Imaging with [89Zr]Zr-DFO-SC16.56 anti-DLL3 antibody in patients with high-grade neuroendocrine tumours of the lung and prostate: a phase 1/2, first-in-human trial.

BACKGROUND: Delta-like ligand 3 (DLL3) is aberrantly expressed on the surface of small-cell lung cancer (SCLC) and neuroendocrine prostate cancer cells. We assessed the safety and feasibility of the DLL3-targeted imaging tracer [89Zr]Zr-DFO-SC16.56 (composed of the anti-DLL3 antibody SC16.56 conjugated to p-SCN-Bn-deferoxamine [DFO] serving as a chelator for zirconium-89) in patients with neuroendocrine-derived cancer. METHODS: We conducted an open-label, first-in-human study of immunoPET-CT imaging with [89Zr]Zr-DFO-SC16.56. The study was done at Memorial Sloan Kettering Cancer Center, New York, NY, USA. Patients aged 18 years or older with a histologically verified neuroendocrine-derived malignancy and an Eastern Cooperative Oncology Group performance status of 0-2 were eligible. An initial cohort of patients with SCLC (cohort 1) received 37-74 MBq [89Zr]Zr-DFO-SC16.56 as a single intravenous infusion at a total mass dose of 2·5 mg and had serial PET-CT scans at 1 h, day 1, day 3, and day 7 post-injection. The primary outcomes of phase 1 of the study (cohort 1) were to estimate terminal clearance half-time, determine whole organ time-integrated activity coefficients, and assess the safety of [89Zr]Zr-DFO-SC16.56. An expansion cohort of additional patients (with SCLC, neuroendocrine prostate cancer, atypical carcinoid tumours, and non-small-cell lung cancer; cohort 2) received a single infusion of [89Zr]Zr-DFO-SC16.56 at the same activity and mass dose as in the initial cohort followed by a single PET-CT scan 3-6 days later. Retrospectively collected tumour biopsy samples were assessed for DLL3 by immunohistochemistry. The primary outcome of phase 2 of the study in cohort 2 was to determine the potential association between tumour uptake of the tracer and intratumoural DLL3 protein expression, as determined by immunohistochemistry. This study is ongoing and is registered with ClinicalTrials.gov, NCT04199741. FINDINGS: Between Feb 11, 2020, and Jan 30, 2023, 12 (67%) men and six (33%) women were enrolled, with a median age of 64 years (range 23-81). Cohort 1 included three patients and cohort 2 included 15 additional patients. Imaging of the three patients with SCLC in cohort 1 showed strong tumour-specific uptake of [89Zr]Zr-DFO-SC16.56 at day 3 and day 7 post-injection. Serum clearance was biphasic with an estimated terminal clearance half-time of 119 h (SD 31). The highest mean absorbed dose was observed in the liver (1·83 mGy/MBq [SD 0·36]), and the mean effective dose was 0·49 mSv/MBq (SD 0·10). In cohort 2, a single immunoPET-CT scan on day 3-6 post-administration could delineate DLL3-avid tumours in 12 (80%) of 15 patients. Tumoural uptake varied between and within patients, and across anatomical sites, with a wide range in maximum standardised uptake value (from 3·3 to 66·7). Tumour uptake by [89Zr]Zr-DFO-SC16.56 was congruent with DLL3 immunohistochemistry in 15 (94%) of 16 patients with evaluable tissue. Two patients with non-avid DLL3 SCLC and neuroendocrine prostate cancer by PET scan showed the lowest DLL3 expression by tumour immunohistochemistry. One (6%) of 18 patients had a grade 1 allergic reaction; no grade 2 or worse adverse events were noted in either cohort. INTERPRETATION: DLL3 PET-CT imaging of patients with neuroendocrine cancers is safe and feasible. These results show the potential utility of [89Zr]Zr-DFO-SC16.56 for non-invasive in-vivo detection of DLL3-expressing malignancies. FUNDING: National Institutes of Health, Prostate Cancer Foundation, and Scannell Foundation.

Impact of rabbit anti-thymocyte globulin (ATG) exposure on outcomes after ex vivo T-cell-depleted hematopoietic cell transplantation in pediatric and young adult patients.

