A Randomized Trial Comparing Quality of Life After Low-Dose Rate or High-Dose Rate Prostate Brachytherapy Boost With Pelvic External Beam Radiation Therapy.

PURPOSE: To compare health-related quality of life (QoL) in urinary, bowel, and sexual domains after combined external beam radiation therapy (EBRT) and either low-dose rate (LDR) or high-dose rate (HDR) prostate brachytherapy (BT). METHODS AND MATERIALS: Eligible men with intermediate or high-risk prostate cancer treated with combined pelvic EBRT and BT were randomly assigned to either HDR (15 Gy) or LDR (110 Gy) boost. International Prostate Symptom Score, Index of Erectile Function, and Expanded Prostate Cancer Composite were collected at baseline, 1, 3, 6, and 12 months, every 6 months to 3 years and then annually along with prostate-specific antigen/testosterone. Fisher's exact test compared categorical variables and the Mann-Whitney U test Expanded Prostate Cancer Index Composite (EPIC) domain scores. RESULTS: From January 2014 to December 2019, a random number generator assigned 195 men: 108 to HDR and 87 to LDR. Median age was 71 years. Risk group was high in 57% and unfavorable intermediate in 43%. Androgen deprivation (used in 74%) began with 3 months neoadjuvant and continued for median 12 months. Baseline EPIC scores were similar for the LDR/HDR cohorts: 89 and 88 respectively for Genito-urinary; 92 and 93 for Gastro-intestinal. EPIC urinary scores decreased at 1 month for HDR but recovered promptly to a steady state by 6 months. LDR scores reached a nadir at 3 months with slow recovery to 18 months, after which urinary QoL was similar for HDR and LDR. Bowel QOL scores fell in both cohorts reaching respective nadirs at 12 months. HDR patients recovered close to baseline and maintained higher scores than LDR patients to 5 years. The decline for LDR patients remained more than the minimum clinically important difference out to 5 years. CONCLUSIONS: The patient experience for combined EBRT and prostate BT is improved with HDR BT. Urinary QoL improves over time to be equivalent between the 2 modalities after 18 months, but LDR patients report lasting bowel symptoms.

Comparison between postoperative TRUS-CT fusion with MRI-CT fusion for postimplant quality assurance in prostate LDR permanent seed brachytherapy.

PURPOSE/OBJECTIVE Permanent seed Low-Dose-Rate brachytherapy is planned and delivered using transrectal ultrasound (TRUS). Post-implant evaluation for quality assurance is usually performed using Computed Tomography (CT). Registration of the CT images with MRI reduces subjectivity in contouring by improving prostate edge detection. We hypothesized that a set of TRUS images post procedure may provide the same benefit. MATERIAL/METHODS Consecutive patients undergoing Low-Dose-Rate prostate brachytherapy were recruited. TRUS images were recorded under anesthesia at completion of their implant. In addition, all patients underwent standard post-implant quality assurance including prostate CT and MRI at day 30. These were co-registered, contoured and seeds were identified. Three independent observers contoured and registered the post implant TRUS images to the Day 30 CT using seed matching. Prostate volumes and dosimetric parameters were compared through Intraclass Correlation Coefficient (ICC) to evaluate the concordance between MRI and ultrasound (US). RESULTS 26 patients were recruited from 10/17 to 01/18. Mean prostate volume was 34.5 (SD 10.8) cm3 at baseline on planning TRUS images, 37.4 (SD 11.3) cm3 on Day 0 post implant TRUS and 36.7 (SD 11.7) cm3 on Day 30 MRI. D90 was 112.6% (SD 9.3) on CT-MRI and 112.9% (SD 11.1) on CT-US. V100 was 94.6% (SD 3.8) for CT-MRI, 95.1% (SD 4.3) for CT-US. Student t-tests were used to compare groups. No significant differences were noted. CONCLUSION Post implant TRUS may be useful for quality assurance for post-implant dosimetry particularly if access to an MRI is limited.

Identification and Successful Negotiation of a Metabolic Checkpoint in Direct Neuronal Reprogramming.

