Local Therapy for Oligoprogressive Disease: A Systematic Review of Prospective Trials.

PURPOSE: The successes of local therapy for oligometastatic cancers cannot be extrapolated to oligoprogressive disease (OPD) because they are distinct clinical entities. Given the limited prospective data on OPD to date, summative analyses are urgently needed. METHODS AND MATERIALS: Inclusion criteria for this Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA)-guided systematic review were as follows. First, only prospective data were included. Second, progression had to have occurred on active/ongoing systemic therapy. Third, the number of progressing areas of disease had to be explicitly listed and ≤5 in number. Fourth, all progressing sites had to undergo local therapy (radiation therapy [RT] /surgery/nonradiation ablative procedures). RESULTS: Eight trials met criteria (summing 290 patients), the vast majority of which used stereotactic RT as the local modality (most commonly, 19-20 Gy in 1 fraction, 27-33 Gy in 3 fractions, or 35-50 Gy in 5 fractions). A study on non-small cell lung cancer (NSCLC) demonstrated that stereotactic RT improved progression-free survival (PFS) and overall survival compared with historical values with systemic therapy alone. Two additional studies on epidermal growth factor receptor mutated (EGFRm) NSCLC also showed acceptable PFS with local therapy, particularly in patients who oligoprogressed on osimertinib. The only randomized trial analyzed herein showed that local therapy improved PFS for NSCLC but not breast cancer. Two trials in castration-resistant prostate cancer illustrated that a substantial proportion of patients did not require any changes in hormonal therapy or delayed the need to change systemic therapies. Lastly, 2 trials of renal cell carcinoma showed high (90%-100%) local control and median PFS of 9 months, and potentially a prolonged time to change systemic therapy. Lastly, from all patients in all trials, local therapy was tolerated well, with only 7 instances of grade 3+ toxicities. CONCLUSIONS: Based on the limited data, local therapy for oligoprogression is safe and yields encouraging short-term preliminary outcomes, but trials with larger sample sizes and longer follow-up are required for more robust conclusions.

Systems Analysis of a Dedicated Ambulatory Respiratory Unit for Seeing and Ensuring Follow-up of Patients With COVID-19 Symptoms.

COVID-19 necessitated significant care redesign, including new ambulatory workflows to handle surge volumes, protect patients and staff, and ensure timely reliable care. Opportunities also exist to harvest lessons from workflow innovations to benefit routine care. We describe a dedicated COVID-19 ambulatory unit for closing testing and follow-up loops characterized by standardized workflows and electronic communication, documentation, and order placement. More than 85% of follow-ups were completed within 24 hours, with no observed staff, nor patient infections associated with unit operations. Identified issues include role confusion, staffing and gatekeeping bottlenecks, and patient reluctance to visit in person or discuss concerns with phone screeners.

Role of Radiation Therapy in Modulation of the Tumor Stroma and Microenvironment.

In recent decades, there has been substantial growth in our understanding of the immune system and its role in tumor growth and overall survival. A central finding has been the cross-talk between tumor cells and the surrounding environment or stroma. This tumor stroma, comprised of various cells, and extracellular matrix (ECM), has been shown to aid in suppressing host immune responses against tumor cells. Through immunosuppressive cytokine secretion, metabolic alterations, and other mechanisms, the tumor stroma provides a complex network of safeguards for tumor proliferation. With recent advances in more effective, localized treatment, radiation therapy (XRT) has allowed for strategies that can effectively alter and ablate tumor stromal tissue. This includes promoting immunogenic cell death through tumor antigen release to increasing immune cell trafficking, XRT has a unique advantage against the tumoral immune evasion mechanisms that are orchestrated by stromal cells. Current studies are underway to elucidate pathways within the tumor stroma as potential targets for immunotherapy and chemoradiation. This review summarizes the effects of tumor stroma in tumor immune evasion, explains how XRT may help overcome these effects, with potential combinatorial approaches for future treatment modalities.

MicroRNA-200c increases radiosensitivity of human cancer cells with activated EGFR-associated signaling.