BACKGROUND AIMS: Traditional weight-based dosing of rabbit anti-thymocyte globulin (rATG) used in allogeneic hematopoietic cell transplantation (HCT) to prevent graft-versus-host disease (GVHD) and graft rejection leads to variable exposures. High exposures induce delayed CD4+immune reconstitution (CD4+IR) and greater mortality. We sought to determine the impact of rATG exposure in children and young adults receiving various types of EX-VIVO T-cell-depleted (EX-VIVO-TCD) HCT. METHODS: Patients receiving their first EX-VIVO-TCD HCT (CliniMACS CD34+, Isolex or soybean lectin agglutination), with removal of residual T cells by E-rosette depletion (E-) between 2008 and 2018 at Memorial Sloan Kettering Cancer Center were retrospectively analyzed. rATG exposure post-HCT was estimated (AU*d/L) using a validated population pharmacokinetic model. Previously defined rATG-exposures, <30, 30-55, ≥55 AU*d/L, were related with outcomes of interest. Cox proportional hazard and cause-specific models were used for analyses. RESULTS: In total, 180 patients (median age 11 years; range 0.1-44 years) were included, malignant 124 (69%) and nonmalignant 56 (31%). Median post-HCT rATG exposure was 32 (0-104) AU*d/L. Exposure <30 AU*d/L was associated with a 3-fold greater probability of CD4+IR (P < 0.001); 2- to 4-fold lower risk of death (P = 0.002); and 3- to 4-fold lower risk of non-relapse mortality (NRM) (P = 0.02). Cumulative incidence of NRM was 8-fold lower in patients who attained CD4+IR compared with those who did not (P < 0.0001). There was no relation between rATG exposure and aGVHD (P = 0.33) or relapse (P = 0.23). Effect of rATG exposure on outcomes was similar in three EX-VIVO-TCD methods. CONCLUSIONS: Individualizing rATG dosing to target a low rATG exposure post-HCT while maintaining total cumulative exposure may better predict CD4+IR, reduce NRM and increase overall survival, independent of the EX-VIVO-TCD method.

Safety and tolerability of intravenous aprepitant and fosaprepitant in children with cancer: A retrospective, single-center review.

NK-1 receptor antagonists (NK1-RA) are key agents for chemotherapy-induced nausea and vomiting (CINV) prevention in patients receiving highly emetogenic chemotherapy. Current pediatric practice guidelines recommend the use of intravenous fosaprepitant or oral aprepitant. However, there are reports of hypersensitivity reactions with fosaprepitant due to polysorbate 80. Intravenous aprepitant does not contain polysorbate 80, but its use in pediatric patients has not been described. In this retrospective, single-center study, 106 pediatric patients received either fosaprepitant or intravenous aprepitant as part of their antiemetic regimen. Intravenous aprepitant was well tolerated and did not lead to any instances of hypersensitivity reactions requiring discontinuation.

The safety and efficacy of methylnaltrexone in pediatric oncology patients: A single center experience.

INTRODUCTION: Peripherally acting µ-opioid receptor antagonists (PAMORAs) are used in the treatment of opioid induced constipation without impacting the actions of opioid analgesics. Subcutaneous methylnaltrexone was one of the first PAMORAs approved in April 2008 for the treatment of opioid induced constipation in adult patients. The safety and effectiveness of methylnaltrexone has not been established in pediatric patients. In this study, the use of subcutaneous methylnaltrexone in pediatric patients is analyzed and reviewed. The primary outcome is occurrence of a bowel movement within 24 h after methylnaltrexone (MNTX) administration and the number of bowel movements following treatment with methylnaltrexone. Secondary outcomes include safety in this patient cohort. METHODS: This is a retrospective study of 79 pediatric patients with opioid induced constipation. Patients were administered methylnaltrexone during their inpatient stay. Data on bowel activity after methylnaltrexone was obtained from the hospital information system. RESULTS: Out of the 79 patients who received methylnaltrexone, there were seven patients from whom data could not be analyzed. Of the 72 patients whose data was available, 38% (N = 27) were documented as having a bowel movement, 62% (N = 45) did not have a bowel movement. Reported adverse events were minimal with nausea (N = 3), vomiting (N = 1), and flatulence (N = 6). CONCLUSION: Methylnaltrexone appears safe in the pediatric population and produces bowel movements in more than a third of pediatric patients. It is a feasible and safe option for opioid induced constipation in pediatric patients.

The use of single-timepoint images to link administered radioiodine activity (MBq) to a prescribed lesion radiation-absorbed dose (cGy): a regression-based prediction interval tool for the management of well-differentiated thyroid cancer patients.