Despite the widespread interest in direct neuronal reprogramming, the mechanisms underpinning fate conversion remain largely unknown. Our study revealed a critical time point after which cells either successfully convert into neurons or succumb to cell death. Co-transduction with Bcl-2 greatly improved negotiation of this critical point by faster neuronal differentiation. Surprisingly, mutants with reduced or no affinity for Bax demonstrated that Bcl-2 exerts this effect by an apoptosis-independent mechanism. Consistent with a caspase-independent role, ferroptosis inhibitors potently increased neuronal reprogramming by inhibiting lipid peroxidation occurring during fate conversion. Genome-wide expression analysis confirmed that treatments promoting neuronal reprogramming elicit an anti-oxidative stress response. Importantly, co-expression of Bcl-2 and anti-oxidative treatments leads to an unprecedented improvement in glial-to-neuron conversion after traumatic brain injury in vivo, underscoring the relevance of these pathways in cellular reprograming irrespective of cell type in vitro and in vivo.

Chromatin Remodeling Factor Brg1 Supports the Early Maintenance and Late Responsiveness of Nestin-Lineage Adult Neural Stem and Progenitor Cells.

Insights from embryonic development suggest chromatin remodeling is important in adult neural stem cells (aNSCs) maintenance and self-renewal, but this concept has not been fully explored in the adult brain. To assess the role of chromatin remodeling in adult neurogenesis, we inducibly deleted Brg1--the core subunit of SWI/SNF-like Brg1/Brm-associated factor chromatin remodeling complexes--in nestin-expressing aNSCs and their progeny in vivo and in culture. This resulted in abnormal adult neurogenesis in the hippocampus, which initially reduced hippocampal aNSCs and progenitor maintenance, and later reduced its responsiveness to physiological stimulation. Mechanistically, deletion of Brg1 appeared to impair cell cycle progression, which is partially due to elevated p53 pathway and p21 expression. Knockdown of p53 rescued the neurosphere growth defects caused by Brg1 deletion. Our results show that epigenetic chromatin remodeling (via a Brg1 and p53/p21-dependent process) determines the aNSCs and progenitor maintenance and responsiveness of neurogenesis.

A randomized trial comparing seed displacement of coated seeds to regular loose seeds at 30 days postimplant.

PURPOSE: To compare 30-day seed displacement and seed loss of standard loose seeds to specially engineered coated seeds. METHODS AND MATERIALS: Forty patients with prostate cancer were randomized and treated with either loose seeds or loose "coated" seeds. Implants were preplanned using transrectal ultrasound and performed using preloaded needles containing either standard or coated iodine-125 seeds according to randomization. Pelvic X-rays and CT were performed on Days 0 and 30 and a pelvic magnetic resonance scan on Day 30. Cranial-caudal displacement relative to the center of mass (COM) of the seed cloud of the six most peripheral basal and apical seeds was determined from Day 0 and 30 CT scans using custom software. Day 30 magnetic resonance-CT fusion was performed using a seed-to-seed match for soft tissue contouring on MRI. RESULTS: The mean displacement for the six basal seeds was 0.32 cm (standard deviation [SD], 0.25 cm) and 0.33 cm (SD, 0.27 cm) toward the COM for the regular and coated seeds, respectively (p = 0.35). For the apical seeds, mean displacement was 0.31 cm (SD, 0.35 cm) and 0.43 cm (SD, 0.26 cm) (p = 0.003) toward the COM. More regular seeds (n = 8) were lost from the apical region as compared with one coated seed (p = 0.015). There was a trend to reduction in total seeds lost: 1% for regular seeds as compared with 0.3% for coated seeds. CONCLUSIONS: Coated seeds were found to have a significant anchoring effect that was effective in reducing the number of apical seeds lost because of venous migration.

A phantom study to assess accuracy of needle identification in real-time planning of ultrasound-guided high-dose-rate prostate implants.

PURPOSE: High-dose-rate brachytherapy of the prostate is commonly performed using transrectal ultrasound (US) guidance, with CT imaging used for needle reconstruction and treatment planning. Transrectal ultrasound images can, however, be used for the entire process, allowing treatment without changes in the patient position. This study assesses needle reconstruction accuracy using US images. METHODS AND MATERIALS: Prostate phantoms were implanted with 10-18 needles. Three-dimensional US images were acquired, and needles were reconstructed using specialized software. A CT scan was also obtained. The image sets were registered and needle reconstruction errors were assessed. A dose plan was obtained using the US images and the dwell times were transferred to the CT reconstruction to obtain the true "delivered dose," which was evaluated using standard dosimetric parameters. RESULTS: Two sources of error were identified. First, reconstruction based on the bright echoes in the US images introduces a systematic error because these echoes correspond to the proximal wall of the needle, and not the center of the needle channel. If left uncorrected, this shift can lead to an underestimate of urethral doses. Second, incorrect needle tip identification can occur in the cranial-caudal direction. Errors up to 5.8mm were observed. A measurement of needle lengths protruding beyond the template can be used to compensate for this. CONCLUSIONS: Factors limiting the accuracy of US-based needle reconstruction have been identified. Once recognized, these errors can be corrected for, resulting in accurate implant geometry. This facilitates a treatment technique combining excellent anatomic definition, minimal prostate motion, and accurate dose planning and delivery.

