sizeable fraction of patients with melanoma and Hodgkin's lymphoma and non-small cell cancers. Most importantly, these immuno-therapeutic treatment modalities have raised the possibility of achieving long-term "containment" as well as "cures" for certain types of cancer. While this represents major advances in cancer immunotherapy, both modalities come with considerable toxicities, including fatalities. Although more work will be needed to bring CAR-T cell-based therapies to the bedside for most major cancers and a good deal more will be needed to make ICI-alone or in combination with other treatment modalities-work more consistently and across most major cancers, these two treatment modalities stand out as superb examples of successful translation of bench research to the bedside as well as represent real progress in the field of cancer immunotherapy.

Randomized double-blind placebo-controlled trial of celecoxib for oral mucositis in patients receiving radiation therapy for head and neck cancer.

OBJECTIVES: Oral mucositis (OM) is a painful complication of radiation therapy (RT) for head and neck cancer (H&NC). OM can compromise nutrition, require opioid analgesics and hospitalization for pain control, and lead to treatment interruptions. Based on the role of inflammatory pathways in OM pathogenesis, we investigated effect of cyclooxygenase-2 (COX-2) inhibition on severity and morbidity of OM. METHODS: In this double-blind placebo-controlled trial, 40 H&NC patients were randomized to daily use of 200 mg celecoxib or placebo, for the duration of RT. Clinical OM, normalcy of diet, pain scores, and analgesic use were assessed 2-3 times/week by blinded investigators during the 6-7 week RT period, using validated scales. RESULTS: Twenty subjects were randomized to each arm, which were similar with respect to tumor location, radiation dose, and concomitant chemotherapy. In both arms, mucositis and pain scores increased over course of RT. Intention-to-treat analyses demonstrated no significant difference in mean Oral Mucositis Assessment Scale (OMAS) scores at 5000 cGy (primary endpoint). There was also no difference between the two arms in mean OMAS scores over the period of RT, mean worst pain scores, mean normalcy of diet scores, or mean daily opioid medication use in IV morphine equivalents. There were no adverse events attributed to celecoxib use. CONCLUSIONS: Daily use of a selective COX-2 inhibitor, during period of RT for H&NC, did not reduce the severity of clinical OM, pain, dietary compromise or use of opioid analgesics. These findings also have implications for celecoxib use in H&NC treatment regimens (NCT00698204).

Metastatic melanoma in the older patient: special considerations.

Cancer is a disease of older age where genomic instability, impaired DNA repair, and weakened immune surveillance against cancer are recognized to play a causative role. Because the incidence of melanoma is increasing at a very fast pace in the elderly and there is a rapid expansion of the aging population, a large number of elderly patients with metastatic melanoma will be encountered in clinical practice. As a result, significant burden is expected to be placed on health care resources as effective treatment of this condition is sought. Because melanoma is an immunogenic tumor and promising immune-based treatments have acquired approval for treatment of metastatic melanoma, their successful use in elderly patients will require knowledge about aging and associated alterations in immune function. The spotlight will likely remain on antitumor immunity, its regulation and quality, and the profiles of the cytokines that shape the tumor microenvironment.

Analyses of T cell-mediated immune response to a human melanoma-associated antigen by the young and the elderly.

Elderly cancer patients are often excluded from immune-based clinical trials and therapies based on the belief that they respond poorly to tumor antigens. Using melanoma as a model and melanoma related Mart-127-35 epitope specific T cell receptor (TCR) engineered T cells as a tool we compared the T cell responses from young and elderly to the Mart-127-35 epitope, ex vivo. We also compared the natural Treg (nTreg) activities and the expression of a number of genes associated with immune response by quantitative real-time reverse Transcription Polymerase Chain Reaction (qRTPCR) in formalin fixed primary melanomas, in situ. We detected a significant difference in CD8(+) T cell response to Flu antigen (influenza matrix peptide Flu MP58-66), but the responses of the two cohorts to melanoma antigen were comparable. nTreg activities in the elderly was significantly compromised. The qPCR analyses of tissues from elderly patients revealed lower levels of Fox-P3 expression but comparable levels of expression of IL-2, IFNγ, TNFα, IL-4, IL-10, IDO, and TGFß. These findings indicate that elderly patients might be capable of responding to tumor antigens, and need not be excluded from immune-based therapies or clinical trials.

Ethical issues in cutaneous melanoma.

Early diagnosis of cutaneous melanoma (CM) is associated with the finding of superficial tumors resulting in high cure rates with surgery, whereas those with deeply invasive tumors are at higher risk of recurrence and melanoma-specific mortality. Unfortunately, once metastatic to the visceral organs, CM is usually refractory to the presently available treatment modalities, resulting in uniformly poor outcomes in patients. Educating susceptible populations about the risk of developing CM has played an important role in preventive strategies despite the fact that benefits of primary skin screening are controversial. Although a number of reliable prognostic factors are recognized, clinical unpredictability is reflected by a small but significant proportion of patients who experience adverse outcomes from CM, even though lacking the known poor prognostic markers. Because CM is an immunogenic tumor, most of the new treatments have engaged in harnessing antimelanoma immunity, and recent advances in genomics have led to promising targeted therapies. A number of ethical issues have confronted health care providers when taking care of CM patients in different stages of the disease, which have included areas of primary prevention, early diagnosis, strategies to reduce recurrence of the tumor, and managing patients with advanced tumors. With the increasing incidence of CM in fair-skinned people, as well as the increasing recognition of CM in nonwhites, addressing the discussed ethical issues will be even more challenging and important as we provide comprehensive management of this disease.

