5-Hydroxymethylcytosine in Cell-Free DNA Predicts Immunotherapy Response in Lung Cancer.

Immune checkpoint inhibitors (ICIs) drastically improve therapeutic outcomes for lung cancer, but accurately predicting individual patient responses to ICIs remains a challenge. We performed the genome-wide profiling of 5-hydroxymethylcytosine (5hmC) in 85 plasma cell-free DNA (cfDNA) samples from lung cancer patients and developed a 5hmC signature that was significantly associated with progression-free survival (PFS). We built a 5hmC predictive model to quantify the 5hmC level and validated the model in the validation, test, and control sets. Low weighted predictive scores (wp-scores) were significantly associated with a longer PFS compared to high wp-scores in the validation [median 7.6 versus 1.8 months; p = 0.0012; hazard ratio (HR) 0.12; 95% confidence interval (CI), 0.03-0.54] and test (median 14.9 versus 3.3 months; p = 0.00074; HR 0.10; 95% CI, 0.02-0.50) sets. Objective response rates in patients with a low or high wp-score were 75.0% (95% CI, 42.8-94.5%) versus 0.0% (95% CI, 0.0-60.2%) in the validation set (p = 0.019) and 80.0% (95% CI, 44.4-97.5%) versus 0.0% (95% CI, 0.0-36.9%) in the test set (p = 0.0011). The wp-scores were also significantly associated with PFS in patients receiving single-agent ICI treatment (p < 0.05). In addition, the 5hmC predictive signature demonstrated superior predictive capability to tumor programmed death-ligand 1 and specificity to ICI treatment response prediction. Moreover, we identified novel 5hmC-associated genes and signaling pathways integral to ICI treatment response in lung cancer. This study provides proof-of-concept evidence that the cfDNA 5hmC signature is a robust biomarker for predicting ICI treatment response in lung cancer.

Cell-Free DNA 5-Hydroxymethylcytosine Signatures for Lung Cancer Prognosis.

Accurate prognostic markers are essential for guiding effective lung cancer treatment strategies. The level of 5-hydroxymethylcytosine (5hmC) in tissue is independently associated with overall survival (OS) in lung cancer patients. We explored the prognostic value of cell-free DNA (cfDNA) 5hmC through genome-wide analysis of 5hmC in plasma samples from 97 lung cancer patients. In both training and validation sets, we discovered a cfDNA 5hmC signature significantly associated with OS in lung cancer patients. We built a 5hmC prognostic model and calculated the weighted predictive scores (wp-score) for each sample. Low wp-scores were significantly associated with longer OS compared to high wp-scores in the training [median 22.9 versus 8.2 months; p = 1.30 × 10-10; hazard ratio (HR) 0.04; 95% confidence interval (CI), 0.00-0.16] and validation (median 18.8 versus 5.2 months; p = 0.00059; HR 0.22; 95% CI: 0.09-0.57) sets. The 5hmC signature independently predicted prognosis and outperformed age, sex, smoking, and TNM stage for predicting lung cancer outcomes. Our findings reveal critical genes and signaling pathways with aberrant 5hmC levels, enhancing our understanding of lung cancer pathophysiology. The study underscores the potential of cfDNA 5hmC as a superior prognostic tool for guiding more personalized therapeutic strategies for lung cancer patients.

HER2-targeted antibody-drug conjugates for breast cancer: ancestry and dose adjustment for thrombocytopenia.

