Ductal Prostate Cancers Demonstrate Poor Outcomes with Conventional Therapies

BackgroundDuctal prostate adenocarcinoma (DAC) is a rare, aggressive, histologic variant of prostate cancer that is treated with conventional therapies, similar to high-risk prostate adenocarcinoma (PAC).ObjectiveTo assess the outcomes of men undergoing definitive therapy for DAC or high-risk PAC and to explore the effects of androgen deprivation therapy (ADT) in improving the outcomes of DAC.Design, setting, and participantsA single-center retrospective review of all patients with cT1–4/N0–1 DAC from 2005 to 2018 was performed. Those undergoing radical prostatectomy (RP) or radiotherapy (RTx) for DAC were compared with cohorts of high-risk PAC patients.Outcome measurements and statistical analysisMetastasis-free survival (MFS) and overall survival (OS) rates were analyzed using Kaplan-Meier and Cox regression models.Results and limitationsA total of 228 men with DAC were identified; 163 underwent RP, 34 underwent RTx, and 31 had neoadjuvant therapy prior to RP. In this study, 163 DAC patients and 155 PAC patients undergoing RP were compared. Similarly, 34 DAC patients and 74 PAC patients undergoing RTx were compared. DAC patients undergoing RP or RTx had worse 5-yr MFS (75% vs 95% and 62% vs 93%, respectively, p < 0.001) and 5-yr OS (88% vs 97% and 82% vs 100%, respectively, p < 0.05) compared with PAC patients. In the 76 men who received adjuvant/salvage ADT after RP, DAC also had worse MFS and OS than PAC (p < 0.01). A genomic analysis revealed that 10/11 (91%) DACs treated with ADT had intrinsic upregulation of androgen-resistant pathways. Further, none of the DAC patients (0/15) who received only neoadjuvant ADT prior to RP had any pathologic downgrading. The retrospective nature was a limitation.ConclusionsMen undergoing RP or RTx for DAC had worse outcomes than PAC patients, regardless of the treatment modality. Upregulation of several intrinsic resistance pathways in DAC rendered ADT less effective. Further evaluation of the underlying biology of DAC with clinical trials is needed.Patient summaryThis study demonstrated worse outcomes among patients with ductal adenocarcinoma of the prostate than among high-grade prostate adenocarcinoma patients, regardless of the treatment modality.     

The effects of exposure to microgravity and reconditioning of the lumbar multifidus and anterolateral abdominal muscles: implications for people with LBP

BACKGROUND CONTEXTOne of the primary changes in the neuromuscular system in response to microgravity is skeletal muscle atrophy, which occurs especially in muscles that maintain posture while being upright on Earth. Reduced size of paraspinal and abdominal muscles has been documented after spaceflight. Exercises are undertaken on the International Space Station (ISS) during and following space flight to remediate these effects. Understanding the adaptations which occur in trunk muscles in response to microgravity could inform the development of specific countermeasures, which may have applications for people with conditions on Earth such as low back pain (LBP).PURPOSEThe aim of this study was to examine the changes in muscle size and function of the lumbar multifidus (MF) and anterolateral abdominal muscles (1) in response to exposure to 6 months of microgravity on the ISS and (2) in response to a 15-day reconditioning program on Earth.DESIGNProspective longitudinal series.PATIENT SAMPLEData were collected from five astronauts who undertook seven long-duration missions on the ISS.OUTCOME MEASURESFor the MF muscle, measures included cross-sectional area (CSA) and linear measures to assess voluntary isometric contractions at vertebral levels L2 to L5. For the abdominal muscles, the thickness of the transversus abdominis (TrA), obliquus internus abdominis (IO) and obliquus externus abdominis (EO) muscles at rest and on contraction were measured.METHODSUltrasound imaging of trunk muscles was conducted at four timepoints (preflight, postflight, mid-reconditioning, and post reconditioning). Data were analyzed using multilevel linear models to estimate the change in muscle parameters of interest across three time periods.RESULTSBeta-coefficients (estimates of the expected change in the measure across the specified time period, adjusted for the baseline measurement) indicated that the CSA of the MF muscles decreased significantly at all lumbar vertebral levels (except L2) in response to exposure to microgravity (L3=12.6%; L4=6.1%, L5=10.3%; p<.001), and CSAs at L3-L5 vertebral levels increased in the reconditioning period (p<.001). The thickness of the TrA decreased by 34.1% (p<.017), IO decreased by 15.4% (p=.04), and the combination of anterolateral abdominal muscles decreased by 16.2% (p<.001) between pre- and postflight assessment and increased (TrA<0.008; combined p=.035) during the postreconditioning period. Results showed decreased contraction of the MF muscles at the L2 (from 12.8% to 3.4%; p=.007) and L3 (from 12.2% to 5%; p=.032) vertebral levels following exposure to microgravity which increased (L2, p=.046) after the postreconditioning period. Comparison with preflight measures indicated that there were no residual changes in muscle size and function after the postreconditioning period, apart from CSA of MF at L2, which remained 15.3% larger than preflight values (p<.001).CONCLUSIONSIn-flight exercise countermeasures mitigated, but did not completely prevent, changes in the size and function of the lumbar MF and anterolateral abdominal muscles. Many of the observed changes in size and control of the MF and abdominal muscles that occurred in response to prolonged exposure to microgravity paralleled those seen in people with LBP or exposed to prolonged bed rest on Earth. Daily individualized postflight reconditioning, which included both motor control training and weight-bearing exercises with an emphasis on retraining strength and endurance to re-establish normal postural alignment with respect to gravity, restored the decreased size and control of the MF (at the L3-L5 vertebral levels) and anterolateral abdominal muscles. Drawing parallels between changes which occur to the neuromuscular system in microgravity and which exercises best recover muscle size and function could help health professionals tailor improved interventions for terrestrial populations. Results suggested that the principles underpinning the exercises developed for astronauts following prolonged exposure to microgravity (emphasizing strength and endurance training to re-establish normal postural alignment and distribution of load with respect to gravity) can also be applied for people with chronic LBP, as the MF and anterolateral abdominal muscles were affected in similar ways in both populations. The results may also inform the development of new astronaut countermeasures targeting the MF and abdominal muscles.     

