Immune checkpoint inhibitors for POLE or POLD1 proofreading-deficient metastatic colorectal cancer.

BACKGROUND: POLE and POLD1 proofreading deficiency (POLE/D1pd) define a rare subtype of ultramutated metastatic colorectal cancer (mCRC; over 100 mut/Mb). Disease-specific data about the activity and efficacy of immune checkpoint inhibitors (ICIs) in POLE/D1pd mCRC are lacking and it is unknown whether outcomes may be different from mismatch repair-deficient (dMMR)/microsatellite instability-high (MSI-H) mCRCs treated with ICIs. PATIENTS AND METHODS: In this global study, we collected 27 patients with mCRC harboring POLE/D1 mutations leading to proofreading deficiency and treated with anti-programmed cell death-ligand 1 alone +/- anti-cytotoxic T-lymphocyte antigen-4 agents. We collected clinicopathological and genomic characteristics, response, and survival outcomes after ICIs of POLE/D1pd mCRC and compared them with a cohort of 610 dMMR/MSI-H mCRC patients treated with ICIs. Further genomic analyses were carried out in an independent cohort of 7241 CRCs to define POLE and POLD1pd molecular profiles and mutational signatures. RESULTS: POLE/D1pd was associated with younger age, male sex, fewer RAS/BRAF driver mutations, and predominance of right-sided colon cancers. Patients with POLE/D1pd mCRC showed a significantly higher overall response rate (ORR) compared to dMMR/MSI-H mCRC (89% versus 54%; P = 0.01). After a median follow-up of 24.9 months (interquartile range: 11.3-43.0 months), patients with POLE/D1pd showed a significantly superior progression-free survival (PFS) compared to dMMR/MSI-H mCRC [hazard ratio (HR) = 0.24, 95% confidence interval (CI) 0.08-0.74, P = 0.01] and superior overall survival (OS) (HR = 0.38, 95% CI 0.12-1.18, P = 0.09). In multivariable analyses including the type of DNA repair defect, POLE/D1pd was associated with significantly improved PFS (HR = 0.17, 95% CI 0.04-0.69, P = 0.013) and OS (HR = 0.24, 95% CI 0.06-0.98, P = 0.047). Molecular profiling showed that POLE/D1pd tumors have higher tumor mutational burden (TMB). Responses were observed in both subtypes and were associated with the intensity of POLE/D1pd signature. CONCLUSIONS: Patients with POLE/D1pd mCRC showed more favorable outcomes compared to dMMR/MSI-H mCRC to treatment with ICIs in terms of tumor response and survival.

Distribution of 10-year risk for coronary heart disease and eligibility for therapeutic approaches among Tehranian adults.

OBJECTIVES: To establish the distribution of 10-year risk for coronary heart disease (CHD) and eligibility for therapeutic approaches among Tehranian adults within the framework of the Tehran Lipid and Glucose Study (TLGS). STUDY DESIGN: Cross-sectional study conducted on data from Phase III of the TLGS (12,521 people aged ≥3 years). METHODS: The modified Framingham algorithm adopted by the National Cholesterol Education Program Adult Treatment Panel III was used to estimate participants' 10-year risk of developing CHD; only participants aged 20-79 years were included. Following the exclusion of subjects without full relevant data, 9483 participants (42.6% men) were enrolled in the final analysis. The distributions of the population needing therapeutic lifestyle changes (TLCs) and additional drug therapy were calculated. RESULTS: Overall, the mean (standard deviation) age was 43.7 (15.4) years; 44.6 (15.9) for men and 43.0 (14.9) for women. Ten-year risk for CHD of <10%, 10-20% and >20% was observed in 86.0%, 12.0% and 2.0% of participants with at least two risk factors and without CHD or a CHD risk equivalent, respectively. For subjects with less than two risk factors and without CHD or a CHD risk equivalent, these values were 14.0%, 8.3% and 14.7%, respectively; 63.1% of subjects had less than two risk factors. The need for TLCs and additional drug therapy was observed in 12% and 12.5% of subjects, respectively. CONCLUSIONS: Regarding the estimated 10-year risk for CHD, about one-quarter of Tehranian adults are eligible for therapeutic approaches.

An arc-sequencing algorithm for intensity modulated arc therapy.

Intensity modulated arc therapy (IMAT) is an intensity modulated radiation therapy delivery technique originally proposed as an alternative to tomotherapy. IMAT uses a series of overlapping arcs to deliver optimized intensity patterns from each beam direction. The full potential of IMAT has gone largely unrealized due in part to a lack of robust and commercially available inverse planning tools. To address this, we have implemented an IMAT arc-sequencing algorithm that translates optimized intensity maps into deliverable IMAT plans. The sequencing algorithm uses simulated annealing to simultaneously optimize the aperture shapes and weights throughout each arc. The sequencer enforces the delivery constraints while minimizing the discrepancies between the optimized and sequenced intensity maps. The performance of the algorithm has been tested for ten patient cases (3 prostate, 3 brain, 2 head-and-neck, 1 lung, and 1 pancreas). Seven coplanar IMAT plans were created using an average of 4.6 arcs and 685 monitor units. Additionally, three noncoplanar plans were created using an average of 16 arcs and 498 monitor units. The results demonstrate that the arc sequencer can provide efficient and highly conformal IMAT plans. An average sequencing time of approximately 20 min was observed.