PURPOSE: To introduce a biomarker-based dosimetry method for the rational selection of a treatment activity for patients undergoing radioactive iodine 131I therapy (RAI) for metastatic differentiated thyroid cancer (mDTC) based on single-timepoint imaging of individual lesion uptake by 124I PET. METHODS: Patients referred for RAI therapy of mDTC were enrolled in institutionally approved protocols. A total of 208 mDTC lesions (in 21 patients) with SUVmax > 1 underwent quantitative PET scans at 24, 48, 72, and 120 h post-administration of 222 MBq of theranostic NaI-124I to determine the individual lesion radiation-absorbed dose. Using a general estimating equation, a prediction curve for biomarker development was generated in the form of a best-fit regression line and 95% prediction interval, correlating individual predicted lesion radiation dose metrics, with candidate biomarkers ("predictors") such as SUVmax and activity in microcurie per gram, from a single imaging timepoint. RESULTS: In the 169 lesions (in 15 patients) that received 131I therapy, individual lesion cGy varied over 3 logs with a median of 22,000 cGy, confirming wide heterogeneity of lesion radiation dose. Initial findings from the prediction curve on all 208 lesions confirmed that a 48-h SUVmax was the best predictor of lesion radiation dose and permitted calculation of the 131I activity required to achieve a lesional threshold radiation dose (2000 cGy) within defined confidence intervals. CONCLUSIONS: Based on MIRD lesion-absorbed dose estimates and regression statistics, we report on the feasibility of a new single-timepoint 124I-PET-based dosimetry biomarker for RAI in patients with mDTC. The approach provides clinicians with a tool to select personalized (precision) therapeutic administration of radioactivity (MBq) to achieve a desired target lesion-absorbed dose (cGy) for selected index lesions based on a single 48-h measurement 124I-PET image, provided the selected activity does not exceed the maximum tolerated activity (MTA) of < 2 Gy to blood, as is standard of care at Memorial Sloan Kettering Cancer Center. TRIAL REGISTRATION: NCT04462471, Registered July 8, 2020. NCT03647358, Registered Aug 27, 2018.

Bleeding in Critically Ill Children With Malignancy or Hematopoietic Cell Transplant: A Single-Center Prospective Cohort Study.

OBJECTIVES: To determine the incidence of bleeding in critically ill children with malignancy and to describe associated patient characteristics, interventions, and clinical outcomes. DESIGN: Prospective cohort study. SETTING: PICU in a specialized cancer hospital. PATIENTS: Children with malignancy or hematopoietic cell transplant 0-18 years of age were admitted to the PICU from November 2020 to November 2021. INTERVENTIONS: None. MEASUREMENTS: Patient demographic data, laboratory values, and PICU outcome data were collected. Bleeding was classified according to the Bleeding Assessment Scale in Critically Ill Children. MAIN RESULTS: Ninety-three bleeding patients were enrolled, and a total of 322 bleeding days were recorded. The median (interquartile range [IQR]) age was 5.8 (2.9-11.8) years and 56% (52/93) of the patients were male. There were 121 new bleeding episodes, in 593 at-risk person-days, translating into a 20% incidence rate per day (95% CI, 17-24%). The incidence of severe, moderate, and minimal bleeding was 2% (95% CI, 1-3), 4% (95% CI, 3-6), and 14% (95% CI, 12-17), respectively. Of the new bleeding episodes, 9% were severe, 25% were moderate and 66% were minimal. Thrombocytopenia was the only laboratory value independently associated with severe bleeding ( p = 0.009), as compared to minimal and moderate bleeding episodes. History of radiation therapy was independently associated with severe bleeding ( p = 0.04). We failed to identify an association between a history of stem cell transplant ( p = 0.49) or tumor type ( p = 0.76), and bleeding severity. Patients were transfused any blood product on 28% (95% CI, 22-34) of the bleeding days. Severe bleeding was associated with increased length of mechanical ventilation ( p = 0.003), longer PICU stays ( p = 0.03), and higher PICU mortality ( p = 0.004). CONCLUSIONS: In this prospective cohort of children with malignancy, the incidence rate of bleeding was 20%. Most events were classified as minimal bleeding. Low platelet count and radiation therapy were variables independently associated with severe bleeding episodes.

18F-DCFPyL PET/CT for Initially Diagnosed and Biochemically Recurrent Prostate Cancer: Prospective Trial with Pathologic Confirmation.

