Association of Convalescent Plasma Therapy With Survival in Patients With Hematologic Cancers and COVID-19.

Importance: COVID-19 is a life-threatening illness for many patients. Prior studies have established hematologic cancers as a risk factor associated with particularly poor outcomes from COVID-19. To our knowledge, no studies have established a beneficial role for anti-COVID-19 interventions in this at-risk population. Convalescent plasma therapy may benefit immunocompromised individuals with COVID-19, including those with hematologic cancers. Objective: To evaluate the association of convalescent plasma treatment with 30-day mortality in hospitalized adults with hematologic cancers and COVID-19 from a multi-institutional cohort. Design, Setting, and Participants: This retrospective cohort study using data from the COVID-19 and Cancer Consortium registry with propensity score matching evaluated patients with hematologic cancers who were hospitalized for COVID-19. Data were collected between March 17, 2020, and January 21, 2021. Exposures: Convalescent plasma treatment at any time during hospitalization. Main Outcomes and Measures: The main outcome was 30-day all-cause mortality. Cox proportional hazards regression analysis with adjustment for potential confounders was performed. Hazard ratios (HRs) are reported with 95% CIs. Secondary subgroup analyses were conducted on patients with severe COVID-19 who required mechanical ventilatory support and/or intensive care unit admission. Results: A total of 966 individuals (mean [SD] age, 65 [15] years; 539 [55.8%] male) were evaluated in this study; 143 convalescent plasma recipients were compared with 823 untreated control patients. After adjustment for potential confounding factors, convalescent plasma treatment was associated with improved 30-day mortality (HR, 0.60; 95% CI, 0.37-0.97). This association remained significant after propensity score matching (HR, 0.52; 95% CI, 0.29-0.92). Among the 338 patients admitted to the intensive care unit, mortality was significantly lower in convalescent plasma recipients compared with nonrecipients (HR for propensity score-matched comparison, 0.40; 95% CI, 0.20-0.80). Among the 227 patients who required mechanical ventilatory support, mortality was significantly lower in convalescent plasma recipients compared with nonrecipients (HR for propensity score-matched comparison, 0.32; 95% CI, 0.14-0.72). Conclusions and Relevance: The findings of this cohort study suggest a potential survival benefit in the administration of convalescent plasma to patients with hematologic cancers and COVID-19.

Clinical impact of COVID-19 on patients with cancer (CCC19): a cohort study.

BACKGROUND: Data on patients with COVID-19 who have cancer are lacking. Here we characterise the outcomes of a cohort of patients with cancer and COVID-19 and identify potential prognostic factors for mortality and severe illness. METHODS: In this cohort study, we collected de-identified data on patients with active or previous malignancy, aged 18 years and older, with confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection from the USA, Canada, and Spain from the COVID-19 and Cancer Consortium (CCC19) database for whom baseline data were added between March 17 and April 16, 2020. We collected data on baseline clinical conditions, medications, cancer diagnosis and treatment, and COVID-19 disease course. The primary endpoint was all-cause mortality within 30 days of diagnosis of COVID-19. We assessed the association between the outcome and potential prognostic variables using logistic regression analyses, partially adjusted for age, sex, smoking status, and obesity. This study is registered with ClinicalTrials.gov, NCT04354701, and is ongoing. FINDINGS: Of 1035 records entered into the CCC19 database during the study period, 928 patients met inclusion criteria for our analysis. Median age was 66 years (IQR 57-76), 279 (30%) were aged 75 years or older, and 468 (50%) patients were male. The most prevalent malignancies were breast (191 [21%]) and prostate (152 [16%]). 366 (39%) patients were on active anticancer treatment, and 396 (43%) had active (measurable) cancer. At analysis (May 7, 2020), 121 (13%) patients had died. In logistic regression analysis, independent factors associated with increased 30-day mortality, after partial adjustment, were: increased age (per 10 years; partially adjusted odds ratio 1·84, 95% CI 1·53-2·21), male sex (1·63, 1·07-2·48), smoking status (former smoker vs never smoked: 1·60, 1·03-2·47), number of comorbidities (two vs none: 4·50, 1·33-15·28), Eastern Cooperative Oncology Group performance status of 2 or higher (status of 2 vs 0 or 1: 3·89, 2·11-7·18), active cancer (progressing vs remission: 5·20, 2·77-9·77), and receipt of azithromycin plus hydroxychloroquine (vs treatment with neither: 2·93, 1·79-4·79; confounding by indication cannot be excluded). Compared with residence in the US-Northeast, residence in Canada (0·24, 0·07-0·84) or the US-Midwest (0·50, 0·28-0·90) were associated with decreased 30-day all-cause mortality. Race and ethnicity, obesity status, cancer type, type of anticancer therapy, and recent surgery were not associated with mortality. INTERPRETATION: Among patients with cancer and COVID-19, 30-day all-cause mortality was high and associated with general risk factors and risk factors unique to patients with cancer. Longer follow-up is needed to better understand the effect of COVID-19 on outcomes in patients with cancer, including the ability to continue specific cancer treatments. FUNDING: American Cancer Society, National Institutes of Health, and Hope Foundation for Cancer Research.