Jaws-only IMRT using direct aperture optimization.

Using direct aperture optimization, we have developed an inverse planning approach that is capable of producing efficient intensity modulated radiotherapy (IMRT) treatment plans that can be delivered without a multileaf collimator. This "jaws-only" approach to IMRT uses a series of rectangular field shapes to achieve a high degree of intensity modulation from each beam direction. Direct aperture optimization is used to directly optimize the jaw positions and the relative weights assigned to each aperture. Because the constraints imposed by the jaws are incorporated into the optimization, the need for leaf sequencing is eliminated. Results are shown for five patient cases covering three treatment sites: pancreas, breast, and prostate. For these cases, between 15 and 20 jaws-only apertures were required per beam direction in order to obtain conformal IMRT treatment plans. Each plan was delivered to a phantom, and absolute and relative dose measurements were recorded. The typical treatment time to deliver these plans was 18 min. The jaws-only approach provides an additional IMRT delivery option for clinics without a multileaf collimator.

A Simple Automated Method for Detecting Recurrence in High-Grade Glioma.

Our aim was to develop an automated multiparametric MR imaging analysis of routinely acquired imaging sequences to identify areas of focally recurrent high-grade glioma. Data from 141 patients treated with radiation therapy with a diagnosis of high-grade glioma were reviewed. Strict inclusion/exclusion criteria identified a homogeneous cohort of 12 patients with a nodular recurrence of high-grade glioma that was amenable to focal re-irradiation (cohort 1). T1WI, FLAIR, and DWI data were used to create subtraction maps across time points. Linear regression was performed to identify the pattern of change in these 3 imaging sequences that best correlated with recurrence. The ability of these parameters to guide treatment decisions in individual patients was assessed in a separate cohort of 4 patients who were treated with radiosurgery for recurrent high-grade glioma (cohort 2). A leave-one-out analysis of cohort 1 revealed that automated subtraction maps consistently predicted the radiologist-identified area of recurrence (median area under the receiver operating characteristic curve = 0.91). The regression model was tested in preradiosurgery MRI in cohort 2 and identified 8 recurrent lesions. Six lesions were treated with radiosurgery and were controlled on follow-up imaging, but the remaining 2 lesions were not treated and progressed, consistent with the predictions of the model. Multiparametric subtraction maps can predict areas of nodular progression in patients with previously treated high-grade gliomas. This automated method based on routine imaging sequences is a valuable tool to be prospectively validated in subsequent studies of treatment planning and posttreatment surveillance.

Evaluation of linear accelerator gating with real-time electromagnetic tracking.

PURPOSE: Intrafraction organ motion can produce dosimetric errors in radiotherapy. Commonly, the linear accelerator is gated using real-time breathing phase obtained by way of external sensors. However, the external anatomy does not always correlate well with the internal position. We examined a beam gating technique using signals from implanted wireless transponders that provided real-time feedback on the tumor location without an imaging dose to the patient. METHODS AND MATERIALS: An interface was developed between Calypso Medical's four-dimensional electromagnetic tracking system and a Varian Trilogy linear accelerator. A film phantom was mounted on a motion platform programmed with lung motion trajectories. Deliveries were performed when the beam was gated according to the signal from the wireless transponders. The dosimetric advantages of beam gating and the system latencies were quantified. RESULTS: Beam gating using on internal position monitoring provided up to a twofold increase in the dose gradients. The percentage of points failing to be within +/-10 cGy of the planned dose (maximal dose, approximately 200 cGy) was 3.4% for gating and 32.1% for no intervention in the presence of motion. The mean latencies between the transponder position and linear accelerator modulation were 75.0 +/-12.7 ms for beam on and 65.1 +/- 12.9 ms for beam off. CONCLUSION: We have presented the results from a novel method for gating the linear accelerator using trackable wireless internal fiducial markers without the use of ionizing radiation for imaging. The latencies observed were suitable for gating using electromagnetic fiducial markers, which results in dosimetric improvements for irradiation in the presence of motion.

Posterior segment triple surgery after traumatic eye injuries.

Cataract extraction, posterior chamber intraocular lens (PC-IOL) implantation, and complete vitrectomy combined in a one-stage procedure were performed in 16 eyes (16 patients) with traumatic eye injuries undergoing anterior lensectomy (seven eyes), extracapsular cataract extraction (six eyes), or pars plana lensectomy (three eyes). Membrane peeling and intraocular foreign-body removal (13 eyes, 6 with intraretinal foreign bodies) were performed as needed. Surgery was performed from 1 week to 10 years after injury. After an average follow up of 8 months, 13 eyes (81%) had a visual acuity of at least 20/200; 50%, at least 20/40.