University of Florida Cancer Hospital

PURPOSE: The National Surgical Adjuvant Breast and Bowel Project C-08 trial was designed to investigate the safety and effectiveness of adding bevacizumab to modified infusional fluorouracil, leucovorin, and oxaliplatin (FOLFOX) 6 regimen for the adjuvant treatment of patients with stage II or III colon cancer. We present safety information in advance of the planned analysis of efficacy. PATIENTS AND METHODS: Among 2,710 randomly assigned patients, demographic factors were balanced. Patients received modified FOLFOX6 every 2 weeks x 12 or modified FOLFOX6 plus bevacizumab (5 mg/kg every 2 weeks x 26, experimental group). RESULTS: Overall rates of grade 4 or 5 toxicities were nearly identical in the FOLFOX6 and FOLFOX6 plus bevacizumab arms (15.2% and 15.0%, respectively). Six-month mortality rates were 0.96% and 0.90% for the control and experimental groups, respectively. Grade 3+ toxicities that occurred more often in the experimental arm versus control arm included hypertension (12% v 1.8%, respectively), wound complications (abdominal incisional hernia or infusion port dehiscence/inflammation; 1.7% v 0.3%, respectively), pain (11.1% v 6.3%, respectively), and proteinuria (2.7% v 0.8%, respectively). Grade 2+ neuropathy was increased in the experimental arm versus the control arm (grade 2, 33% v 29%, respectively; grade 3, 16% v 14%, respectively; and grade 4, < 1% each). In the experimental arm versus control arm, significantly less thrombocytopenia (1.4% v 3.4%, respectively) and fewer allergic reactions (3.1% v 4.7%, respectively) were observed. Advanced age was associated with a significantly greater rate of grade 4 and 5 toxicities regardless of treatment. CONCLUSION: Bevacizumab with modified FOLFOX6 is well tolerated in the surgical adjuvant setting in these patients. No significant increase in GI perforation, hemorrhage, arterial or venous thrombotic events, or death with the addition of bevacizumab to modified FOLFOX6 has been observed. Follow-up for potential delayed adverse effects and efficacy is ongoing.

Most prostate cancer-related deaths are due to advanced disease with patients with metastatic prostate cancer having a 5-year survival rate of only 34%. Overexpression of c-Met receptor tyrosine kinase has been highly associated with prostate cancer progression and metastasis. In the present studies, the effect of BMS-777607, a selective and potent small-molecule Met kinase inhibitor that has been advanced to clinical evaluation, on hepatocyte growth factor (HGF)-mediated cell functions and signaling pathways was evaluated in c-Met-expressing PC-3 and DU145 prostate cancer cells. BMS-777607 treatment had little effect on tumor cell growth but inhibited cell scattering activated by exogenous HGF, with almost complete inhibition at 0.5 micromol/L in PC-3 and DU145 cells. This agent also suppressed HGF-stimulated cell migration and invasion in a dose-dependent fashion (IC(50) < 0.1 micromol/L) in both cell lines. Mechanistically, nanomolar doses of BMS-777607 potently blocked HGF-stimulated c-Met autophosphorylation and downstream activation of Akt and extracellular signal-regulated kinase. In addition, both wortmannin and U0126, but not dasatinib, attenuated cell scattering and migration induced by HGF, suggesting the involvement of the phosphoinositide 3-kinase and mitogen-activated protein kinase pathways, but not of Src or focal adhesion kinase, in HGF-mediated motogenic effects. Taken together, these data indicate that the downregulation of c-Met signaling by BMS-777607 treatment can significantly disrupt key steps in the metastatic cascade, suggesting that such a targeting strategy may hold promise for the treatment of advanced prostate cancer.

BACKGROUND: In retrospective studies of dietary habits and breast cancer risk, recall bias is a concern since diet has been publicized as a cause of breast cancer. METHODS: In a case-control study of diet and breast cancer risk nested within a cohort of women screened with mammography, we contrasted answers to a retrospective dietary interview with answers to a dietary questionnaire which was filled out before any diagnostic procedures for breast cancer were undertaken. The source population was all women aged 40-74 in two counties in Sweden invited to mammographic screening and asked to fill out a questionnaire before the screening. Cases and controls were subsequently defined -- matched on age, county of residence, and time of mammography -- and approached for an interview. RESULTS: In all, 265 cases and 431 controls participated in the study. Means of frequencies differed between the agreement in the questionnaire's and the interview's classifications of study subjects into quartiles of monthly intake varied between 31 percent and 57 percent. Kappa statistics in all food groups were below 0.41. In a regression analysis, case subjects with low responses on the questionnaire about intake of meat, snacks, and coffee and tea gave higher responses on interview than did controls who had low questionnaire responses for these food groups. The reverse was also true: cases' responses that were high on the questionnaire were lower on interview for these food groups than were controls' responses. CONCLUSIONS: We found few signs of recall bias, and the few indications of a differential misclassification that we found were not in food groups that have been publicly discussed as causes of breast cancer.

