The latency associated with bone metastasis emergence in castrate‐resistant prostate cancer is attributed to dormancy, a state in which cancer cells persist prior to overt lesion formation. Using ...single‐cell transcriptomics and ex vivo profiling, we have uncovered the critical role of tumor‐intrinsic immune signaling in the retention of cancer cell dormancy. We demonstrate that loss of tumor‐intrinsic type I IFN occurs in proliferating prostate cancer cells in bone. This loss suppresses tumor immunogenicity and therapeutic response and promotes bone cell activation to drive cancer progression. Restoration of tumor‐intrinsic IFN signaling by HDAC inhibition increased tumor cell visibility, promoted long‐term antitumor immunity, and blocked cancer growth in bone. Key findings were validated in patients, including loss of tumor‐intrinsic IFN signaling and immunogenicity in bone metastases compared to primary tumors. Data herein provide a rationale as to why current immunotherapeutics fail in bone‐metastatic prostate cancer, and provide a new therapeutic strategy to overcome the inefficacy of immune‐based therapies in solid cancers.
Synopsis
Tumor‐intrinsic type I IFN is lost upon outgrowth of dormant prostate cancer cells in bone, driving metastasis. Therapeutic reversal of tumor‐intrinsic IFN loss enhances tumor cell visibility and the effectiveness of systemic immunomodulatory agents against bone‐metastasis.
Tumor‐intrinsic type I IFN and associated immune signaling is lost in prostate cancer cells that have spread to bone.
Tumor‐intrinsic type I IFN status is linked to the outgrowth of dormant prostate cancer cells in bone.
Therapeutic restoration of tumor‐intrinsic type I IFN inflates immunogenicity and immunotherapeutic response.
Tumor‐intrinsic type I IFN is lost upon outgrowth of dormant prostate cancer cells in bone, driving metastasis. Therapeutic reversal of tumor‐intrinsic IFN loss enhances tumor cell visibility and the effectiveness of systemic immunomodulatory agents against bone‐metastasis.
Abstract
Between 15 and 19 March 2022, East Antarctica experienced an exceptional heat wave with widespread 30°–40°C temperature anomalies across the ice sheet. In Part I, we assessed the ...meteorological drivers that generated an intense atmospheric river (AR) that caused these record-shattering temperature anomalies. Here, we continue our large collaborative study by analyzing the widespread and diverse impacts driven by the AR landfall. These impacts included widespread rain and surface melt that was recorded along coastal areas, but this was outweighed by widespread high snowfall accumulations resulting in a largely positive surface mass balance contribution to the East Antarctic region. An analysis of the surface energy budget indicated that widespread downward longwave radiation anomalies caused by large cloud-liquid water contents along with some scattered solar radiation produced intense surface warming. Isotope measurements of the moisture were highly elevated, likely imprinting a strong signal for past climate reconstructions. The AR event attenuated cosmic ray measurements at Concordia, something previously never observed. Last, an extratropical cyclone west of the AR landfall likely triggered the final collapse of the critically unstable Conger Ice Shelf while further reducing an already record low sea ice extent.
Significance Statement
Using our diverse collective expertise, we explored the impacts from the March 2022 heat wave and atmospheric river across East Antarctica. One key takeaway is that the Antarctic cryosphere is highly sensitive to meteorological extremes originating from the midlatitudes and subtropics. Despite the large positive temperature anomalies driven from strong downward longwave radiation, this event led to huge amounts of snowfall across the Antarctic interior desert. The isotopes in this snow of warm airmass origin will likely be detectable in future ice cores and potentially distort past climate reconstructions. Even measurements of space activity were affected. Also, the swells generated from this storm helped to trigger the final collapse of an already critically unstable Conger Ice Shelf while further degrading sea ice coverage.
Cardiac contractility modulation (CCM) is an innovative therapy for heart failure with reduced ejection fraction delivered by a cardiac implantable device (Optimizer Smart
). One of the most ...prominent periprocedural complications common to all cardiac implantable devices (CIDs) is tricuspid regurgitation (TR) due to the placement of the right ventricular endocardial leads. To date, no published studies have assessed the changes in the TR degree in patients with heart failure with reduced ejection fraction (HFrEF) who received an implantable cardioverter-defibrillator (ICD) after the implantation of cardiac contractility modulation therapy devices.
This study aimed to evaluate the effect of the implantation of the trans-tricuspid leads required to deliver CCM therapy on the severity of TR in patients with HFrEF who previously underwent ICD implantation.
We enrolled 30 HFrEF patients who underwent CCM therapy between November 2020 and October 2021. For all the patients, echocardiographic evaluations of TR were performed according to current guidelines 24 h before and six months after the Optimizer Smart
implant was applied.
At the 6-month follow-up, the grade of TR remained unchanged compared to the preimplant grade. The value of the vena contracta (VC) of TR was 0.40 ± 0.19 cm in the preimplant period and 0.45 ± 0.21 cm at the 6-month follow-up (
= 0.33). Similarly, the TR proximal isovelocity surface area (PISA) radius value was unchanged at follow-up (0.54 ± 0.22 cm vs. 0.62 ± 0.20 cm;
= 0.18). No statistically significant difference existed between the preimplant VC and PISA radius values, irrespective of the device type.
