Salvage radiotherapy (SRT) after radical prostatectomy can potentially eradicate residual microscopic disease. Defining the optimal patient and treatment factors is essential and is particularly ...relevant within the context of adjuvant vs early vs delayed postoperative radiotherapy (RT).
A systematic review of all published SRT studies was performed to identify the pathologic, clinical, and treatment factors associated with relapse-free survival (RFS) after SRT. A total of 41 studies encompassing 5597 patients satisfied the study entry criteria. Radiobiologic interpretation of biochemical tumor control was used to provide the framework for the observed relationships.
Prostate-specific antigen (PSA) level before SRT (P<.0001) and RT dose (P=.0052) had a significant and independent association with RFS. There was an average 2.6% loss of RFS for each incremental 0.1 ng/mL PSA at the time of SRT (95% CI, ∼2.2-3.1). With a PSA level of 0.2 ng/mL or less before SRT, the RFS approached 64%. The dose for salvage RT in the range of 60-70 Gy seemed to be on the steep part of the sigmoidal dose-response curve, with a dose of 70 Gy achieving 54% RFS compared with only 34% for 60 Gy. There was a 2% improvement in RFS for each additional Gy (95% CI, ∼0.9-3.2). The observed dose-response was less robust on sensitivity analysis.
This study provides Level 2a evidence for initiating SRT at the lowest possible PSA. Dose escalation is also suggested by the data. Progressively better tumor control rates with SRT after radical prostatectomy are achieved with a lower PSA at initiation and with a higher RT dose. Early salvage RT may be an equivalent strategy to adjuvant RT.
Abstract Purpose/objectives To date neither the optimal radiotherapy dose nor the existence of a dose–response has been established for salvage RT (SRT). Materials/methods A systematic review from ...1996 to 2015 and meta-analysis was performed to identify the pathologic, clinical and treatment factors associated with relapse-free survival (RFS) after SRT (uniformly defined as a PSA > 0.2 ng/mL or rising above post-SRT nadir). A sigmoidal dose–response curve was objectively fitted and a non-parametric statistical test used to determine significance. Results 71 studies (10,034 patients) satisfied the meta-analysis criteria. SRT dose ( p = 0.0001), PSA prior to SRT ( p = 0.0009), ECE+ ( p = 0.039) and SV+ ( p = 0.046) had significant associations with RFS. Statistical analyses confirmed the independence of SRT dose–response. Omission of series with ADT did not alter results. Dose–response is well fit by a sigmoidal curve ( p = 0.0001) with a TCD50 of 65.8 Gy, with a dose of 70 Gy achieving 58.4% RFS vs. 38.5% for 60 Gy. A 2.0% 95% CI 1.1–3.2 improvement in RFS is achieved for each Gy. The SRT dose–response remarkably parallels that for definitive RT of localized disease. Conclusions This study provides level 2a evidence for dose-escalated SRT > 70 Gy. The presence of an SRT dose–response for microscopic disease supports the hypothesis that prostate cancer is inherently radio-resistant.
Despite the development of pharmacological therapies that are effective in slowing the progression of idiopathic pulmonary fibrosis (IPF), it remains a debilitating and lethal condition. In addition ...to the adverse effects caused by pulmonary fibrosis, most patients with IPF have associated comorbid conditions, which might negatively affect functional status, quality of life, and survival. Comorbid conditions can be pulmonary or extrapulmonary. Pulmonary comorbidities include pulmonary hypertension, emphysema, and lung cancer, while non-pulmonary conditions include venous thromboembolism, coronary artery disease, congestive heart failure, sleep-disordered breathing, gastro-oesophageal reflux disease, and anxiety or depression. Although some of these comorbid conditions share risk factors with IPF, the likelihood for their presence or development in patients with IPF is still greater than expected. This might indicate that IPF fosters an environment for the development or perpetuation of comorbid conditions, or alternatively that they share causative factors. Optimal management of IPF therefore requires a comprehensive approach, which includes the identification and treatment of comorbid conditions to optimise patient outcomes.
To evaluate the early and late health-related quality of life (QOL) outcomes among prostate cancer patients following stereotactic body radiation therapy (SBRT).