Serum concentrations of insulin-like growth factors I and II (IGF I and IGF II) were measured before, during and after pregnancy in a GH-deficient dwarf. At no time during these periods did the patient secrete GH in response to an arginine infusion or insulin tolerance test. IGF I and IGF II concentrations before pregnancy were low and similar to those of patients deficient only in GH. During the 35th week of gestation, IGF I and IGF II serum concentrations were within the normal range (165 and 127 ng/ml for IGF I and 740 and 860 ng/ml for IGF II). Abnormally low values of IGF I and IGF II were again recorded 36 h postpartum and 35 days later. These data indicate that some material, probably of placental origin, stimulates the secretion of not only IGF I, but IGF II as well. Alternatively, the human placenta may produce IGF. Such secretion can occur without the prior maternal secretion of pituitary GH.

MicroRNAs belonging to the miR-302 family are emerging as key players in the control of cell growth, and maintaining pluripotency during cell fate determination and differentiation in embryonic stem cells. However, the mechanisms whereby ephA2/ephirnA1 signaling regulates miR-302b expression and attenuates malignant pleural mesothelioma (MPM) cell growth are not known. Our study identified a novel mechanism of ephrin-A1 mediated anti-oncogenic signaling in MPM. Ephrin-A1 treatment up regulates miR-302b expression in MPM cells and attenuates cell proliferation and tumorsphere formation via repression of myeloid cell leukemia-1 (Mcl-1). The expression of miR-302b was analyzed by qPCR, the expression of Mcl-1 was analyzed by RT-PCR, immuno-blotting and Immunofluorescence staining. To confirm that ephrin-A1 regulates the expression of Mcl-1 mRNA through miR-302b up regulation, cells were transfected with and without miR-302b and miR-302b inhibitor prior to ephrinA1 treatment. The cell proliferation and tumorsphere formation was measured by WST-1 and matrigel assays respectively. In addition, to confirm the binding of miR-302b to the 3'UTR of Mcl-1 Luciferase assay was performed. Ephrin-A1 treatment induced several fold increases of miR-302b expression in MM cells. In ephrin-A1 treated MM cells, Mcl-1 expression was significantly down regulated when compared to control. Moreover, ephrin-A1 activation significantly inhibited MM cell proliferation and tumorsphere growth. Furthermore, ephrinA1 and miR-302b induced apoptosis in MM cells. The present data suggests that ephrin-A1 induces the expression of miR-302b in MM cells which targets Mcl-1 thereby inhibits MM tumorsphere growth by inducing apoptosis.

The field of immunotoxins is continuing to grow, as shown by the increase in attendance (175 vs. 145) and abstracts (110 vs. 60) at the symposium. Advances in the molecular biology of the toxins and clinical applications were notable at this meeting. The next 2 years should see better definition of the mechanism of action of peptide toxins as well as improvements in the design of targeted toxins for potential therapy of a wide variety of human diseases.

BACKGROUND: Hemoglobin-Based Oxygen Carriers (HBOCs) can act as an "oxygen bridge" in acute severe anemia when transfusion is indicated, but not possible. We present data on 10 Expanded Access (EA) patients treated with high cumulative doses of Hemopure (HBOC-201), to assess the ability of HBOC-201 to safely treat life threatening anemia in situations where high volumes of product were administered over an extended period of time. STUDY DESIGN AND METHODS: Inclusion in this study required that the patient receive at least 10 units of HBOC-201 between 2014 and 2017 under the FDA-sanctioned EA program. Depending on a patient's geographical location, treatment with HBOC-201 was obtained through either a single patient emergency Investigational New Drug (IND) application, or an intermediate size population IND. Of the 41 patients who were treated during this period, 10 patients received 10 or more units of the product. Data were obtained from medical records. RESULTS: Treatments with HBOC-201 started within 24 hours of signing consent and were administered at an average rate of 1.99 (SD 0.17) units per day over a mean of 8.2 days (SD 2.9), during which patients received on average 16.2 units (SD 5.7 units) of HBOC-201. The median pre-treatment nadir corpuscular hemoglobin (Hb) concentration was 3.3 (SD 0.9) g/dL and post-treatment Hemoglobin was 7.3 (SD 1.7) g/dL. Common side effects included methemoglobinemia, gastrointestinal symptoms, and hypertension. However, no product-related serious adverse events (SAEs) were noted. All patients survived. CONCLUSIONS: Administration of HBOC-201 over an extended period is a feasible and safe oxygen bridge for severely anemic patients who cannot be transfused with RBC.