Background Prostate-specific membrane antigen (PSMA) PET is standard for newly diagnosed high-risk and biochemically recurrent (BCR) prostate cancer. Although studies suggest high specificity of 2-(3-{1-carboxy-5-[(6-[(18)F]fluoro-pyridine-3-carbonyl)-amino]-pentyl}-ureido)-pentanedioic acid (DCFPyL) for targeting PSMA, false-positive findings have been identified and most studies lack histologic confirmation of malignancy. Purpose To estimate the positive predictive value (PPV) of DCFPyL PET/CT by providing histopathologic proof for DCFPyL-avid lesions suspected of being distant metastases at initial diagnosis and recurrence in BCR prostate cancer. Materials and Methods In this prospective trial, men with newly diagnosed high-risk prostate cancer (sample 1) or BCR prostate cancer and negative findings at conventional CT and/or bone scanning (sample 2) were enrolled between January and December 2021. All men underwent DCFPyL PET/CT. Suspected distant metastases and/or recurrences were biopsied. PPV was calculated. Results A total of 92 men with newly diagnosed prostate cancer (median age, 70 years; IQR, 64-75 years) (sample 1) and 92 men with BCR prostate cancer (median age, 71 years; IQR, 66-75 years) (sample 2) were enrolled. In sample 1, 25 of the 92 men (27%) demonstrated DCFPyL-avid lesions suspicious for distant metastases. Biopsy was performed in 23 of the 25 men (92%), with 17 of the 23 (74%) biopsies positive for malignancy and six (26%) benign. Of the six benign biopsies, three were solitary rib foci and three were solitary pelvic bone foci. In sample 2, 57 of the 92 men (62%) demonstrated DCFPyL-avid lesions suspicious for recurrence. Biopsy was performed in 37 of the 57 men (65%), with 33 of the 37 (89%) biopsies positive for malignancy and four (11%) benign. Of the four benign biopsies, two were subcentimeter pelvic nodes and/or nodules, one was a rib, and one was a pelvic bone focus. Conclusion PET/CT with 2-(3-{1-carboxy-5-[(6-[(18)F]fluoro-pyridine-3-carbonyl)-amino]-pentyl}-ureido)-pentanedioic acid (DCFPyL) had a high biopsy-proven positive predictive value for distant metastases in newly diagnosed prostate cancer (74%) and for recurrence sites in men with biochemical recurrence (89%). However, there were DCFPyL-avid false-positive findings (particularly in ribs and pelvic bones). Solitary DCFPyL avidity in these locations should not be presumed as malignant. Biopsy may still be needed prior to therapy decisions. ClinicalTrials.gov registration no. NCT04700332 © RSNA, 2022 See also the editorial by Zukotynski and Kuo in this issue.

Time to initiation of pre-emptive therapy for cytomegalovirus impacts overall survival in pediatric hematopoietic stem cell transplant recipients.

BACKGROUND AIMS: Cytomegalovirus (CMV) reactivation is a significant complication following allogeneic hematopoietic stem cell transplant (HSCT) and affects upwards of 40% of pediatric HSCT patients. Pre-emptive therapy remains the only effective treatment strategy available for pediatric patients following CMV reactivation. Little is known about how the timing of induction treatment following CMV reactivation impacts outcomes in pediatric patients, especially following ex vivo T-cell-depleted (TCD) HSCT. METHODS: The authors evaluated how the timing of induction treatment after CMV reactivation impacts overall survival (OS) and CMV disease in pediatric patients undergoing TCD HSCT at a single institution. The authors retrospectively analyzed patients treated on the pediatric service who received an initial ex vivo TCD HSCT at Memorial Sloan Kettering Cancer Center (MSKCC) from January 2010 to June 2018. CMV reactivation was defined as ≥1 CMV polymerase chain reaction >500 copies/mL in whole blood or >137 IU/mL in plasma within the first 180 days after allogeneic HSCT. To analyze the impact of the timing of induction treatment, the authors' primary study outcome was OS and secondary outcome was CMV disease. RESULTS: A total of 169 patients who underwent an initial allogeneic TCD HSCT on the pediatric service at MSKCC from January 2010 to June 2018 were included in the analysis. Thirty-seven (22%) patients reactivated CMV during the first 180 days following HSCT. Of those patients who reactivated CMV, CMV donor/recipient (D/R) serostatus was as follows: D+/R+ n = 28 (76%) and D-/R+ n = 9 (24%). There was no CMV reactivation observed among recipients who were CMV-seronegative irrespective of donor serostatus. In those patients who reactivated CMV, the median time from HSCT to CMV reactivation was 24 days (interquartile range, 20-31). Eleven patients ultimately developed CMV disease in addition to CMV viremia, whereas the remaining patients had only CMV viremia. The cumulative incidence of CMV reactivation at 60 days was 45.2% (95% confidence interval [CI], 32.8-57.5) in the D+/R+ subgroup and 31% (95% CI, 14.2-47.9) in the D-/R+ subgroup. For those patients who reactivated CMV, 30 (81%) received induction treatment with ganciclovir or foscarnet. To analyze the impact of the timing of induction treatment on clinical outcomes, the authors restricted the analysis to those patients who reactivated CMV and received induction treatment (n = 30). The timing of induction treatment was significantly associated with OS, with optimal timing of initiation within a week of CMV reactivation (P = 0.02). There was no significant impact on the timing of induction treatment and risk of CMV disease (P = 0.30). CONCLUSIONS: In ex vivo TCD HSCT in pediatric patients, early initiation of induction treatment after CMV reactivation is associated with improved OS.