BACKGROUND: Thrombocytopenia is a common adverse event on HER2-targeted therapies, fam-trastuzumab deruxtecan (T-DXd) and ado-trastuzumab emtansine (T-DM1). A reported association of Asian ancestry with this event merits investigation to rule out potential confounding. METHODS: Subjects in this retrospective cohort were female patients with HER2 positive breast cancer, of Asian or non-Hispanic White ancestry, who initiated T-DM1 or T-DXd from January 2017 through October 2021. Follow-up closed in January 2022. Primary endpoint was dose adjustment for thrombocytopenia. Competing endpoints were discontinuation of drug for other toxicity, disease progression, or for completion of prescribed cycles. The association between Asian ancestry and thrombocytopenia-related dose adjustment was tested at p < 0.01 in a proportional hazards model for the sub-distributions of 4 (primary and competing) endpoints. Covariates examined as potential confounders were age, metastatic disease, specific HER2-targeted drug, and prior drug switching for toxicity. RESULTS: Among 181 subjects, 48 reported Asian ancestry. Incidence of dose adjustment for thrombocytopenia was higher in patients with Asian ancestry and among patients switched to T-DXd after experiencing thrombocytopenia on T-DM1. Independent of specific drug and prior drug switching, Asian ancestry was associated with dose adjustment for thrombocytopenia (hazards ratio 2.95, 95% confidence interval 1.41-6.18) but not with competing endpoints. Among participants of Asian ancestry, the ancestral origin was usually China or the Philippines (where Chinese ancestry is common). CONCLUSIONS: The association between Asian ancestry and thrombocytopenia on HER2-targeted therapy is independent of age, metastatic disease, drug, and history of similar toxicity. This association may have a genetic basis linked to Chinese ancestry.

Thrombopoietin Receptor Agonists for Thrombocytopenia Secondary to HER2-Targeted Antibody Drug Conjugates.

Trastuzumab emtansine and trastuzumab deruxtecan are widely used in breast cancer and other solid tumor malignancies. Thrombocytopenia is a common adverse event associated with the use of these agents that can lead to a treatment delay, reduction in dose intensity, and discontinuation. The role of thrombopoietin receptor agonists (TPO-RA) remains unknown in this setting. We report a case series of 6 individuals with breast cancer that experienced dose-reductions and therapy delays due to thrombocytopenia secondary to trastuzumab emtansine or trastuzumab deruxtecan therapy and received intervention with TPO-RA. All 6 were able to resume therapy with TPO-RA support.

Difficulties in Defining Oligometastatic Prostate Cancer: Implications for Clinical Trial Accrual and Community Practice Adoption of Metastasis-Directed Therapy Approaches.

BACKGROUND: Metastasis-directed therapy is widely utilized for oligometastatic prostate cancer patients, but standard imaging does not always identify metastases definitively and, even with PSMA PET, there may be equivocal findings. Not all clinicians have access to detailed imaging review, particularly outside of academic cancer centers, and PET scan access is also limited. We sought to understand how imaging interpretation impacted recruitment to a clinical trial for oligometastatic prostate cancer. METHODS: IRB approval was obtained to review medical records from all patients screened for the institutional IRB-approved clinical trial for men with oligometastatic prostate cancer involving androgen deprivation plus stereotactic radiation to all metastatic sites, as well as radium223 (NCT03361735). Clinical trial inclusion required at least one bone metastatic lesion and no more than five total sites of metastasis, including soft tissue sites. Tumor board discussion records were reviewed, along with results from additional radiology studies ordered or confirmatory biopsies performed. Clinical characteristics such as PSA level and Gleason score were studied for association with likelihood of oligometastatic disease confirmation. RESULTS: At the time of data analysis, 18 subjects were deemed eligible and 20 were not eligible. The most common reasons for ineligibility were no confirmed bone metastasis in 16 patients (59%) and too many metastatic sites in 3 (11%). The median PSA of eligible subjects was 3.28 (range 0.4-45.5), whereas the median PSA of those found to be ineligible was 10.45 (range 3.7-26.3) when there were too many metastases identified, and 2.7 (range 0.2-34.5) when metastases were unconfirmed. PET imaging (PSMA or fluciclovine PET) increased the number of metastases, while MRI resulted in downstaging to non-metastatic disease. CONCLUSIONS: This research suggests that additional imaging (i.e., at least two independent imaging modalities of a possible metastatic lesion) or tumor board adjudication of imaging findings may be critical to correctly identify patients appropriate for enrollment in oligometastatic protocols. This should be considered as trials of metastasis-directed therapy for oligometastatic prostate cancer accrue and results are translated to broader oncology practice.