Metastatic melanoma in the older patient: immunologic insights and treatment outcomes.

Cutaneous melanoma (CM) is a highly curable skin cancer of melanocytes if diagnosed early. Unfortunately, its invasion into the deeper dermis increases the risk of it spreading to the lymph nodes and distant organs. Spread of metastatic melanoma (MM) to other organs is among one of the most dangerous conditions that is almost uniformly fatal for the majority of patients with the currently available treatment modalities. Since melanoma is an immunogenic tumor, developing novel immune strategies will continue to play a critical role in designing effective treatment modalities for those at high risk of recurrence and those with distant metastasis. While older age is believed to be a poor prognostic marker for CM, rapid expansion of the aging population and its projected increase in the coming decades is expected to result in a large number of elderly melanoma patients seeking treatment in all stages of disease. This will not only bring with it unique management challenges in this population, but also an increased burden on communities to provide financial and social resources. Comprehensive efforts will need to be directed towards early diagnosis, as well as developing safe and effective treatment. Renewed interest in the cancer immune surveillance theory coupled with recognition of aging-associated weaknesses in the immune system has put the spotlight on immunsenescence as a important risk factor for the rising incidence of CM in the aging population. Comprehensive assessment of the aging immune system might shed light, not only on weaknesses of individual components of the adaptive immune system, but also on the critical imbalances resulting from these weaknesses on anti-melanoma immunity. Identifying these imbalances might help harness novel immune-based treatment of MM in selected elderly patients. This article describes our experience of treating elderly patients with MM and the issues unique to them, with particular emphasis on insights into the aging immune system.

Intrathoracic lymphadenopathy: sarcoidosis or metastatic seminoma? The diagnostic dilemma revisited.

There exists a rare enigmatic relation between testicular germ cell tumors (particularly seminoma) and granulomatous inflammation of lymph nodes and organs akin to sarcoidosis. We report a young patient with stage I testicular seminoma followed by close surveillance after radical orchidectomy, who developed hilar and subcarinal lymphadenopathy more than two years after the original diagnosis. A mediastinal biopsy was consistent with noncaseating granuloma with no evidence of tumor. Our case highlights the importance of histologic confirmation of the etiology of lymphadenopathy in these cases. We reiterate that histological examination remains the cornerstone for establishing a definite and accurate diagnosis of testicular seminoma relapse.

Melanoma in the elderly patient: relevance of the aging immune system.

The rapidly expanding segment of the aging population with its rising incidence of cutaneous melanoma will present major challenges in therapeutic management. Immune strategies will be important in designing effective treatment of melanoma because it is a highly immunogenic tumor. Aging, however, is associated with dysregulation of the immune system and is likely to affect the success of melanoma treatment in the elderly population. This population represents an ideal in vivo model to study the effects of the aging immune system on the natural history of melanoma in the elderly. We review the epidemiology, histopathologic features, and treatment outcomes of elderly melanoma patients with reference to their immune function. Various components of the normal immune system are described, and the immune response to melanoma is recapitulated. Particular emphasis is placed on the growing understanding of the innate, adaptive, and regulatory arms of the aging immune system.

Rituximab treatment of refractory fludarabine-associated immune thrombocytopenia in chronic lymphocytic leukemia.

Fludarabine can exacerbate idiopathic thrombocytopenia (ITP) in chronic lymphocytic leukemia (CLL). We report 3 CLL patients with refractory fludarabine-associated ITP who responded to rituximab. The patients had Rai stages III, III, and IV disease. Before fludarabine treatment, the platelet counts were 141 000/microL, 118 000/microL, and 70 000/microL. ITP developed within week 1 of cycle 3 in 2 patients and within week 2 of cycle 1 in 1 patient. Platelet count nadirs were 4000/microL, 1000/microL, and 2000/microL, respectively, and did not respond to treatment with steroids or intravenous immunoglobulin. Rituximab therapy (375 mg/m(2) per week for 4 weeks) was begun on days 18, 23, and 20 of ITP. Patient 1 achieved a platelet count of more than 50 000/microL at day 21 and more than 133 000/microL at day 28, patient 2 achieved a platelet count of more than 50 000/microL at day 4 and more than 150 000/microL at day 10, and patient 3 achieved a platelet count of more than 50 000/microL at day 5 and 72 000/microL at day 28 of rituximab therapy, with platelet response durations of 17+, 6+, and 6 months. These results suggest rituximab can rapidly reverse refractory fludarabine-associated ITP.