Pneumatosis intestinalis in the pediatric oncology population: An 11-year retrospective review at Memorial Sloan Kettering Cancer Center.

BACKGROUND: Pneumatosis intestinalis (PI) is characterized by the presence of intramural gas in the gastrointestinal (GI) tract. The overall aim of this study was to review risk factors and outcome of pediatric oncology patients at our institution who developed PI. PROCEDURE: Patients diagnosed with PI between 2007 and 2018 were identified from ICD-10 coding of radiology reports at Memorial Sloan Kettering Kids, a tertiary pediatric oncology center. Outcomes of interest were (a) resolution and time to resolution of PI, (b) surgical intervention within 2 weeks of diagnosis of PI, or (c) death secondary to PI. To capture the resolution of PI, we defined the "time to recovery (TTR)" as the time elapsed between date of PI diagnosis and the date of recovery. RESULTS: Forty-two patients were identified. Within 30 days of diagnosis of PI, three patients had surgical intervention for PI (7%) and two patients died (5%) due to non-PI causes. Median TTR of PI was 4.5 days (95% CI: 3-7 days). In univariable and multivariable analyses, only steroid use in the prior 30 days was significantly associated with a faster TTR of PI (HR = 2.27 [95% CI: 1.17-4.41], p = .02). CONCLUSIONS: This is the largest case series of patients with PI in the pediatric oncology population, which reveals significantly lower surgical and mortality rates than other published PI series. For the majority of patients, conservative medical management is indicated. A prospective study is warranted to define diagnosis and management guidelines for PI in the pediatric oncology population in a cooperative group setting.

Chemotherapy-induced thrombocytopenia in pediatric oncology: Scope of the problem and opportunities for intervention.

BACKGROUND: Chemotherapy-induced thrombocytopenia (CIT) is a known hematologic complication of oncology treatment. This single-institution study examines the degree with which CIT impacts specific pediatric solid tumor cohorts reflected by platelet transfusion burden and treatment modifications. PROCEDURE: Data regarding clinically relevant CIT were obtained via a retrospective chart review of pediatric solid tumor patients treated at Memorial Sloan Kettering Cancer Center from 2013 to 2020. Patients were stratified based on histologic diagnoses as well as chemotherapy regimen. CIT impact was assessed through platelet transfusion means, chemotherapy dose reductions, and treatment delays. RESULTS: A total of 150 patients were included with mean age 10.3 [0.2-21.0]. Patients receiving therapy for high-risk neuroblastoma and localized Ewing sarcoma, both of which included high-dose cyclophosphamide and doxorubicin, required the most platelet transfusions over the treatment course, with a mean of 13 and 9, respectively. Reduced relative dose intensity (RDI), due in part to CIT, was greatest for the patients receiving therapy for high-risk and intermediate-risk rhabdomyosarcoma. Fifty-six percent of high-risk patients experienced a reduced RDI during the final two cycles of treatment and 69% of intermediate-risk patients experienced one during the final four cycles of treatment. CONCLUSIONS: The impact of CIT varied by the administered chemotherapy regimens and dose intensity of chemotherapy agents. This study demonstrated that CIT causes both marked platelet transfusion burden as well as treatment reduction and delay within certain solid tumor cohorts. This can lend to future studies aimed at reducing the burden of CIT and targeting the most at-risk populations.

Accounting for the rarity of the disease when designing clinical trials with a focus on pediatric cancers.