A Practical Guide to Relugolix: Early Experience With Oral Androgen Deprivation Therapy.

BACKGROUND: Relugolix is the newest form of androgen deprivation therapy (ADT) approved for prostate cancer. However, as an oral drug, several real-world concerns exist, particularly medication compliance, safety with other androgen receptor-targeted agents, and financial burden to patients. METHODS: A single institution retrospective chart review was conducted evaluating all patients who were prescribed relugolix for any prostate cancer indication from January 1, 2021 to January 31, 2022. Demographic data, cardiac risk factors, concomitant therapy usage, and PSA/testosterone levels, were abstracted from the chart review. Adverse effects were obtained by examining progress notes. Compliance was assessed by clinic notes as well as prescription fills by specialty pharmacy records. The reasons patients did not fill or discontinued the medication were noted. RESULTS: Hundred and one patients were prescribed relugolix, and 91 patients consented to research. Seventy-one (78%) patients filled the prescription to relugolix, with a median follow-up of 5 months. Prescription fill data were available for 45 (63%) patients, with 94% of days covered. The most commonly reported reason not to fill was cost at 50%. Sixty-six (93%) patients reported never missing a dose. PSA levels were available in 71 (100%) patients with 69 (97%) showing stable or improved PSA. Testosterone levels were available in 61 (86%) of patients, which showed 61 (100%) stable or successful castration. Twenty-four (34%) patients used relugolix in combination. No new major safety signals were seen in combination therapy. Nineteen (27%) patients had switched to another form of ADT. Fifteen of these (79%) felt similar or better on relugolix therapy. CONCLUSIONS: Compliance with relugolix seemed acceptable. No major new safety signals were seen, even in combination. Among patients who switched therapy, most tolerated relugolix similarly or better than the previous form of ADT. The cost was a major reason for patients not initiating and for discontinuing therapy.

Recurrent small bowel obstruction caused by Burkitt lymphoma in an elderly man: a case report and review of the literature.

BACKGROUND: Acute small bowel obstruction is a common surgical emergency usually caused by abdominal adhesions, followed by intraluminal tumors from metastatic disease. Although lymphomas have been known to cause bowel obstruction, Burkitt lymphoma is seldom reported to induce an obstruction in the adult population. CASE PRESENTATION: A 78-year-old Hispanic man with a history of abdominal interventions presented to our hospital with abdominal pain. Computed tomography revealed a partial small bowel obstruction attributed to local inflammation or adhesions. Medical management with bowel rest and nasogastric decompression resulted in resolution of symptoms and quick discharge. He returned 2 days later with worsening abdominal pain. Repeat imaging showed progression of the partial small bowel obstruction, but with an additional 1.6-cm nodular density abutting the anterior aspect of the gastric antrum and lobulated anterior gastric antral wall thickening. He was taken to the operating room, where several masses were found. Intraoperative frozen sections were consistent with lymphoma, and pathology later revealed Burkitt lymphoma. Disease was found on both sides of the diaphragm by positron emission tomography. After the initial resection and adjuvant chemotherapy, the patient is alive and well about 14 months after resection. CONCLUSIONS: Small bowel obstruction is uncommonly due to Burkitt lymphoma in the geriatric population and is more frequently seen in the pediatric and young adult populations. Burkitt lymphoma is very aggressive with rapid cell turnover leading to significant morbidity. The rapid recurrence of an acute abdominal process should prompt an investigation for a more sinister cause such as malignancy.

Pancreatic adenocarcinoma with early esophageal metastasis: A case report and review of literature.

