Utility of TTMV-HPV DNA in resolving indeterminate findings during oropharyngeal cancer surveillance.

OBJECTIVES: Clinical and imaging examinations frequently have indeterminate results during cancer surveillance, which can lead to overtreatment and cause psychological and financial harm to the patient. This study addresses the critical need to enhance diagnostic precision and decision-making in the management of HPV-associated oropharyngeal cancer. This study evaluated the utility of tumor tissue-modified viral (TTMV)-HPV DNA to resolve indeterminate disease status following definitive treatment for HPV-associated oropharyngeal cancer. MATERIALS AND METHODS: In this retrospective cohort, patients treated for HPV-associated oropharyngeal cancer at eight U.S. institutions and who received one or more TTMV-HPV DNA tests during post-treatment surveillance between February 2020 and January 2022 were included. RESULTS: Among 543 patients, 210 patients (38.7%; 210/543) experienced one or more clinically indeterminate findings (CIFs) during surveillance, with 503 CIFs recorded. Of those patients with an "indeterminate" disease status at a point during surveillance, 79 were associated with contemporaneous TTMV-HPV DNA testing. TTMV-HPV DNA testing demonstrated high accuracy (97.5%; 77/79) in correctly determining recurrence status. Patients whose disease status was "indeterminate" at the time of a positive TTMV-HPV DNA test were clinically confirmed to recur faster than those whose disease status was "no evidence of disease." Only 3% of patients (17/543) experienced indeterminate TTMV-HPV DNA tests during surveillance. Discordance between TTMV-HPV DNA tests and clinical results was minimal, with only 0.6% (3/543) of patients showing positive tests without recurrence. CONCLUSION: Our findings support the utility of circulating TTMV-HPV DNA in resolving indeterminate disease status and informing the subsequent clinical course.

Negative Predictive Value of Circulating Tumor Tissue Modified Viral (TTMV)-HPV DNA for HPV-driven Oropharyngeal Cancer Surveillance.

PURPOSE: Human papillomavirus (HPV) is causally linked to oropharyngeal squamous cell carcinoma (OPSCC). Consensus guidelines recommend clinical exams and imaging in decreasing frequency as part of posttreatment surveillance for recurrence. Plasma tumor tissue modified viral (TTMV)-HPV DNA testing has emerged as a biomarker which can inform disease status during surveillance. EXPERIMENTAL DESIGN: This retrospective observational cohort study involved 543 patients who completed curative-intent therapy for HPV-associated OPSCC between February 2020 and January 2022 at eight U.S. cancer care institutions. We determined the negative predictive value (NPV) of TTMV-HPV DNA for recurrence when matched to physician-reported clinical outcome data (median follow-up time: 27.9 months; range: 4.5-154). RESULTS: The cohort included mostly men with a median age of 61 who had locoregionally advanced disease. HPV status was determined by p16 positivity in 87% of patients, with a positive HPV PCR/ISH among 55%; while pretreatment TTMV-HPV DNA status was unknown for most (79%) patients. Patients had a mean of 2.6 tests and almost half had three or more TTMV-HPV DNA results during surveillance. The per-test and per-patient sensitivity of the assay was 92.5% [95% confidence interval (CI): 87.5-97.5] and 87.3% (95% CI: 79.1-95.5), respectively. The NPV for the assay was 99.4% (95% CI: 98.9-99.8) and 98.4% (95% CI: 97.3-99.5), respectively. CONCLUSIONS: TTMV-HPV DNA surveillance testing yields few false negative results and few missed recurrences. These data could inform decisions on when to pursue reimaging following first disease restaging and could inform future surveillance practice. Additional study of how pretreatment TTMV-HPV DNA status impacts sensitivity for recurrence is needed.

Clinical implications of loss of bone marrow minimal residual disease negativity in multiple myeloma.

Multiple myeloma (MM) patients frequently attain a bone marrow (BM) minimal residual disease (MRD) negativity status in response to treatment. We identified 568 patients who achieved BM MRD negativity following autologous stem cell transplantation (ASCT) and maintenance combination therapy with an immunomodulatory agent and a proteasome inhibitor. BM MRD was evaluated by next-generation flow cytometry (sensitivity of 10-5 cells) at 3- to 6-month intervals. With a median follow-up of 9.9 years from diagnosis (range, 0.4-30.9), 61% of patients maintained MRD negativity, whereas 39% experienced MRD conversion at a median of 6.3 years (range, 1.4-25). The highest risk of MRD conversion occurred within the first 5 years after treatment and was observed more often in patients with abnormal metaphase cytogenetic abnormalities (95% vs 84%; P = .001). MRD conversion was associated with a high risk of relapse and preceded it by a median of 1.0 years (range, 0-4.9). However, 27% of MRD conversion-positive patients had not yet experienced a clinical relapse, with a median follow-up of 9.3 years (range, 2.2-21.2). Landmark analyses using time from ASCT revealed patients with MRD conversion during the first 3 years had an inferior overall and progression-free survival compared with patients with sustained MRD negativity. MRD conversion correctly predicted relapse in 70%, demonstrating the utility of serial BM MRD assessment to complement standard laboratory and imaging to make informed salvage therapy decisions.