Implications of CT imaging for postplan quality assessment in prostate brachytherapy.

PURPOSE: Postplan quality assurance using CT shows considerable interobserver contour variability. We examined CT postplans of four experienced brachytherapists for comparison with MR-determined prostate volumes. METHODS AND MATERIALS: Seventy-five patients had CT and MR scans 1 month post-(125)I prostate brachytherapy. CT scans were contoured by the treating physician and dosimetry calculated. The prostate was contoured independently on MR by one observer with extensive MR experience, the scans were fused and dosimetric parameters compared. RESULTS: The mean prostate volume on CT was 38.3 cc (17.5-78.6 cc), on MR 33.3 cc (16.3-66.1 cc). On average, the volume on CT was 16.1% larger than on MR (range, 8% smaller to 64% larger). Craniocaudal discordance of the CT vs. MR prostate contours ranged from 4 mm cranial to 10 mm caudal to MR base and from 6 mm cranial to 14 mm caudal to MR apex. The CT prostate volume not only included an average of 90% of the MR prostate (range, 75-99%) but also included normal tissue (mean, 8.3 cc; range, 2.9-17.1 cc). The average difference between the calculated D(90) from CT contours vs. MR contours was 10.0 Gy (standard deviation, 8.8; range, -37.6 to +41.6 Gy). CONCLUSIONS: On average, only 90% of the MR-defined prostate is included in CT contours, while a volume of normal tissue is erroneously designated as prostate. Lack of awareness of this deficiency in planning and/or operative technique gives a false sense of appreciation of the true conformality, delays implementation of corrective measures, and risks unnecessary side effects.

Modulation by the BK accessory ß4 subunit of phosphorylation-dependent changes in excitability of dentate gyrus granule neurons.

Large-conductance voltage- and calcium-activated potassium (BK) channels are large-conductance calcium- and voltage-activated potassium channels critical for neuronal excitability. Some neurons express so called fast-gated, type I BK channels. Other neurons express BK channels assembled with the accessory ß4 subunit conferring slow gating of type II BK channels. However, it is not clear how protein phosphorylation modulates these two distinct BK channel types. Using ß4-knockout mice, we compared fast- or slow-gated BK channels in response to changes in phosphorylation status of hippocampus dentate gyrus granule neurons. We utilized the selective PP2A/PP4 phosphatase inhibitor Fostriecin to study changes in action potential shape and firing properties of the neurons. In ß4-knockout neurons, Fostriecin increases BK current, speeds up BK channel activation and reduces action potential amplitudes. Fostriecin increases spiking during early components of an action potential train. In contrast, inhibition of BK channels through ß4 in wild-type neurons or by the BK channel inhibitor Paxilline opposes Fostriecin effects. Voltage clamp recordings of neurons reveal that Fostriecin increases both calcium and BK currents. However, Fostriecin does not activate BK α channels in transfected HEK293 cells lacking calcium channels. In summary, these results suggest that fast-gating, type I BK channels lacking ß4 can increase neuronal excitability in response to reduced phosphatase activity and activation of calcium channels. By opposing BK channel activation, the ß4 subunit plays an important role in moderating firing frequency regardless of changes in phosphorylation status.

Comparison of treatment results between adult and juvenile nasopharyngeal carcinoma.

PURPOSE: Nasopharyngeal carcinoma (NPC) has a bimodal age distribution. In contrast to the adult variant, little is known about the juvenile form. This study examined the treatment results between adult (aNPC) and juvenile NPC (jNPC) patients for future treatment considerations in jNPC. METHODS AND MATERIALS: The jNPC population included 53 patients treated at two institutions between 1972 and 2004. The aNPC population included 84 patients treated at one institution. The patients had received a median dose of 66 Gy of external beam radiotherapy and 72% underwent chemotherapy. The mean follow-up for surviving patients was 12.6 years for jNPC and 6.6 years for aNPC. RESULTS: The jNPC patients presented with more advance stages than did the aNPC patients (92% vs. 67% Stage III-IV, p = .006). However, jNPC patients had significantly better overall survival (OS) than did aNPC patients. The 5-year OS rate was 71% for jNPC and 58% for aNPC (p = .03). The jNPC group also demonstrated a trend for greater relapse-free survival than the aNPC group (5-year relapse-free survival rate, 69% vs. 49%; p = .056). The pattern of failure analysis revealed that the jNPC patients had greater locoregional control and freedom from metastasis but the differences were not statistically significant. Univariate analysis for OS revealed that age group, nodal classification, and chemotherapy use were significant prognostic factors. Age group remained significant for OS on multivariate analysis, after adjusting for N classification and treatment. CONCLUSION: Despite more advance stage at presentation, jNPC patients had better survival than did aNPC patients. Future treatment strategies should take into consideration the long-term complications in these young patients.