Patient self-reported QOL was ...prospectively measured among 864 patients from phase 2 clinical trials of SBRT for localized prostate cancer. Data from the Expanded Prostate Cancer Index Composite (EPIC) instrument were obtained at baseline and at regular intervals up to 6 years. SBRT delivered a median dose of 36.25 Gy in 4 or 5 fractions. A short course of androgen deprivation therapy was given to 14% of patients.
Median follow-up was 3 years and 194 patients remained evaluable at 5 years. A transient decline in the urinary and bowel domains was observed within the first 3 months after SBRT which returned to baseline status or better within 6 months and remained so beyond 5 years. The same pattern was observed among patients with good versus poor baseline function and was independent of the degree of early toxicities. Sexual QOL decline was predominantly observed within the first 9 months, a pattern not altered by the use of androgen deprivation therapy or patient age.
Long-term outcome demonstrates that prostate SBRT is well tolerated and has little lasting impact on health-related QOL. A transient and modest decline in urinary and bowel QOL during the first few months after SBRT quickly recovers to baseline levels. With a large number of patients evaluable up to 5 years following SBRT, it is unlikely that unexpected late adverse effects will manifest themselves.
Hypofractionated, stereotactic body radiotherapy (SBRT) is an emerging treatment approach for prostate cancer. We present the outcomes for low-risk prostate cancer patients with a median follow-up of ...5 years after SBRT.
Between Dec. 2003 and Dec. 2005, a pooled cohort of 41 consecutive patients from Stanford, CA and Naples, FL received SBRT with CyberKnife for clinically localized, low-risk prostate cancer. Prescribed dose was 35-36.25 Gy in five fractions. No patient received hormone therapy. Kaplan-Meier biochemical progression-free survival (defined using the Phoenix method) and RTOG toxicity outcomes were assessed.
At a median follow-up of 5 years, the biochemical progression-free survival was 93% (95% CI = 84.7% to 100%). Acute side effects resolved within 1-3 months of treatment completion. There were no grade 4 toxicities. No late grade 3 rectal toxicity occurred, and only one late grade 3 genitourinary toxicity occurred following repeated urologic instrumentation.
Five-year results of SBRT for localized prostate cancer demonstrate the efficacy and safety of shorter courses of high dose per fraction radiation delivered with SBRT technique. Ongoing clinical trials are underway to further explore this treatment approach.
Hypofractionated radiotherapy has an intrinsically different normal tissue and tumor radiobiology. The results of a prospective trial of stereotactic body radiotherapy (SBRT) for prostate cancer with ...long-term patient-reported toxicity and tumor control rates are presented.
From 2003 through 2009, 67 patients with clinically localized low-risk prostate cancer were enrolled. Treatment consisted of 36.25 Gy in 5 fractions using SBRT with the CyberKnife as the delivery technology. No patient received hormone therapy. Patient self-reported bladder and rectal toxicities were graded on the Radiation Therapy Oncology Group scale (RTOG).
Median follow-up was 2.7 years. There were no grade 4 toxicities. Radiation Therapy Oncology Group Grade 3, 2, and 1 bladder toxicities were seen in 3% (2 patients), 5% (3 patients), and 23% (13 patients) respectively. Dysuria exacerbated by urologic instrumentation accounted for both patients with Grade 3 toxicity. Urinary incontinence, complete obstruction, or persistent hematuria was not observed. Rectal Grade 3, 2, and 1 toxicities were seen in 0, 2% (1 patient), and 12.5% (7 patients), respectively. Persistent rectal bleeding was not observed. Low-grade toxicities were substantially less frequent with QOD vs. QD dose regimen (p = 0.001 for gastrointestinal and p = 0.007 for genitourinary). There were two prostate-specific antigen (PSA), biopsy-proven failures with negative metastatic workup. Median PSA at follow-up was 0.5 ± 0.72 ng/mL. The 4-year Kaplan-Meier PSA relapse-free survival was 94% (95% confidence interval, 85%-102%).