The implantation of right ventricular electrodes for the delivery of CCM therapy did not worsen tricuspid regurgitation in patients with HFrEF and ICD.
Background
A critical knowledge gap exists regarding the impact of neurologic deficits on surgical outcomes and health‐related quality of life (HRQOL) for patients surgically treated for metastatic ...epidural spinal cord compression (MESCC).
Methods
This prospective, multicenter and international study analyzed the impact of the neurologic status on functional status, HRQOL, and postoperative survival. The collected data included the patient demographics, overall survival, American Spinal Injury Association (ASIA) impairment scale, Spinal Instability Neoplastic Score, treatment details and complications and HRQOL measures, including version 2 of the 36‐Item Short Form Health Survey (SF‐36v2) and version 2.0 of the Spine Oncology Study Group Outcomes Questionnaire (SOSGOQ2.0).
Results
A total of 239 patients surgically treated for spinal metastases were included. Six weeks after treatment, 99 of the 108 patients with a preoperative ASIA grade of E remained stable, 8 deteriorated to ASIA D, and 1 deteriorated to ASIA A. Of 55 patients with ASIA D, 27 improved to ASIA E, 27 remained stable and 1 deteriorated to ASIA C. Of 11 patients with ASIA A to C, 2 improved to ASIA E, 4 improved to ASIA D, and 5 remained stable. At the 6‐ and 12‐week follow‐up, better ASIA scores were associated with better scores on multiple SF‐36v2 and SOSGOQ items. Postoperatively, patients with ASIA grades of A to D were more likely to have urinary tract infections and wound complications. Patients with a baseline ASIA grade of E or D survived significantly longer.
Conclusions
Patients with neurologic deficits due to MESCC have worse HRQOL and decreased overall survival. Nevertheless, surgery can result in stabilization or improvement of neurologic function which may translate into better HRQOL. Postoperative care and follow‐up are challenging for patients with neurologic deficits because they experience more complications.
Patients with neurologic deficits due to metastatic epidural spinal cord compression have worse health‐related quality of life and decreased overall survival. Prospective, multicenter data demonstrate that surgery can result in stabilization or improvement of neurologic function which may translate into better health‐related quality of life.
BACKGROUND AND OBJECTIVES: The palliative impact of spine surgery for metastatic disease is evolving with improvements in surgical technique and multidisciplinary cancer care. The goal of this study ...was to prospectively evaluate long-term clinical outcomes including health-related quality-of-life (HRQOL) measures, using spine cancer–specific patient-reported-outcome (PRO) measures, in patients with symptomatic spinal metastases who underwent surgical management. METHODS: The Epidemiology, Process, and Outcomes of Spine Oncology (EPOSO, ClinicalTrials.gov identifier: NCT01825161) trial is a prospective-observational cohort study that included 10 specialist centers in North America and Europe. Patients aged 18 to 75 years who underwent surgery for spinal metastases were included. Prospective assessments included both spine tumor–specific and generic PRO tools which were collected for a minimum of 2 years post-treatment or until death. RESULTS: Two hundred and eighty patients (51.8% female, mean age 57.9 years) were included. At presentation, the mean Charlson Comorbidity Index was 6.0, 35.7% had neurological deficits as defined by the American Spinal Cord Injury Association scores, 47.2% had high-grade epidural spinal cord compression (2-3), and 89.6% had impending or frank instability as measured by a Spinal Instability Neoplastic Score of ≥7. The most common primary tumor sites were breast (20.2%), lung (18.8%), kidney (16.2%), and prostate (6.5%). The median overall survival postsurgery was 501 days, and the 2-year progression-free-survival rate was 38.4%. Compared with baseline, significant and durable improvements in HRQOL were observed at the 6-week, 12-week, 26-week, 1-year, and 2-year follow-up assessments from a battery of PRO questionnaires including the spine cancer–specific, validated, Spine Oncology Study Group Outcomes Questionnaire v2.0, the Short Form 36 version 2, EuroQol-5 Dimension (3L), and pain numerical rating scale score. CONCLUSION: Multi-institutional, prospective-outcomes data confirm that surgical decompression and/or stabilization provides meaningful and durable improvements in multiple HRQOL domains, including spine-specific outcomes based on the Spine Oncology Study Group Outcomes Questionnaire v2.0, for patients with metastatic spine disease.
Duchenne muscular dystrophy (DMD) is a progressive severe muscle‐wasting disease caused by mutations in DMD, encoding dystrophin, that leads to loss of muscle function with cardiac/respiratory ...failure and premature death. Since dystrophic muscles are sensed by infiltrating inflammatory cells and gut microbial communities can cause immune dysregulation and metabolic syndrome, we sought to investigate whether intestinal bacteria support the muscle immune response in mdx dystrophic murine model. We highlighted a strong correlation between DMD disease features and the relative abundance of Prevotella. Furthermore, the absence of gut microbes through the generation of mdx germ‐free animal model, as well as modulation of the microbial community structure by antibiotic treatment, influenced muscle immunity and fibrosis. Intestinal colonization of mdx mice with eubiotic microbiota was sufficient to reduce inflammation and improve muscle pathology and function. This work identifies a potential role for the gut microbiota in the pathogenesis of DMD.