Assessment of NETest Clinical Utility in a U.S. Registry-Based Study.

BACKGROUND: The clinical relevance of molecular biomarkers in oncology management has been recognized in breast and lung cancers. We evaluated a blood-based multigene assay for management of neuroendocrine tumors (NETs) in a real-world study (U.S. registry NCT02270567). Diagnostic accuracy and relationship to clinical disease status in two cohorts (treated and watch-and-wait) were evaluated. MATERIALS AND METHODS: Patients with NETs (n = 100) were followed for 6-12 months. Patients' primary tumors were gastroenteropancreatic (68%), lung 20%, and of unknown origin (12%). Characteristics included well-differentiated, low-grade tumors (97%), stage IV disease (96%); treatment with surgery (70%); and drug treatment (56%). NETest was measured at each visit and disease status determined by RECIST. Scores categorized as low (NETest 14%-40%) or high (≥80%) defined disease as stable or progressive. Multivariate analyses determined the strength of the association with progression-free survival (PFS). RESULTS: NETest diagnostic accuracy was 96% and concordant (95%) with image-demonstrable disease. Scores were reproducible (97%) and concordant with clinical status (98%). The NETest was the only feature linked to PFS (odds ratio, 6.1; p < .0001). High NETest correlated with progressive disease (81%; median PFS, 6 months), and low NETest correlated with stable disease (87%; median PFS, not reached). In the watch-and-wait cohort, low NETest was concordant with stable disease in 100% of patients, and high NETest was associated with management changes in 83% of patients. In the treated cohort, all low NETest patients (100%) remained stable. A high NETest was linked to intervention and treatment stabilization (100%). Use of NETest was associated with reduced imaging (biannual to annual) in 36%-38% of patients. CONCLUSION: Blood NETest is an accurate diagnostic and can be of use in monitoring disease status and facilitating management change in both watch-and-wait and treatment cohorts. IMPLICATIONS FOR PRACTICE: A circulating multigene molecular biomarker to guide neuroendocrine tumor (NET) management has been developed because current biomarkers have limited clinical utility. NETest is diagnostic (96%) and in real time defines the disease status (>95%) as stable or progressive. It is >90% effective in guiding treatment decisions in conjunction with diagnostic imaging. Monitoring was effective in watch-and-wait or treatment groups. Low levels supported no management change and reduced the need for imaging. High levels indicated the need for management intervention. Real-time liquid biopsy assessment of NETs has clinical utility and can contribute additional value to patient management strategies and outcomes.

High response rates and prolonged survival in patients with corticotroph pituitary tumors and refractory Cushing disease from capecitabine and temozolomide (CAPTEM): a case series.

BACKGROUND AND IMPORTANCE: Rarely, corticotrophic pituitary tumors take on an aggressive form characterized by rapid growth, invasion into local structures, compression of cranial nerves, and possible spread to distant sites. When conventional surgery, radiation therapy, and hormones fail to control progression and symptoms, alternative therapies are needed. A novel chemotherapeutic regimen of capecitabine and temozolomide (CAPTEM), originally designed in our laboratory, demonstrated dramatic antineoplastic effects against corticotrophic pituitary tumors. CLINICAL PRESENTATION: We present a case series of 4 patients with aggressive, adrenocorticotrophic hormone--producing pituitary tumors who had previously depleted all surgical, radiation, and hormonal therapies and were then treated with CAPTEM. Dramatic clinical improvements in neurological deficits and Cushing symptoms were evident in all patients after treatment was initiated. Confirmed by radiographic imaging, 2 of 4 patients demonstrated complete regression of disease, 1 patient had a 75% regression, and the fourth patient has ongoing stable disease for > 4.5 years at the time of this writing. Immunohistochemical analysis of patients' tumor samples showed low O-methyguanyl methyltransferase expression and adequate levels of mismatch repair enzymes (MLH-1, MSH-2, MSH-6, and PMS-2), which are important for the in vivo efficacy of CAPTEM. CONCLUSION: This is the first report of prolonged antitumor response to and radiographic complete remissions as a result of CAPTEM in patients with aggressive pituitary tumors who had exhausted all other therapies.