BACKGROUND: The efficacy of different commercial beverage compositions for meeting oral rehydration therapy (ORT) goals in the treatment of acute dehydration in healthy humans has not been systematically tested. The objective of the study was to compare fluid retention, plasma volume (PV), and interstitial fluid (ISF) volume restoration when using 1 popular glucose-based and 1 novel amino acid-based (AA) commercial ORT beverage following experimental hypertonic or isotonic dehydration. METHODS: Twenty-six healthy adults (21 males, 5 females) underwent either a controlled bout of hypertonic (n = 13) or isotonic (n = 13) dehydration (3%-4% body mass) via eccrine or renal body water and electrolyte losses induced using exercise-heat stress (EHS) or Lasix administration (LAS), respectively. Rehydration was achieved over 90 minutes by matching fluid intake to water losses (1:1) using a sports drink (SP) or AA commercial ORT beverage. Fluid retention (water and electrolytes), PV, and ISF volume changes were tracked for 180 minutes. RESULTS: AA produced significantly (P <0.05) greater fluid retention (75% vs 57%), ISF volume restoration, and tended (P = 0.06) to produce greater PV restoration in trial EHS. In trial LAS, neither beverage exceeded 65% retention, but AA replaced electrolytes and preserved ISF volume better than SP (P <0.05). CONCLUSION: The results of this study demonstrate superior rehydration when using AA compared with SP for both hypertonic and isotonic dehydration.

Macrophage infiltration is a hallmark in the majority of solid tumors. Our studies demonstrated that macrophages that infiltrate human renal cells carcinoma (RCC) display markedly enhanced expression and activity of 15-lipoxygenase-2 (15-LOX2). Obtained data suggest that enhanced lipoxygenase activity in tumor-associated macrophages stimulates cancer inflammation and causes immune dysfunction.

Despite the critical role of DNA methylation, clinical implementations harnessing its promise have not been described in acute myeloid leukemia. Utilizing DNA methylation from 3314 leukemia patient samples across 11 harmonized cohorts, we describe the Acute Leukemia Methylome Atlas, which includes robust models capable of accurately predicting AML subtypes. A genome-wide prognostic model as well as a targeted panel of 38 CpGs significantly predict five-year survival in our pediatric and adult test cohorts. To accelerate rapid clinical utility, we develop a specimen-to-result protocol that uses long-read nanopore sequencing and machine learning to characterize patients' whole genomes and epigenomes. Clinical validation on patient samples confirms high concordance between epigenomic signatures and genomic lesions, though uniquely rare karyotypes remained challenging due to limited available training data. These results unveil the potential for increased affordability, speed, and accuracy for patients in need of complex molecular diagnosis and prognosis.

Human sarcoma cells can be killed by radio- and chemotherapy, but tumor cells acquiring resistance frequently kill the patient. A keen understanding of the intracellular course of oncogenic cascades leads to the discovery of small molecular inhibitors of the involved phosphorylated kinases. Targeted therapy complements chemotherapy. Oncogene silencing is feasible by small interfering RNA. The restoration of some of the mutated or deleted tumor-suppressor genes (p53, Rb, PTEN, hSNF, INK/ARF and WT) by demethylation or reacetylation of their histones has been accomplished. Genetically engineered or naturally oncolytic viruses selectively lyse tumors and leave healthy tissues intact. Adeno- or retroviral vectors deliver genes of immunological costimulators, tumor antigens, chemo- or cytokines and/or tumor-suppressor proteins into tumor (sarcoma) cells. Suicide gene delivery results in apoptosis induction. Genes of enzymes that target prodrugs as their substrates render tumor cells highly susceptible to chemotherapy, with the prodrug to be targeted intracellularly. It will be combinations of sophisticated surgical removal of the nonencapsulated and locally invasive primary sarcomas, advanced forms of radiotherapy to the involved sites and immunotherapy with sarcoma vaccines that will cure primary sarcomas. Adoptive immunotherapy with immune lymphocytes will be operational in metastatic disease only when populations of regulatory T cells are controlled. Targeted therapy with small molecular inhibitors of oncogene cascades, the driving forces of sarcoma cells, alteration of the tumor stroma from a supportive to a tumor-hostile environment, reactivation or replacement of wild-type tumor-suppressor genes, and radio-chemotherapy (with much reduced toxicity) will eventually accomplish the cure of metastatic sarcomas.