Morphine modulates cathepsin B and L activity in isolated glomeruli and mesangial cells

Altered matrix degradation may be playing a role in the development of initial mesangial expansion and subsequent glomerulosclerosis in persons with heroin abuse. We studied whether morphine, a metabolite of heroin, had any effect on lysosomal content of cathepsin B and L in mesangial cells. Morphine (10^–6 M) increased (P<0.01) mesangial cathepsin B and L activity (control, 22.1+2.2 vs. morphine, 31.4+1.4 mol NMec/g protein,N=5). Morphine (10^–6 M) also increased (P<0.01) glomerular cathepsin B and L activity (control, 0.1+0.01 vs. morphine, 2.2±0.2 pmol NMec/g protein,N=3). This effect of morphine occurred in a dose-dependent manner. These results suggest that morphine enhances cathepsin B and L activity in mesangial cells and isolated glomeruli. This effect of morphine may enhance capacity of mesangial cells to degrade increased amount of mesangial macromolecules.     

Age-related changes in brain: II. Positron emission tomography of frontal and temporal lobe glucose metabolism in normal subjects

While many neuropsychological studies have demonstrated age-related performance alterations in tests thought to reflect frontal and temporal lobe function, there is little direct observation and comparison of these hypothesized brain changesin vivo. The cerebral glucose metabolism of frontal, temporal, and cerebellar regions was examined in 40 young ( =27.5±4.9) and 31 elderly ( =67.6 ± 8.8) normal males using PET-FDG. Univariate analysis showed age-related metabolic reductions in all frontal and temporal lobe regions. The reductions ranged from 13%–24% with the greatest changes in the frontal lobes. Multiple regression analyses showed a stronger age relationship with frontal lobe than with temporal lobe metabolism. The dorsal lateral frontal lobe was the region that appears to change most within the frontal lobes. Examination of the temporal lobe showed that age contributed equally to the metabolic variance of both the lateral temporal lobe and hippocampus. These results suggest that age-related metabolic changes exist in both frontal and temporal lobes and that the frontal lobe change is greater.     