BACKGROUND: Pancreatic adenocarcinoma is an aggressive malignancy with a high propensity to metastasize. Esophageal metastasis manifesting as dysphagia is rarely reported in the literature and has not to our knowledge been reported prior to the appearance of the primary disease. CASE SUMMARY: A patient presented with progressive dysphagia to solids and a persistent earache. Computed tomography of the neck and chest revealed a 3.0 cm × 1.8 cm heterogeneous mass originating from the upper third of the esophagus, necrotic cervical and supraclavicular lymphadenopathy, and bilateral pulmonary nodules. She underwent a core needle biopsy of a right cervical node, which suggested a well-differentiated adenocarcinoma of unknown primary. She had an upper endoscopy with biopsy of the esophageal mass suggestive of a well-differentiated adenocarcinoma. Positron emission tomography imaging revealed increased uptake in the esophageal mass, cervical, and mediastinal lymph nodes. She was started on folinic acid, fluorouracil, and oxaliplatin. Prior to initiation of cycle 8, the patient was found to have a pancreatic body mass that was not present on prior radiographic imaging, confirmed by endoscopic ultrasonography and biopsy to be pancreatic adenocarcinoma. CA19-9 was > 10000 U/mL, suggesting a primary pancreaticobiliary origin. CONCLUSION: Esophageal metastasis diagnosed before primary pancreatic adenocarcinoma is rare. This case highlights the profound metastatic potential of pancreatic adenocarcinoma.

Hyperprogressive NSCLC With Two Immune-Checkpoint Inhibitors.

INTRODUCTION: Immune-checkpoint inhibitors (ICIs) are transforming the modern era of cancer therapy. As new treatment options are becoming available, new patterns of disease behavior are manifesting. One such phenomenon, known as hyperprogressive disease (HPD), is a rare complication resulting in exponential disease progression on exposure to an ICI. Herein, we report an uncommon case of a patient who experienced HPD on 2 different occasions with 2 different immunotherapy agents. CASE PRESENTATION: A 77-year-old black man was diagnosed with stage IV squamous cell carcinoma of the lung. He was enrolled in a clinical trial that involved viral transduction and stereotactic body radiation followed by pembrolizumab administration. His disease progressed markedly after the first cycle of immunotherapy. He was switched to carboplatin and protein-bound paclitaxel. He continued to have steady disease progression. After the third cycle of chemotherapy, he was again given immunotherapy, this time with atezolizumab. Again, after a single infusion, he exhibited substantial disease progression and further clinical deterioration. CONCLUSIONS: HPD is a rare yet disturbing complication of immunotherapy with devastating effects on morbidity and mortality. Although there is accumulating literature supporting the phenomenon of HPD, to our knowledge, this is the first reported case of HPD occurring with 2 different ICIs in the same patient. This case suggests that the presence of HPD during treatment with 1 checkpoint inhibitor may preclude the use of another one. It also raises concerns about using other forms of immunomodulating agents. As immunotherapy becomes a major form of cancer therapy, more data are needed to better understand HPD and determine which patients are at risk.

A Case of Histiocytic Sarcoma Arising from Mycosis Fungoides.

Histiocytic sarcoma (HS) is an uncommon malignant neoplasm arising from mature histiocytes and most commonly characterized by the immunophenotypic expression of CD68, CD163, or lysozyme. Although rare, HS arising as a second primary malignancy following hematolymphoid neoplasms has been reported. To our knowledge, this is the first reported case of HS occurring as a second primary malignancy in a patient with mycosis fungoides (MF), with the retained immunophenotype markers CD30 and CD4.

Macrophage Activation Syndrome Secondary to Underlying Sarcoidosis.

Hemophagocytic lymphohistiocytosis (HLH) due to an underlying rheumatologic condition is known as macrophage activation syndrome (MAS), a rare and serious complication that often has a delayed diagnosis. MAS can complicate any rheumatologic disease, although it is most prevalent in systemic juvenile idiopathic arthritis. MAS occurring as a sequela of sarcoidosis is seldom reported. Herein, we present an uncommon case of MAS occurring secondary to suspected extrapulmonary sarcoidosis and the associated diagnostic challenges. A 53-year-old White female presented with a 20-month history of constitutional symptoms of an unclear etiology. Her extensive workup included equivocal bone marrow and liver biopsies, suggestive of occasional hemophagocytosis. On admission, she met criteria for HLH based on the HLH-94 diagnostic guidelines. A repeat liver biopsy was performed revealing non-necrotizing granulomas in the parenchyma. Given the concern for an extrapulmonary sarcoidosis, she was started on pulse-dose steroids with subsequent symptomatic resolution. Two years later, she remains in complete remission. As a systemic disease, sarcoidosis can manifest in any organ and present in a variety of ways. While HLH and MAS have numerous etiologies, sarcoidosis should be considered as a potential underlying diagnosis, and prompt treatment initiation with steroids may reduce morbidity and mortality.