Capecitabine and temozolomide (CAPTEM) for metastatic, well-differentiated neuroendocrine cancers: The Pancreas Center at Columbia University experience.

PURPOSE: We evaluated the efficacy and safety of capecitabine and temozolomide (CAPTEM) in patients with metastatic neuroendocrine tumors (NETs) to the liver. This regimen was based on our studies with carcinoid cell lines that showed synergistic cytotoxicity with sequence-specific dosing of 5-fluorouracil preceding temozolomide (TMZ). METHODS: A retrospective review was conducted of 18 patients with NETs metastatic to the liver who had failed 60 mg/month of Sandostatin LAR™ (100%), chemotherapy (61%), and hepatic chemoembolization (50%). Patients received capecitabine at 600 mg/m(2) orally twice daily on days 1-14 (maximum 1,000 mg orally twice daily) and TMZ 150-200 mg/m(2) divided into two doses daily on days 10-14 of a 28-day cycle. Imaging was performed every 2 cycles, and serum tumor markers were measured every cycle. RESULTS: Using RECIST parameters, 1 patient (5.5%) with midgut carcinoid achieved a surgically proven complete pathological response (CR), 10 patients (55.5%) achieved a partial response (PR), and 4 patients (22.2%) had stable disease (SD). Total response rate was 61%, and clinical benefit (responders and SD) was 83.2%. Of four carcinoid cases treated with CAPTEM, there was 1 CR, 1 PR, 1 SD, and 1 progressive disease. Median progression-free survival was 14.0 months (11.3-18.0 months). Median overall survival from diagnosis of liver metastases was 83 months (28-140 months). The only grade 3 toxicity was thrombocytopenia (11%). There were no grade 4 toxicities, hospitalizations, opportunistic infections, febrile neutropenias, or deaths. CONCLUSIONS: CAPTEM is highly active, well tolerated and may prolong survival in patients with well-differentiated, metastatic NET who have progressed on previous therapies.

Treatment of multiple endocrine neoplasia 1/2 tumors: case report and review of the literature.

BACKGROUND: Neuroendocrine tumors are uncommon tumors that are histopathologically and biologically heterogeneous and include the multiple endocrine neoplasia (MEN) 1 and 2 syndromes. The morbidity of MEN-1 and MEN-2 is often due to the symptomatology of the endocrine hormones produced, and the mortality mainly occurs from hepatic dysfunction incurred by liver metastases. At present, there is essentially no effective cure once the tumor has metastasized to the liver. PATIENT: We present a patient with progressive, metastatic MEN-1 with the classic '3 P's' triad of neuroendocrine tumor of the pancreas, parathyroid adenoma and a pituitary adenoma. RESULTS: After progression on high-dose Sandostatin LAR (60 mg/month) and multiple surgeries, the patient had a partial response (40% decrease) to a novel regimen of capecitabine and temozolomide (CAPTEM) and progression-free survival of 18 months. He had minor grade 1 toxicities and no grade 2, 3 or 4 toxicities. DISCUSSION: The history and treatment options for MEN-1/2 cancers are reviewed, as well as the data behind our novel regimen, CAPTEM. CONCLUSION: The CAPTEM regimen is a tolerable, safe, easy to administer oral regimen with possible efficacy for MEN-1 tumors.

Retinal neovascularization and hemorrhage associated with the use of imatinib (Gleevec(®)) in a patient being treated for gastrointestinal stromal tumor (GIST).