Early desensitization of somato-dendritic 5-HT1A autoreceptors in rats treated with fluoxetine or paroxetine

Electrophysiological and autoradiographic approaches were used to assess possible changes in 5-hydroxytryptamine (serotonin) 5-HT_1A receptors in the rat dorsal raphe nucleus after a subchronic treatment with fluoxetine or paroxetine, two specific serotonin reuptake inhibitors with antidepressant properties. Fluoxetine or paroxetine were injected daily (5 mg/kg, i.p.) for various time periods up to 21 days. Electrophysiological recordings performed 24 h after the last injection showed that the potency of the 5HT_1A receptor agonist, 8-OH-DPAT, to depress the firing of serotoninergic neurons in the dorsal raphe nucleus within brain stem slices was significantly reduced as early as after a 3-day treatment with either drug. The proportion of recorded neurons showing desensitization of somatodendritic 5-HT_1A autoreceptors increased along the treatment from 40% on the 3rd day to 60–80% on the 21st day. At no time during the treatment, was the specific binding of [³H]8-OHDPAT (agonist radioligand) or [³H] WAY-100 635 (antagonist radioligand) to 5-HT_1A receptors modified in the dorsal raphe nucleus or in other brain areas, suggesting that neither the density nor the coupling of these receptors to G-proteins were probably altered in rats injected with fluoxetine or paroxetine for up to 21 days.These results show that adaptive desensitization of somatodendritic 5-HT_1A autoreceptors within the dorsal raphe nucleus can already be detected after a 3-day treatment with selective serotonin reuptake inhibitors. Rather than the desensitization per se, it may be the progressive increase in the number of serotoninergic neurons with desensitized 5-HT_1A autoreceptors which plays a critical role in the (slowly developing) antidepressant action of these drugs.     

Survey on use of palliative radiotherapy in hospice care.

PURPOSE: Radiation oncologists and hospice professionals both provide end-of-life care for oncology patients, and little has been written about the interface between these two groups of specialists. Hospice professionals were surveyed to assess the perceived need for palliative radiotherapy in the hospice setting, to investigate factors that limit the access of hospice patients to radiotherapy, and to suggest areas of future collaboration on education, research, and patient advocacy. PATIENTS AND METHODS: Members of the National Hospice and Palliative Care Organization (NHPCO) and American Society for Therapeutic Radiology and Oncology jointly authored a questionnaire to investigate the beliefs of hospice professionals toward the use of radiotherapy for oncology patients in hospice. The questionnaire was distributed to all NHPCO member institutions, and the results were compiled and statistically analyzed. RESULTS: Four hundred eighty of more than 1,800 surveyed facilities responded to the questionnaire. The findings suggest that the majority of hospice professionals feel that radiotherapy is important in palliative oncology and that radiotherapy is widely available in the United States. Yet less than 3% on average of hospice patients served by hospices responding to the survey actually received radiotherapy in 2002. The most common barriers to radiotherapy in hospice care include radiotherapy expense, transportation difficulties, short life expectancy, and educational deficiencies between the specialties. CONCLUSION: Multiple barriers act to limit the use of palliative radiotherapy in hospice care. Finding ways to surmount these obstacles will provide opportunity for improvement in the end-of-life care of cancer patients.     

Preoperative sensitivity and specificity for early-stage ovarian cancer when combining cancer antigen CA-125II, CA 15-3, CA 72-4, and macrophage colony-stimulating factor using mixtures of multivariate normal distributions.

PURPOSE: In CA-125-based ovarian cancer screening trials, overall specificity and screening sensitivity of ultrasound after an elevated CA-125 exceeded 99.6% and 70%, respectively, thereby yielding a positive predictive value (PPV) exceeding 10%. However, sensitivity for early-stage disease was only 40%. This study aims to increase preoperative sensitivity for early-stage ovarian cancer while maintaining the annual referral rate to ultrasound at 2% by combining information across CA-125II, CA 15-3, CA 72-4, and macrophage colony-stimulating factor (M-CSF). For direct comparisons between marker panels, all sensitivity results correspond to a 98% fixed first-line specificity (referral rate 2%). PATIENTS AND METHODS: Logistic regression, classification tree, and mixture discriminant analysis (MDA) models were fit to a training data set of preoperative serum measurements (63 patients, 126 healthy controls) from one center. Estimates from the training set applied to an independent validation set (60 stage I to II patients, 98 healthy controls) from two other centers provided unbiased estimates of sensitivity. RESULTS: Preoperative sensitivities for early-stage disease of the optimal panels were 45% for CA-125II; 67% for CA-125II and CA 72-4; 70% for CA-125II, CA 72-4, and M-CSF; and 68% for all four markers (latter two results using MDA). CONCLUSION: Efficiently combining information on CA-125II, CA 72-4, and M-CSF significantly increased preoperative early-stage sensitivity from 45% with CA-125II alone to 70%, while maintaining 98% first-line specificity. Screening trials with these markers using MDA followed by referral to ultrasound may maintain previously high levels of specificity and PPV, while significantly increasing early-stage screening sensitivity. MDA is a useful, biologically justified method for combining biomarkers.