MicroRNA-200c (miR-200c) recently was found to have tumor-suppressive properties by inhibiting the epithelial-mesenchymal transition (EMT) in several cancers. miR-200c also interacts with various cellular signaling molecules and regulates many important signaling pathways. In this study, we investigated the radiosensitizing effect of miR-200c and its mechanism in a panel of human cancer cell lines. Malignant glioma (U251, T98G), breast cancer (MDA-MB-468), and lung carcinoma (A549) cells were transfected with control pre-microRNA, pre-miR-200c, or anti-miR-200c. Then, RT-PCR, clonogenic assays, immunoblotting, and immunocytochemisty were performed. To predict the potential targets of miR-200c, microRNA databases were used for bioinformatics analysis. Ectopic overexpression of miR-200c downregulated p-EGFR and p-AKT and increased the radiosensitivity of U251, T98G, A549, and MDA-MB-468 cells. In contrast, miR-200c inhibition upregulated p-EGFR and p-AKT, and decreased radiation-induced cell killing. miR-200c led to persistent γH2AX focus formation and downregulated pDNA-PKc expression. Autophagy and apoptosis were major modes of cell death. Bioinformatics analysis predicted that miR-200c may be associated with EGFR, AKT2, MAPK1, VEGFA, and HIF1AN. We also confirmed that miR-200c downregulated the expression of VEGF, HIF-1α, and MMP2 in U251 and A549 cells. In these cells, overexpressing miR-200c inhibited invasion, migration, and vascular tube formation. These phenotypic changes were associated with E-cadherin and EphA2 downregulation and N-cadherin upregulation. miR-200c showed no observable cytotoxic effect on normal human fibroblasts and astrocytes. Taken together, our data suggest that miR-200c is an attractive target for improving the efficacy of radiotherapy via a unique modulation of the complex regulatory network controlling cancer pro-survival signaling and EMT.

The Effects of Resident Peer- and Self-Chart Review on Outpatient Laboratory Result Follow-up.

PURPOSE: Performing and teaching appropriate follow-up of outpatient laboratory results (LRs) is a challenge. The authors tested peer-review among residents as a potentially valuable intervention. METHOD: Investigators assigned residents to perform self-review (n = 27), peer-review (n = 21), or self- + peer-review (n = 30) of outpatient charts. They also compared residence performance with that of historical controls (n = 20). In September 2012, residents examined 10 LRs from April 2012 onward. A second review in November 2012 ascertained whether performing chart review improved residents' practice behaviors. RESULTS: Initially, the least-square (LS) mean number of LRs without documentation of follow-up per resident in the self-, peer-, and self- + peer-review group was, respectively, 0.5 (SD 1.0), 1.0 (SD 1.7), and 0.9 (SD 1.3), and post intervention, this was 1.0 (SD 0.2), 0.3 (SD 0.2), and 0.6 (SD 0.2) (self- versus peer-review P = .03). Initially the LS mean follow-up time per resident in the self-, peer-, and self- + peer-review group was, respectively, 4.2 (SD 1.2), 6.9 (SD 1.4), and 5.9 (SD 1.2) days, and after the intervention, LS mean time was 5.0 (SD 0.5), 2.5 (SD 0.6), and 3.9 (SD 0.5) days (self- versus peer-review P < .01). Self-review was not associated with significant improvements in practice. CONCLUSIONS: In this comparison of self- and peer-review, only residents who performed peer-review demonstrated significant improvements in their documentation practices. These findings support the use of resident peer-review in improving LR follow-up, and potentially, in other, broader resident quality improvement initiatives.

Enhanced cytotoxic effect of radiation and temozolomide in malignant glioma cells: targeting PI3K-AKT-mTOR signaling, HSP90 and histone deacetylases.

BACKGROUND: Despite aggressive treatment with radiation therapy and concurrent adjuvant temozolomide (TMZ), glioblastoma multiform (GBM) still has a dismal prognosis. We aimed to identify strategies to improve the therapeutic outcome of combined radiotherapy and TMZ in GBM by targeting pro-survival signaling from the epidermal growth factor receptor (EGFR). METHODS: Glioma cell lines U251, T98G were used. Colony formation, DNA damage repair, mode of cell death, invasion, migration and vasculogenic mimicry as well as protein expression were determined. RESULTS: U251 cells showing a low level of methyl guanine transferase (MGMT) were highly responsive to the radiosensitizing effect of TMZ compared to T98G cells having a high level of MGMT. Treatment with a dual inhibitor of Class I PI3K/mTOR, PI103; a HSP90 inhibitor, 17-DMAG; or a HDAC inhibitor, LBH589, further increased the cytotoxic effect of radiation therapy plus TMZ in U251 cells than in T98G cells. However, treatment with a mTOR inhibitor, rapamycin, did not discernibly potentiate the radiosensitizing effect of TMZ in either cell line. The mechanism of enhanced radiosensitizing effects of TMZ was multifactorial, involving impaired DNA damage repair, induction of autophagy or apoptosis, and reversion of EMT (epithelial-mesenchymal transition). CONCLUSIONS: Our results suggest possible strategies for counteracting the pro-survival signaling from EGFR to improve the therapeutic outcome of combined radiotherapy and TMZ for high-grade gliomas.

Endovascular management of the patent inferior mesenteric artery in two cases of uncontrolled type II endoleak after endovascular aneurysm repair.