Abstract Background We investigated the quality of life (QOL) impact of post‐radiation therapy (RT) superselective/selective neck dissection after de‐intensified chemoradiation for human papillomavirus‐associated oropharynx cancer. Methods A total of 147 patients received 60 Gy and weekly low‐dose cisplatin on two phase 2 trials with planned post‐RT neck dissection or surveillance positron emission tomography with neck dissection reserved for salvage. UW‐QOL Shoulder Score, EORTC H&amp;N‐35, and EAT‐10 were assessed. Results In all, 48 of 147 patients had post‐RT neck dissection. At 2 years, 37% and 13% of patients receiving post‐RT neck dissection had Shoulder Score ≥ 1 (any shoulder symptoms) and ≥ 2 (symptoms affecting work/hobbies), respectively, versus only 16% and 3% of patients not receiving post‐RT neck dissection. Post‐RT neck dissection was associated with Shoulder Score ≥ 1 ( P = 0.005) and Shoulder Score ≥ 2 ( P = 0.03) at 2 years, but not H&amp;N‐35 or EAT‐10 scores. Conclusions Post‐RT superselective/selective neck dissection was associated with modest but persistent shoulder symptoms. These toxicities should be weighed against the probability of persistent disease when evaluating patients for post‐RT neck dissection.

OBJECTIVE: As cancer patients increasingly use chatbots, it is crucial to recognize ChatGPT's potential in enhancing health literacy while ensuring validation to prevent misinformation. This study aims to assess ChatGPT-3.5's capability to provide appropriate staging and treatment recommendations for head and neck mucosal malignancies for vulnerable populations. STUDY DESIGN AND SETTING: Forty distinct clinical vignettes were introduced into ChatGPT to inquire about staging and treatment recommendations for head and neck mucosal malignancies. METHODS: Prompts were created based on head and neck cancer (HNC) disease descriptions (cancer location, tumor size, lymph node involvement, and symptoms). Staging and treatment recommendations according to the 2021 National Comprehensive Cancer Network (NCCN) guidelines were scored by three fellowship-trained HNC surgeons from two separate tertiary care institutions. HNC surgeons assessed the accuracy of staging and treatment recommendations, such as the completeness of surgery and the appropriateness of treatment modality. RESULTS: Whereas ChatGPT's responses were 95% accurate at recommending the correct first-line treatment based on the 2021 NCCN guidelines, 55% of the responses contained inaccurate staging. Neck dissection was incorrectly omitted from treatment recommendations in 50% of the cases. Moreover, 40% of ChatGPT's treatment recommendations were deemed unnecessary. CONCLUSION: This study emphasizes ChatGPT's potential in HNC patient education, aligning with NCCN guidelines for mucosal malignancies, but highlights the importance of ongoing refinement and scrutiny due to observed inaccuracies in tumor, nodal, metastasis staging, incomplete surgery options, and inappropriate treatment recommendations. Otolaryngologists can use this information to caution patients, families, and trainees regarding the use of ChatGPT for HNC education without expert guidance.

SummaryConcentrations of reduced, oxidized, and total ascorbic acid in the fore-stomach, glandular stomach, and adrenals of the rat have been reported. Direct contact of a eugenol emulsion with the gastric mucosa resulted in a gastritis and a 13% decrease in the total gastric ascorbic acid. Systemic absorption of the eugenol, avoiding direct gastric contact, did not induce these changes. A decrease in adrenal ascorbic acid after eugenol administration suggests a systemic stress effect also associated with the presence of the eugenol, but distinct from the direct gastric effect.

The ionization constants of 14 basic dyes belonging to 5 chemical classes, azo, azines, xanthenes, oxazines and thiazines, each containing 2-4 compounds, were determined spectrophotometrically in buffered 50% alcoholic solutions. The dyes were those which Ingraham and Visscher have found to be secreted by the stomach. Fairly good agreement for the ionization constants by 3 different methods (spectrophotometric in buffered 50% alcohol, titration in water and in 50% unbuffered alcohol) is obtained for Nile Blue A, Bismarck Brown Y, Rhodamine B, Chrysoidin Y, Neutral Red and Pyronine B. With the exception of Acridine Red these are all the weaker bases. Higher values were found for the other dyes by the spectrophotometric method. The spectrophotometric pKa values paralleled the buffer/benzene ratios. The order of basicity varies in different media. It was not possible to correlate satisfactorily the secretion of dyes in a biological system with their ionization constants in aqueous or buffered 50% alcoholic solution.