BACKGROUND: Clinical trials are challenging in rare diseases like pediatric cancers, where the accrual is limited. In these trials, inference assumptions are the same as in common diseases, that is the sample comes from a quasi-infinite population. This leads to overestimating the variance of the mean treatment effect. The finite-population correction factor correcting this bias is often used in surveys, but not in clinical trials. With few assumptions, the use of this correction factor can improve trials efficiency, showing that the power of those trials is sometimes higher than it appears. METHODS: First, a simulation study assesses the standard error of the mean treatment effect and coverage of the 95% confidence interval with and without the correction. Second, the analytical power of a z-test with and without the correction is given. Finally, the impact on the sample size calculation is investigated. The impact of assuming a finite population is assessed for varying treatment effect, sample size and population size. RESULTS: The simulation results confirm the overestimation of the standard error without the correction factor. When using the correction factor, the gain in power reaches up to 10.1%, 15.3% and 12.3% to detect a difference in treatment effect of 10%, 15% and 20%, respectively. The gain is negligible for n = 30, in scenarios with high power (>95%), and for large populations. This gain in power translates into a decrease in sample size: if the conventional calculation leads to a sample size 10% of the population size, then the sample size can be divided by 1.1; if the conventional calculation leads to a sample size 20% of the population size, then the sample size can be divided by 1.2, in order to reach the planned type I error and power. CONCLUSION: When dealing with rare diseases like pediatric cancers, the power of clinical trials might be higher than it appears if using conventional sample sizes. When correcting the variance of the mean using the population size, a gain in efficiency is observed with reasonable sample sizes and treatment differences for very small population sizes, showing that this approach can be useful for some pediatric cancer clinical trials.

Prognostic value of [18F]FDG PET/CT in patients with CNS lymphoma receiving ibrutinib-based therapies.

PURPOSE: Current clinical and imaging tools remain suboptimal for predicting treatment response and prognosis in CNS lymphomas. We investigated the prognostic value of baseline [18F]FDG PET in patients with CNS lymphoma receiving ibrutinib-based treatments. METHODS: Fifty-three patients enrolled in a prospective clinical trial and underwent brain PET before receiving single-agent ibrutinib or ibrutinib in combination with methotrexate with or without rituximab. [18F]FDG uptake in these lesions was quantified by drawing PET volumes of interest around up to five [18F]FDG-avid lesions per patient (with uptake greater than surrounding brain). We measured standardized uptake values (SUVmax), metabolic tumor volumes, total lesion glycolysis (TLG), and the sum thereof in these lesions. We analyzed the relationship between PET parameters and mutation status, overall response rates, and progression-free survival (PFS). RESULTS: Thirty-eight patients underwent single-agent therapy and 15 received combination therapy. On PET, 15/53 patients had no measurable disease. In the other 38 patients, a total of 71 lesions were identified on PET. High-intensity [18F]FDG uptake and a larger volume of [18F]FDG-avid disease were inversely related to treatment outcome (p ≤ 0.005). In univariable analysis, PFS was linearly correlated with all PET parameters, with stronger association when sum-values were used. A multivariable model showed that risk of progression increased by 9% for every 5-unit increase in sumSUVmax (hazard ratio = 1.09 [95% CI: 1.04 to 1.14]). CONCLUSION: Higher lesional metabolic parameters are inversely related to outcome in patients undergoing ibrutinib-based therapies, and sumSUVmax emerged as a strong independent prognostic factor. TRIAL REGISTRATION: NCT02315326; https://clinicaltrials.gov/ct2/show/NCT02315326?term=NCT02315326&draw=2&rank=1.

A phase I study of a PARP1-targeted topical fluorophore for the detection of oral cancer.

BACKGROUND: Visual inspection and biopsy is the current standard of care for oral cancer diagnosis, but is subject to misinterpretation and consequently to misdiagnosis. Topically applied PARPi-FL is a molecularly specific, fluorescent contrast-based approach that may fulfill the unmet need for a simple, in vivo, non-invasive, cost-effective, point-of-care method for the early diagnosis of oral cancer. Here, we present results from a phase I safety and feasibility study on fluorescent, topically applied PARPi-FL. Twelve patients with a histologically proven oral squamous cell carcinoma (OSCC) gargled a PARPi-FL solution for 60 s (15 mL, 100 nM, 250 nM, 500 nM, or 1000 nM), followed by gargling a clearing solution for 60 s. Fluorescence measurements of the lesion and surrounding oral mucosa were taken before PARPi-FL application, after PARPi-FL application, and after clearing. Blood pressure, oxygen levels, clinical chemistry, and CBC were obtained before and after tracer administration. RESULTS: PARPi-FL was well-tolerated by all patients without any safety concerns. When analyzing the fluorescence signal, all malignant lesions showed a significant differential in contrast after administration of PARPi-FL, with the highest increase occurring at the highest dose level (1000 nM), where all patients had a tumor-to-margin fluorescence signal ratio of >3. A clearing step was essential to increase signal specificity, as it clears unbound PARPi-FL trapped in normal anatomical structures. PARPi-FL tumor cell specificity was confirmed by ex vivo tabletop confocal microscopy. We have demonstrated that the fluorescence signal arose from the nuclei of tumor cells, endorsing our macroscopic findings. CONCLUSIONS: A PARPi-FL swish & spit solution is a rapid and non-invasive diagnostic tool that preferentially localizes fluorescent contrast to OSCC. This technique holds promise for the early detection of OSCC based on in vivo optical evaluation and targeted biopsy of suspicious lesions in the oral cavity. TRIAL REGISTRATION: Clinicaltrials.gov -NCT03085147, registered on March 21st, 2017.