Synopsis
The susceptibility of DMD patients to inflammatory events cannot solely be explained by skeletal muscle genetic defects but rather favors a new paradigm linking development of chronic inflammation with a strict regulation between epigenetics factors and degenerative environment.
Gut microbiota–specific alterations (dysbiosis) correlate with the dystrophic pathology in mdx mice, influencing muscle immunity and fibrosis.
Dysbiotic mdx microbiota induces a decreased innate immune response and altered muscle metabolism.
The study of the dysregulated immune system‐microbiota axis in mdx mice highlights the importance of microbiota as a potential target for therapeutic interventions.
The susceptibility of DMD patients to inflammatory events cannot solely be explained by skeletal muscle genetic defects but rather favors a new paradigm linking the development of chronic inflammation with a strict regulation between epigenetics factors and degenerative environment.
Systematic review.
To determine evidence-based guidelines for the management of locally recurrent spinal chordoma.
Chordoma of the spine is a low-grade malignant tumor with a strong propensity for ...local recurrence. Salvage therapy is challenging due to its relentless nature and refractoriness to adjuvant therapies. There are currently no guidelines regarding the best management of recurrent chordoma.
We combined the results of a systematic review with expert opinion to address the following research questions: (1) For locally recurrent chordoma of the spine without systemic disease, if surgery is planned, should en bloc resection be attempted if technically feasible with acceptable morbidity? (2) For locally recurrent chordoma without systemic disease, in which wide en bloc excision is not possible, what is the treatment of choice? (2) Should adjuvant or neoadjuvant radiation therapy be used in the treatment of locally recurrent chordoma?
A total of nine surgical and seven radiation therapy articles met study criteria. Evidence quality was low or very low. Recurrent disease is associated with predominantly poor outcome, regardless of treatment modality. As for primary chordoma, resection with wide margins appears to confer an advantage with respect to local control, although this effect is attenuated in the setting of relapse. Postoperative radiation therapy likely reduces the rate of further relapse.
(1) For locally recurrent chordoma of the spine without systemic disease, when surgery is planned, wide en bloc resection should be performed if technically feasible with acceptable morbidity. Strong recommendation, Low Quality of Evidence. (2) For locally recurrent chordoma without systemic disease, in which wide en bloc excision is not possible, partial resection is the treatment of choice. Weak recommendation, Very Low Quality of Evidence. (3) For the treatment of locally recurrent chordoma, high-dose conformal radiation therapy should be administered postoperatively to reduce the risk of further recurrence, and may be considered as a primary therapy. Strong recommendation, Very Low Quality of Evidence.
2.
Background
The treatment of oligometastatic (≤5 metastases) spinal disease has trended toward ablative therapies, yet to the authors’ knowledge little is known regarding the prognosis of patients ...presenting with oligometastatic spinal disease and the value of this approach. The objective of the current study was to compare the survival and clinical outcomes of patients with cancer with oligometastatic spinal disease with those of patients with polymetastatic (>5 metastases) disease.
Methods
The current study was an international, multicenter, prospective study. Patients who were admitted to a participating spine center with a diagnosis of spinal metastases and who underwent surgical intervention and/or radiotherapy between August 2013 and May 2017 were included. Data collected included demographics, overall survival, local control, and treatment information including surgical, radiotherapy, and systemic therapy details. Health‐related quality of life (HRQOL) measures included the EuroQOL 5 dimensions 3‐level questionnaire (EQ‐5D‐3L), the 36‐Item Short Form Health Survey (SF‐36v2), and the Spine Oncology Study Group Outcomes Questionnaire (SOSGOQ).
Results
Of the 393 patients included in the current study, 215 presented with oligometastatic disease and 178 presented with polymetastatic disease. A significant survival advantage of 90.1% versus 77.3% at 3 months and 77.0% versus 65.1% at 6 months from the time of treatment was found for patients presenting with oligometastatic disease compared with those with polymetastatic disease. It is important to note that both groups experienced significant improvements in multiple HRQOL measures at 6 months after treatment, with no differences in these outcome measures noted between the 2 groups.
Conclusions
The treatment of oligometastatic disease appears to offer a significant survival advantage compared with polymetastatic disease, regardless of treatment choice. HRQOL measures were found to improve in both groups, demonstrating a palliative benefit for all treated patients.
There appears to be a significant survival advantage for patients presenting with oligometastatic disease compared with those with polymetastatic disease at the time of the initial treatment of spinal metastases regardless of the treatment method used. In the current study, both groups are reported to experience significant improvements in multiple measures of health‐related quality of life at 6 months.
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