Abstract The COVID-19 pandemic has resulted in 153 million infections and 3.2 million deaths as of May 2021. While effective vaccines are being administered globally, there is still a great need for antiviral therapies as potentially antigenically distinct SARS-CoV-2 variants continue to emerge across the globe. Viruses require host factors at every step in their life cycle, representing a rich pool of candidate targets for antiviral drug design. To identify host factors that promote SARS-CoV-2 infection with potential for broad-spectrum activity across the coronavirus family, we performed genome-scale CRISPR knockout screens in two cell lines (Vero E6 and HEK293T ectopically expressing ACE2) with SARS-CoV-2 and the common cold-causing human coronavirus OC43. While we identified multiple genes and functional pathways that have been previously reported to promote human coronavirus replication, we also identified a substantial number of novel genes and pathways. Of note, host factors involved in cell cycle regulation were enriched in our screens as were several key components of the programmed mRNA decay pathway. Finally, we identified novel candidate antiviral compounds targeting a number of factors revealed by our screens. Overall, our studies substantiate and expand the growing body of literature focused on understanding key human coronavirus-host cell interactions and exploit that knowledge for rational antiviral drug development. One Sentence Summary Genome-wide CRISPR screens identified host factors that promote human coronavirus infection, revealing novel antiviral drug targets.

An unusual pattern of pulmonary density in the left lung, simulating pleural effusion, was observed in children with marked cardiomegaly. From a study of plain films and lung scans, this radiodensity was proved to be caused by lingular collapse and rotation of the major fissure into a position parallel to the central ray. The pattern was found in six children during the past 18 months. It is sufficiently characteristic to be diagnosed from plain films in frontal, oblique, lateral and decubitus positions.

In a study of the relation of physical chemical properties of dyes to the extent of their secretion by the. stomach, new determinations of the pKB values and absorption maxima were made. A somewhat better correlation of pKB and stomach: blood ratios was obtained by using commercial instead of pure samples of dyes. The distribution of the dyes between benzene and aqueous buffers of pH 2 and pH 6.73 was measured but no satisfactory correlation found. The method is limited by the tendency of compounds to dissolve 100% in either the buffer or the benzene.

BACKGROUND: External-beam radiotherapy (EBRT) has been used in the treatment of adenocarcinoma of the prostate gland for more than 30 years. Well-documented clinical series have demonstrated the effectiveness of EBRT in achieving both cause-specific survival and freedom from biochemical (prostate-specific antigen [PSA]) progression. METHODS: The indications and expected treatment results for treatment by EBRT in the management of adenocarcinoma of the prostate gland are reviewed. The treatment of early-stage disease definitively by EBRT alone or as complement to radioactive seed implant is emphasized. In the management of locally advanced disease, the use of EBRT with combined androgen ablation is discussed as definitive therapy and also as indicated in the postoperative adjuvant management of surgically identified pathologic stage T3 disease. RESULTS: The relative clinical benefit of EBRT compared with the mostly predictable and well-defined moderate side effects, which are manageable in most instances by conservative measures treatment, is well established. Advances in defining radiation-beam parameters have led to more effective and safer treatment for prostate cancer. CONCLUSIONS: EBRT has historically been a mainstay in the management of prostate cancer. It remains a useful and indicated treatment modality in patients with early-stage, locally advanced, and metastatic disease.

Administering myelosuppressive chemotherapy to patients with aggressive malignant hematologic disorders typically poses serious infectious complications, which can be exacerbated by the presence of active COVID-19 infection. We report on a case of a successfully treated fit elderly woman with refractory acute myeloid leukemia (AML) who also had mild COVID-19 infection and detectable viral load at the time she was found to have recurrent disease. Prior to initiation of reinduction treatment with cytarabine/idarubicin, this 2-dose COVID-19-vaccinated patient received antiviral therapy with remdesivir with resolution of upper respiratory symptoms. This was followed by sotrovimab on the third day of chemotherapy. Throughout her hospital course, she remained hemodynamically stable with one episode of neutropenic fever without other identified infections. Symptomatic reactivation of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causing COVID-19 was not observed. After achieving biopsy-confirmed morphologic remission of AML and with neutrophil recovery, the patient gradually cleared the virus, eventually testing negative on polymerase chain reaction test of the nasopharynx. This case underlines the importance of considering initiation of timely chemotherapy, although myelosuppressive, in appropriate patients with aggressive hematologic malignancies and concomitant SARS-CoV-2. It demonstrates management of active COVID-19 infection in this group of patients and the dynamics of SARS-CoV-2 viral load during leukemia treatment.