Plasma osteopontin is an independent prognostic marker for head and neck cancers.

PURPOSE: To confirm the relationship between plasma osteopontin (OPN) levels and treatment outcomes in head and neck squamous cell carcinoma (HNSCC) patients in an expanded study. PATIENTS AND METHODS: One hundred forty patients with newly diagnosed HNSCC were enrolled onto this study, 54 previously reported and 86 new patients. Pretreatment plasma OPN levels were assessed in all patients by an enzyme-linked immunosorbent assay method. OPN levels were correlated to treatment outcomes in the new group of patients. Detailed analyses were also performed on the relationship between OPN and tumor control rate, event-free survival (EFS), and postrelapse survival for the entire group. RESULTS: Using a previously defined cut off point of 450 ng/mL, there was a significant correlation between OPN and freedom-from-relapse (P = .047), overall survival (P = .019), and EFS (P = .023) in the new, independent patient cohort (n = 86). Sequence of event analyses using the entire group (N = 140) revealed that OPN was an independent prognostic factor for initial tumor control, EFS in those who have achieved tumor control, and postrelapse survival. CONCLUSION: In this expanded study, we were able to replicate the prognostic significance of OPN using a predefined cut off point in an independent patient group and demonstrated that plasma OPN is an independent prognostic marker for HNSCC.

Nonsurgical therapy for stages I and II non-small cell lung cancer.

For patients who have stages I and II non-small cell lung cancer (NSCLC) and who are unable or unwilling to undergo surgical resection, nonsurgical treatment modalities have been used with curative intent. Conventionally fractionated radiotherapy has been the mainstay of nonsurgical therapy; however, advances in technology and the clinical application of radiobiologic principles have allowed more accurately targeted treatment that delivers higher effective doses to the tumor, while respecting the tolerance of surrounding normal tissues. This article discusses nonsurgical approaches to the treatment of early-stage NSCLC, including several promising techniques, such as radiation dose escalation, altered radiation fractionation, stereotactic radiotherapy, and radiofrequency ablation.

Association between extent of axillary lymph node dissection and patient, tumor, surgeon, and hospital factors in patients with early breast cancer.

BACKGROUND AND OBJECTIVES: Axillary lymph node dissection (ALND) in patients with breast cancer is crucial for accurate staging, provides excellent regional tumor control, and is included in the standard of care for the surgical treatment of breast cancer. However, the extent of ALND varies, and the extent of dissection and the number of lymph nodes that comprise an optimal axillary dissection are under debate. Despite conflicting evidence, several studies have shown that improved survival is correlated with more lymph nodes removed in both node-negative and node-positive patients. The purpose of this study is to determine which patient, tumor, surgeon, and hospital characteristics are associated with the number of nodes excised in early breast cancer patients. METHODS: A random sample of 938 women with node-negative breast cancer was drawn from the Ontario Cancer Registry and the data supplemented with chart reviews. The extent of axillary dissection was studied by examining the number of nodes examined in relation to the patient, tumor, surgeon, and hospital factors. RESULTS: The mean number of lymph nodes excised was 9.8 (SD = 4.8; range, 1-31), and 49% of patients had >/=10 nodes excised. Lower patient age was associated with the excision of more lymph nodes (>/=10 nodes: 63% of patients <40 years vs. 38% of patients >/=80 years). Surgeon academic affiliation and surgery in a teaching hospital were highly correlated with each other and were significantly associated with the excision of >/=10 nodes. The number of nodes excised was not associated with any tumor factors, nor with the breast operation performed. These results were confirmed with multivariable models. CONCLUSIONS: Even though the number of lymph nodes found in the pathologic specimen can be influenced by factors other than surgical technique (e.g., number of nodes present, specimen handling, and pathologic examination), this study shows significant variation of this variable and an association with several patient and surgeon/hospital factors. This variation and the association with survival warrant further study and effort at greater consistency.