Intravascular Large B-Cell Lymphoma: A Diagnostic Dilemma.

Intravascular large B-cell lymphoma is a rare malignancy characterized by the presence of lymphoma cells within the lumen of blood vessels. The annual incidence of cases is fewer than 0.5 cases per 1,000,000. It usually affects the elderly with an average age of diagnosis around 70 years. Due to the absence of lymphoma cells in the peripheral smear and lymphadenopathy, it is difficult to diagnose these cases. Although the central nervous system and skin are the commonly involved organs, they can involve any organ system. Prompt diagnosis and initiation of treatment are very crucial as it carries a high mortality. We describe two patients who presented with constitutional symptoms and fever of unknown origin, later diagnosed as intravascular large B- cell lymphoma. The diagnosis was difficult in both cases as the presenting symptoms were atypical. One of the patients was diagnosed at autopsy. The delay in diagnosis often leads to fatal outcomes as the disease is very aggressive. A high degree of clinical suspicion is the key to prompt diagnosis and improved outcomes.

Clinical and histological response to combination nivolumab and ipilimumab in metastatic renal cell carcinoma.

Patients with renal cell carcinoma (RCC) often remain asymptomatic until the disease is advanced, with about 25% presenting at an advanced stage. We present a case of metastatic RCC treated with combination ipilimumab and nivolumab with complete radiological and pathological response. Currently, combination nivolumab and ipilimumab is a preferred option for intermediate- and poor-risk patients with clear cell stage IV RCC.

Acquired hemophilia A.

Acquired inhibitors of coagulation are a group of rare but potentially life-threatening blood disorders characterized by the presence of autoantibodies directed against clotting factor. Autoantibody against factor VIII is the most common form of clotting factor inhibitor, a condition also known as acquired hemophilia A. We present a clinical series of nine patients diagnosed and treated for acquired hemophilia A at our institution. Among these nine patients, there were five men and four women with a median age of 64 years. All patients presented with bleeding diathesis. Factor eight inhibitor bypassing agent and/or recombinant factor VIIa were predominantly used for control of active bleeding. For elimination of autoantibodies, either steroids alone or the combination of steroids with rituximab or oral cyclophosphamide was used. Despite aggressive measures, two of the patients had a poor outcome; seven of the nine patients (77%) had a good clinical outcome. Acquired hemophilia A should be strongly suspected in any patient presenting with bleeding and a prolonged activated partial thromboplastin time. Early initiation of factor bypassing agents such as activated prothrombin complex concentrates or recombinant factor VIIa, along with the use of immunosuppressive agents, can be lifesaving.

Immunotherapy Outcomes in Advanced Melanoma in Relation to Age.

INTRODUCTION: Older age is a melanoma risk factor. Elderly individuals are likelier to have immunosenescence, which could help melanoma cells escape immune surveillance. Hence, it is believed that elderly people cannot mount a potent immune response to checkpoint inhibitors to eliminate melanoma. OBJECTIVES: To investigate age-related differences in the time to progression, overall survival, and immunotherapy-related adverse events among patients with metastatic melanoma who received checkpoint inhibitors. METHODS: We retrospectively identified patients at our institution between January 2012 and December 2016 with stage IV melanoma who received at least 1 dose of ipilimumab, pembrolizumab, nivolumab, or combined ipilimumab and nivolumab. Demographic, pathologic, and clinical characteristics were obtained. Immune-related response criteria were used to define responses. RESULTS: Twenty-nine patients were younger than age 65 years and 31 were age 65 years or older. Time to progression was comparable between the age groups (hazard ratio = 0.79, 95% confidence interval = 0.37-1.70, p = 0.46). Overall survival was not significantly different after immunotherapy between groups (hazard ratio = 0.75, 95% confidence interval = 0.31-1.82, p = 0.491). Overall, immunotherapy-related adverse events were comparable between groups, with 62% in younger patients (18/29) and 45% in older patients (14/31 p = 0.19). Of 60 patients, 30 responded to immunotherapy. Nonresponders were more likely than responders to have BRAF-mutated melanomas (16 [53.3%] vs 8 [27.6%]; p = 0.04) and less likely to have immunotherapy-related adverse events (12 [40%] vs 20 [66.7%]; p = 0.04). CONCLUSION: Aging does not seem to affect response to checkpoint inhibitors. Elderly patients with metastatic melanoma should be treated similarly to younger patients.

Hemophagocytic lymphohistiocytosis in adults.