Testing tumors from different anatomic sites for clonal relatedness using somatic mutation data.

A common task for the cancer pathologist is to determine, in a patient suffering from cancer, whether a new tumor in a distinct anatomic site from the primary is an independent occurrence of cancer or a metastasis. As mutational profiling of tumors becomes more widespread in routine clinical practice, this diagnostic task can be greatly enhanced by comparing mutational profiles of the tumors to determine if they are sufficiently similar to conclude that the tumors are clonally related, that is, one is a metastasis of the other. We present here a likelihood ratio test for clonal relatedness in this setting and provide evidence of its validity. The test is unusual in that there are two possible alternative hypotheses, representing the two anatomic sites from which the single clonal cell could have initially emerged. Although evidence for clonal relatedness is largely provided by the presence of exact mutational matches in the two tumors, we show that it is possible to observe data where the test is statistically significant even when no matches are observed. This can occur when the mutational profile of one of the tumors is closely aligned with the anatomic site of the other tumor, suggesting indirectly that the tumor originated in that other site. We exhibit examples of this phenomenon and recommend a strategy for interpreting the results of these tests in practice.

Diagnostic and Prognostic Utility of 18F-FDG PET/CT in Recurrent Salivary Gland Cancers.

OBJECTIVE. The role of 18F-FDG PET/CT in the evaluation of recurrent salivary gland tumors remains poorly defined. We investigated the diagnostic and prognostic utility of PET in this setting. MATERIALS AND METHODS. A total of 146 patients with recurrent salivary gland cancer were treated at our institution between January 2002 and December 2015. Patients who underwent FDG PET/CT and conventional imaging (CT or MRI) within 3 months of recurrence (n = 78) were included in this retrospective analysis. On FDG PET/CT, we measured the SUVmax, total body metabolic tumor volume of all lesions, and total lesion glycolysis of all lesions to determine the intensity and extent of FDG-avid disease. We assessed the correlation of FDG PET/CT findings with clinicopathologic features, progression-free survival, and overall survival. RESULTS. FDG PET/CT was positive for recurrence in 74 of 78 patients (94.9%) and falsely negative in four patients (5.1%). In comparison with conventional imaging, FDG PET/CT performed for restaging detected additional recurrent lesions in 14 patients (17.9%). The median SUVmax was 7.4, the median total body metabolic tumor volume was 30.1 cm3, and median total lesion glycolysis was 97.3 g/mL × cm3. Sixty-six patients had progressive disease, and 54 died. Univariate and multivariate Cox hazards analysis identified pathologic risk group (p = .04), total body metabolic tumor volume (p < .001), and total lesion glycolysis (p < .001) as independent prognostic factors for progression-free survival and identified age (p = .05), total body metabolic tumor volume (p < .001), and total lesion glycolysis (p < .001) as independent prognostic factors for overall survival. CONCLUSION. In patients with recurrent salivary gland cancer, FDG PET/CT is useful as a single test for defining the extent of disease and providing prognostic information, which may help in selecting appropriate treatment strategies.

TOXICITY AND EFFICACY OF INTRAVITREAL MELPHALAN FOR RETINOBLASTOMA: 25 µg Versus 30 µg.