Significant late bladder and rectal toxicities from SBRT for prostate cancer are infrequent. PSA relapse-free survival compares favorably with other definitive treatments. The current evidence supports consideration of stereotactic body radiotherapy among the therapeutic options for localized prostate cancer.
Pulmonary hypertension (PH) due to interstitial lung disease (ILD; PH-ILD) can complicate a multitude of ILDs, including idiopathic pulmonary fibrosis, chronic hypersensitivity pneumonitis, and ...nonspecific interstitial pneumonia. Development of PH-ILD is associated with increased need for supplemental oxygen, reduced mobility, and decreased survival. A high index of suspicion is required to make the diagnosis, given the substantial overlap in symptoms with those of ILD without PH. Severely reduced diffusing capacity or 6-min walk test distance, prominent exertional desaturation, and impaired heart rate recovery after exercise are all suggestive of the development of PH-ILD. Traditional transthoracic echocardiography is the most commonly used screening test for PH-ILD, but it lacks sensitivity and specificity. Newer echocardiographic tools involving 3-dimensional assessment of the right ventricle may have a role in both prognosis and the monitoring of patients with PH-ILD. Right-sided heart catheterization remains the gold standard for confirming a diagnosis of PH-ILD. Although there is little debate about the use of supplemental oxygen and diuretic therapy in the treatment of PH-ILD, treatment with pulmonary vasodilator therapy remains controversial. Although several studies have been terminated prematurely for harm, the recently completed INCREASE trial of inhaled treprostinil appears to validate the concept of treating PH-ILD with pulmonary vasodilators and, we hope, will serve as a foundation from which future studies can be developed.
The outcomes of patients requiring invasive mechanical ventilation for COVID-19 remain poorly defined. We sought to determine clinical characteristics and outcomes of patients with COVID-19 managed ...with invasive mechanical ventilation in an appropriately resourced US health care system.
Outcomes of COVID-19 infected patients requiring mechanical ventilation treated within the Inova Health System between March 5, 2020 and April 26, 2020 were evaluated through an electronic medical record review.
1023 COVID-19 positive patients were admitted to the Inova Health System during the study period. Of these, 164 (16.0%) were managed with invasive mechanical ventilation. All patients were followed to definitive disposition. 70/164 patients (42.7%) had died and 94/164 (57.3%) were still alive. Deceased patients were older (median age of 66 vs. 55, p <0.0001) and had a higher initial d-dimer (2.22 vs. 1.31, p = 0.005) and peak ferritin levels (2998 vs. 2077, p = 0.016) compared to survivors. 84.3% of patients over 70 years old died in the hospital. Conversely, 67.4% of patients age 70 or younger survived to hospital discharge. Younger age, non-Caucasian race and treatment at a tertiary care center were all associated with survivor status.
Mortality of patients with COVID-19 requiring invasive mechanical ventilation is high, with particularly daunting mortality seen in patients of advanced age, even in a well-resourced health care system. A substantial proportion of patients requiring invasive mechanical ventilation were not of advanced age, and this group had a reasonable chance for recovery.
The endoplasmic reticulum (ER) is the site of synthesis of secretory and membrane proteins and contacts every organelle of the cell, exchanging lipids and metabolites in a highly regulated manner. ...How the ER spatially segregates its numerous and diverse functions, including positioning nanoscopic contact sites with other organelles, is unclear.We demonstrate that hypotonic swelling of cells converts the ER and other membrane-bound organelles into micrometer-scale large intracellular vesicles (LICVs) that retain luminal protein content and maintain contact sites with each other through localized organelle tethers. Upon cooling, ER-derived LICVs phase-partition into microscopic domains having different lipid-ordering characteristics, which is reversible upon warming. Ordered ER lipid domains mark contact sites with ER and mitochondria, lipid droplets, endosomes, or plasma membrane, whereas disordered ER lipid domains mark contact sites with lysosomes or peroxisomes. Tethering proteins concentrate at ER–organelle contact sites, allowing time-dependent behavior of lipids and proteins to be studied at these sites. These findings demonstrate that LICVs provide a useful model system for studying the phase behavior and interactive properties of organelles in intact cells.
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