Hemophagocytic lymphohistiocytosis (HLH) is an underrecognized disorder due to the variability of its presentation and the fact that in adults, its diagnosis is based on cumbersome, pediatric-based criteria. Data regarding demographics, underlying causes, clinical features, laboratory results, complications, treatments received, and clinical outcomes were collected and analyzed in 41 patients who were diagnosed and treated at University of Arkansas for Medical Sciences between 2007 and 2019. In this group, 51% were male, the median age at diagnosis was 47 years, and 85% (35/41) met the HLH-2004 diagnostic criteria (5/8 variables). When evaluating seven extended variables easily obtained by routine laboratory test, 93% (38/41) of patients met 8 out of 15 criteria. The overall mortality in our patient population was 54% (22/41). The 30-day and 1-year overall survival estimates were 0.73 (95% confidence interval 0.56, 0.84) and 0.46 (95% confidence interval 0.29, 0.62), respectively. Thirty-five patients (85.4%) received HLH-directed therapy, and 19 patients (46.3%) achieved remission. The most common regimen for treating HLH was dexamethasone plus etoposide (53.7%). The patients with malignancy-related HLH had a worse prognosis than those without underlying malignancy, with a 73.33% (11/15) vs 34.62% (9/26) mortality (P = 0.02). In conclusion, despite increasing recognition, HLH remains an enigmatic disorder with increased mortality, even more so with malignancy-associated HLH.

Diarrhea-associated Hemolytic Uremic Syndrome in Adults: Two Case Reports and Review of the Literature.

Hemolytic uremic syndrome (HUS) is a type of thrombotic microangiopathy syndrome (TMA) defined as a triad of non-immune microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney injury. Shiga toxin (Stx) or diarrhea-associated HUS is one of the major categories of secondary HUS, which is seen predominantly in children and is regarded as a rare entity in the adult population. We present two cases of sporadic Stx or diarrhea-associated HUS in adult females. Our first case is a 74-year-old Caucasian woman who presented to the emergency department with nausea, vomiting, and bloody diarrhea for five days. The patient reported a history of consuming meatloaf from a local store three days prior to the onset of symptoms. On presentation, laboratory workup was consistent with hemolytic anemia, thrombocytopenia, and acute kidney injury. Thrombocytopenic purpura was ruled out with normal ADAMTS13 activity. The patient's kidney function improved and the platelet count recovered to normal with supportive measures and did not require renal replacement therapy. In the second case, we describe a 79-year-old Caucasian woman with a history of metastatic lung cancer who presented with abdominal pain, nausea, vomiting, and bloody diarrhea. History was positive for consuming meat from a local restaurant a day prior to the onset of symptoms. Initial laboratory work showed severe thrombocytopenia, microangiopathic hemolytic process, and acute kidney injury requiring continuous renal replacement therapy. Due to the unfavorable prognosis of her metastatic lung cancer, the patient and the family members decided to opt for hospice care and she was subsequently transferred to the inpatient hospice. Diarrhea-associated HUS or Stx-HUS is a relatively underreported entity among the adult population. The treatment of typical or Stx-HUS is mainly supportive, but it is critical to rule out other causes of TMAs, especially thrombotic thrombocytopenic purpura (TTP), as it is a medical emergency that requires prompt plasmapheresis.

Acute Influenza Infection Presenting with Cardiac Tamponade: A Case Report and Review of Literature.

INTRODUCTION: Cardiac complications associated with influenza infection can occur either via a direct effect of the virus on the heart or through exacerbation of preexisting cardiovascular disease. We present a case of a 57-year-old man with acute influenza infection complicated by pericardial effusion and cardiac tamponade. CASE PRESENTATION: A 57-year-old white man presented to the Emergency Department with sudden onset of severe, nonexertional, retrosternal, pressure-like chest pain for a few hours and with fever and muscle aches for 2 days. The patient was initially admitted because of suspected acute coronary syndrome. The next morning, he complained of acute-onset shortness of breath and had hypotension and tachycardia. On examination, his peripheral extremities were cold and heart sounds were distant. Pulsus paradoxus was 20 mmHg. The electrocardiogram showed low-voltage QRS complex with electrical alternans. An urgently performed bedside echocardiogram showed moderate pericardial effusion with a small right ventricular cavity with diastolic collapse. Emergent pericardiocentesis was performed, with removal of 250 mL of fluid from the pericardial space. The patient's hemodynamic status immediately improved. Analyses of pericardial fluid demonstrated no bacteria, acid-fast bacilli, or malignant cells. The result of a rapid influenza diagnostic test with polymerase chain reaction was positive for influenza A virus, with other viral panels yielding normal results. The patient was treated with oseltamivir for 5 days. DISCUSSION: Pericardial involvement is a rare and perhaps underreported complication of influenza infection. Early recognition of cardiac symptoms and appropriate diagnostic workup in a patient presenting with influenza-like symptoms is important to avoid life-threatening complications.