PURPOSE: To compare retinal toxicity as measured by electroretinogram, ocular, and patient survival in retinoblastoma treated with intravitreal melphalan at two concentrations (25 vs. 30 µg). METHODS: Single-center, retrospective analysis of retinoblastoma eyes receiving 25-µg or 30-µg intravitreal melphalan from September 2012 to January 2019. Ocular toxicity was measured by electroretinogram of evaluable injections in 449 injections in 136 eyes. A repeated-measures linear mixed model with a random intercept and slope was applied to account for repeated measures for each eye. RESULTS: Average decline in electroretinogram after each additional injection was -4.9 µV (95% confidence interval -6.3 to -3.4); electroretinogram declined by -4.6 µV (95% confidence interval -7.0 to -2.2) after 25-µg injections and -5.2 µV (95% confidence interval -6.6 to -3.8) after 30-µg injections (P = 0.66). Injection at a new clock site hour was associated with a -3.91-µV lower average (95% confidence interval -7.8 to -0.04). CONCLUSION: Electroretinogram-measured toxicity in retinoblastoma eyes treated with intravitreal injections was not found to be different across 25-µg and 30-µg injections. There were no cases of extraocular extension or metastatic deaths in our patient population.

Testing clonal relatedness of two tumors from the same patient based on their mutational profiles: update of the Clonality R package.

SUMMARY: The Clonality R package is a practical tool to assess the clonal relatedness of two tumors from the same patient. We have previously presented its functionality for testing tumors using loss of heterozygosity data or copy number arrays. Since then somatic mutation data have been more widely available through next generation sequencing and we have developed new methodology for comparing the tumors' mutational profiles. We thus extended the package to include these two new methods for comparing tumors as well as the mutational frequency estimation from external data required for their implementation. The first method is a likelihood ratio test that is readily available on a patient by patient basis. The second method employs a random-effects model to estimate both the population and individual probabilities of clonal relatedness from a group of patients with pairs of tumors. The package is available on Bioconductor. AVAILABILITY AND IMPLEMENTATION: Bioconductor (http://bioconductor.org/packages/release/bioc/html/Clonality.html). SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Restaging [18F] fludeoxyglucose positron emission tomography/computed tomography scan in recurrent cutaneous squamous cell carcinoma: Diagnostic performance and prognostic significance.

BACKGROUND: There are no specific recommendations for [18F] fludeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) in assessing recurrent cutaneous squamous cell carcinoma (cSCC). OBJECTIVE: To evaluate FDG-PET/CT in recurrent cSCC. METHODS: FDG-PET/CT scans were retrospectively reviewed. Sites of abnormal uptake were noted and correlated with biopsy/histopathology studies, where available, and with follow-up imaging or clinical data in others. Comparison with available CT/magnetic resonance imaging was performed. The prognostic significance of PET/CT parameters was evaluated, and PET/CT-based change in management was recorded. RESULTS: A total of 115 FDG-PET/CT scans were analyzed in 100 consecutive patients with cSCC. Of these, 96 (84%) scans were positive for recurrence, and 25 showed distant metastases. PET/CT detected unsuspected disease sites in 39 of 115 scans (34%), locoregional disease in 14, distant metastases in 11, both locoregional disease and distant metastases in 8, additional local cutaneous disease in 5, and second malignancy in 1. Comparison of 78 PET/CT scans with available CT/magnetic resonance imaging showed 37 additional abnormalities on 23 PET/CT scans, predominantly including skin/subcutaneous lesions and nodes. PET/CT led to change in management in 28% of patients. On univariate/multivariate analysis, increased number of FDG-positive lesions and lung metastases on PET/CT was associated with increased risk of death/disease progression. LIMITATIONS: Retrospective study. CONCLUSIONS: FDG-PET/CT was sensitive in detecting recurrent disease in cSCC, led to change in management for 28% of patients, and proved to be of prognostic value.

An EM algorithm to improve the estimation of the probability of clonal relatedness of pairs of tumors in cancer patients.

BACKGROUND: We previously introduced a random-effects model to analyze a set of patients, each of which has two distinct tumors. The goal is to estimate the proportion of patients for which one of the tumors is a metastasis of the other, i.e. where the tumors are clonally related. Matches of mutations within a tumor pair provide the evidence for clonal relatedness. In this article, using simulations, we compare two estimation approaches that we considered for our model: use of a constrained quasi-Newton algorithm to maximize the likelihood conditional on the random effect, and an Expectation-Maximization algorithm where we further condition the random-effect distribution on the data. RESULTS: In some specific settings, especially with sparse information, the estimation of the parameter of interest is at the boundary a non-negligible number of times using the first approach, while the EM algorithm gives more satisfactory estimates. This is of considerable importance for our application, since an estimate of either 0 or 1 for the proportion of cases that are clonal leads to individual probabilities being 0 or 1 in settings where the evidence is clearly not sufficient for such definitive probability estimates. CONCLUSIONS: The EM algorithm is a preferable approach for our clonality random-effect model. It is now the method implemented in our R package Clonality, making available an easy and fast way to estimate this model on a range of applications.