BACKGROUND: Gastrointestinal stromal tumor (GIST) is a mesenchymal malignancy of the gastrointestinal tract. Imatinib mesylate (Gleevec(®), ST1571, Novartis Pharmaceuticals, Basel, Switzerland) is a selective inhibitor of break point cluster-Ableson (BCR-ABL), c-Kit, and platelet-derived growth factor receptor alpha (PDGFRα) tyrosine kinases. Imatinib has been approved in the U.S. for the treatment of Philadelphia-chromosome positive chronic myeloid leukemia, KIT (CD117)-positive unresectable and metastatic malignant GIST and adjuvant treatment of adult patients following resection. Ocular side effects are commonly reported with Gleevec(®), the most common being periorbital edema and epiphora. CASE REPORT: Here we present the case of a 62-year-old male with a history of GIST in the jejunum who was started with imatinib mesylate at 400 milligrams daily. Seven months into his therapy, he reported blurry vision. He was evaluated by an ophthalmologist, and was ultimately found to have retinal hemorrhage and neovascularization. His dose was reduced by 50% to 200 milligrams daily with an almost complete resolution of symptoms within several weeks. No recurrence of symptoms or signs was noticed at 6 months follow-up. DISCUSSION: This patient's Naranjo scale was calculated to be 7, indicating a probable adverse drug reaction. Our patient's symptoms significantly improved with a dose reduction of imatinib, and this hints that there was a dose-dependent effect. The World Health Organization has categorized retinal hemorrhage as an unlikely side-effect of therapy, and to our knowledge this has never been reported before in a patient receiving imatinib mesylate for GIST treatment. Neovascularization also has not been previously reported in patients receiving this medication. It is important to identify less common ocular toxicity in patients receiving imatinib.

The clinical management of BRCA1 and BRCA2 mutation carriers.

Mutations in the cancer susceptibility genes BRCA1 and BRCA2 are associated with significantly increased risks of breast and ovarian cancer. Fortunately, effective strategies are available to reduce these risks, including genetic testing, which is an important consideration in determining management of patients with a strong family history of cancer. This article reviews the current evidence for risk-reducing strategies in BRCA1 and BRCA2 mutation carriers and outlines future research directions. In particular, screening controversies and current guidelines are discussed, as are issues related to prophylactic mastectomy and oophorectomy.

Mutant human tumor suppressor p53 modulates the activation of mitogen-activated protein kinase and nuclear factor-kappaB, but not c-Jun N-terminal kinase and activated protein-1.

The roles of the mitogen-activated kinase protein (MAPK) pathway, nuclear factor-kappa B (NF-kappaB), and activator protein-1 (AP-1) in cellular responses to growth factors and mitogen are well established. However, the manner by which these proliferative pathways are affected by the tumor suppressor protein p53 is not fully understood. We report here the results of an investigation of the status of p53 on two human melanoma cell lines with wild-type p53 (SK-Mel-186) or mutant p53 (SK-Mel-110). The basal levels of the activated extracellular-signal regulated kinases 1 and 2 (ERK1/2) were high in cells with wild-type p53, but low in cells with mutant p53. The 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced activation of ERK1/2 through the phosphorylation of threonine and tyrosine at 202 and 204, respectively, was demonstrated in both cell lines, however, in a discrete manner. TPA-induced activation of ERK1/2 was sustained in wild-type p53 cells, while only a transient activation was seen in mutant p53 cells. Inhibition of MAPK kinase (MEK), an upstream kinase, by U0126, blocked TPA-induced activation of ERK1/2 in wild-type p53 cells and in mutant p53 cells. Treatment of wild-type p53 (SK-Mel 186) cells with small interfering RNA (siRNA) of p53 displayed a transient induction of activation of ERK1/2 following TPA treatment, indicating that p53 has a role in the regulation of the activation of ERK1/2. NF-kappaB activity decreased significantly in cells with wild-type p53, while enhanced NF-kappaB activity was evident in cells with mutant p53. The expression of either wild-type or mutant p53 had a similar effect on TPA-induced Jun N-terminal kinase (JNK) activation, indicating specificity for the ERK pathway. Similarly, AP-1 binding activity showed a transient variation in both cell lines after TPA treatment but with different kinetics. These observations suggest that both wild-type and mutant p53 can modulate the activation pathways for ERK1/2, and NF-kappaB distinctively, while modulating the pathways of JNK and AP-1 similarly. These differences may influence cellular processes such as proliferation, differentiation, and apoptosis.