Cryptococcal meningoencephalitis in patients with mantle cell lymphoma on ibrutinib.

Ibrutinib, a Bruton's tyrosine kinase inhibitor, has been increasingly widely used in relapsed and refractory mantle cell lymphoma (MCL) and chronic lymphocytic leukaemia [1, 2]. With its use becoming more common, there have been emerging case reports of opportunistic infections like cryptococcal infections [3-8]. These infections in patients receiving ibrutinib were mostly reported in patients with chronic lymphocytic leukaemia, who have poor immune reconstitution. Here, we report two cases of cryptococcal meningoencephalitis in patients with MCL on ibrutinib.

HIV-specific Immunity Derived From Chimeric Antigen Receptor-engineered Stem Cells.

The human immunodeficiency virus (HIV)-specific cytotoxic T lymphocyte (CTL) response is critical in controlling HIV infection. Since the immune response does not eliminate HIV, it would be beneficial to develop ways to enhance the HIV-specific CTL response to allow long-term viral suppression or clearance. Here, we report the use of a protective chimeric antigen receptor (CAR) in a hematopoietic stem/progenitor cell (HSPC)-based approach to engineer HIV immunity. We determined that CAR-modified HSPCs differentiate into functional T cells as well as natural killer (NK) cells in vivo in humanized mice and these cells are resistant to HIV infection and suppress HIV replication. These results strongly suggest that stem cell-based gene therapy with a CAR may be feasible and effective in treating chronic HIV infection and other morbidities.

CD4 ligation on human blood monocytes triggers macrophage differentiation and enhances HIV infection.

UNLABELLED: A unique aspect of human monocytes, compared to monocytes from many other species, is that they express the CD4 molecule. However, the role of the CD4 molecule in human monocyte development and function is not known. We determined that the activation of CD4 via interaction with major histocompatibility complex class II (MHC-II) triggers cytokine expression and the differentiation of human monocytes into functional mature macrophages. Importantly, we determined that CD4 activation induces intracellular signaling in monocytes and that inhibition of the MAPK and Src family kinase pathways blocked the ability of CD4 ligation to trigger macrophage differentiation. We observed that ligation of CD4 by MHC-II on activated endothelial cells induced CD4-mediated macrophage differentiation of blood monocytes. Finally, CD4 ligation by MHC-II increases the susceptibility of blood-derived monocytes to HIV binding and subsequent infection. Altogether, our studies have identified a novel function for the CD4 molecule on peripheral monocytes and suggest that a unique set of events that lead to innate immune activation differ between humans and mice. Further, these events can have effects on HIV infection and persistence in the macrophage compartment. IMPORTANCE: The CD4 molecule, as the primary receptor for HIV, plays an important role in HIV pathogenesis. There are many cell types that express CD4 other than the primary HIV target, the CD4(+) T cell. Other than allowing HIV infection, the role of the CD4 molecule on human monocytes or macrophages is not known. We were interested in determining the role of CD4 in human monocyte/macrophage development and function and the potential effects of this on HIV infection. We identified a role for the CD4 molecule in triggering the activation and development of a monocyte into a macrophage following its ligation. Activation of the monocyte through the CD4 molecule in this manner increases the ability of monocytes to bind to and become infected with HIV. Our studies have identified a novel function for the CD4 molecule on peripheral monocytes in triggering macrophage development that has direct consequences for HIV infection.