CONTEXT: Endovascular aneurysm repair (EVAR) has well documented advantages over traditional open repair and has been widely adopted as the alternative treatment modality for abdominal aortic aneurysm. However, endoleaks specifically type II can be a significant problem with this technique leading to aortic sac expansion and potential rupture. A large number of type II endoleaks are caused by persistent inferior mesenteric artery (IMA) retrograde bleeding. Various methods to try to manage this complication have been previously described. IMA embolization via the marginal artery of Drummond, however, has not been adequately popularized as an alternative less invasive approach to the treatment of type II endoleak. CASE REPORT: Two men, ages 77 and 81, underwent uneventful EVAR for 5.5 and 5.0 cm infrarenal abdominal aortic aneurysms, respectively, using Zenith Cook(®) bifurcated stent grafts. Computed tomography angiography at 1 and 6 months postoperatively demonstrated small type II endoleaks in both cases which were followed clinically. Subsequent follow-up tomography scan at 12 months revealed persistent type II endoleaks related to retrograde filling from the IMA with significant enlargement of the aneurysm sacs. Both patients underwent successful IMA coil embolization via the marginal artery of Drummond. CONCLUSIONS: Percutaneous IMA embolization using standard endovascular techniques to access the marginal artery of Drummond is an alternative, and in our opinion, preferred technique for controlling type II endoleaks caused by a persistently patent IMA.

The revolving door of resident continuity practice: identifying gaps in transitions of care.

BACKGROUND: It is well documented that transitions of care pose a risk to patient safety. Every year, graduating residents transfer their patient panels to incoming interns, yet in our practice we consistently find that approximately 50% of patients do not return for follow-up care within a year of their resident leaving. OBJECTIVE: To examine the implications of this lapse of care with respect to chronic disease management, follow-up of abnormal test results, and adherence with routine health care maintenance. DESIGN: Retrospective chart review SUBJECTS: We studied a subset of patients cared for by 46 senior internal medicine residents who graduated in the spring of 2008. 300 patients had been identified as high priority requiring follow-up within a year. We examined the records of the 130 of these patients who did not return for care. MAIN MEASURES: We tabulated unaddressed abnormal test results, missed health care screening opportunities and unmonitored chronic medical conditions. We also attempted to call these patients to identify barriers to follow-up. KEY RESULTS: These patients had a total of 185 chronic medical conditions. They missed a total of 106 screening opportunities including mammogram (24), Pap smear (60) and colon cancer screening (22). Thirty-two abnormal pathology, imaging and laboratory test results were not followed-up as the graduating senior intended. Among a small sample of patients who were reached by phone, barriers to follow-up included a lack of knowledge about the need to see a physician, distance between home and our office, difficulties with insurance, and transportation. CONCLUSIONS: This study demonstrates the high-risk nature of patient handoffs in the ambulatory setting when residents graduate. We discuss changes that might improve the panel transfer process.

Frosted branch angiitis, presumably related to dermatomyositis.

PURPOSE: To report the first case of frosted branch angiitis associated with dermatomyositis in a Korean woman. METHODS: Case report. RESULTS: A 42-year-old woman with history of dermatomyositis presented with unilateral decreased visual acuity. Fundus examination showed findings consistent with frosted branch angiitis. After 1 month of oral prednisolone, the patient made significant visual recovery with near complete resolution of vascular sheathing. CONCLUSIONS: To the best of the authors' knowledge, this is the first case of frosted branch angiitis associated with dermatomyositis. Dermatomyositis should be considered in the differential diagnosis of patients presenting with frosted branch angiitis.

The influence of adjuvant radiotherapy on patterns of failure and survivals in uterine carcinosarcoma.

PURPOSE: To evaluate the impact of postoperative radiotherapy (PORT) on patterns of failure and survivals in uterine carcinosarcoma patients treated with radical surgery. MATERIALS AND METHODS: Between October 1998 and August 2010, 19 patients with stage I-III uterine carcinosarcoma received curative hysterectomy and bilateral salpingo-oophorectomy with or without PORT at Seoul National University Hospital. Their hospital medical records were retrospectively reviewed. PORT and non-PORT groups included 11 and 8 patients, respectively. They were followed for a mean of 22.7 months (range, 7.8 to 126.6 months). RESULTS: At 5 years, the overall survival rates were 51.9% for entire, 61.4% for PORT, and 41.7% for non-PORT groups, respectively. There was no statistical difference between PORT and non-PORT groups with regard to overall survival (p = 0.682). Seven out of 19 (36.8%) patients showed treatment failures, which all happened within 12 months. Although the predominant failures were distant metastasis in PORT group and loco-regional recurrence in non-PORT group, there was no statistically significant difference in loco-regional recurrence-free survival (LRRFS) (p = 0.362) or distant metastasis-free survival (DMFS) (p = 0.548). Lymph node metastasis was found to be a significant prognostic factor in predicting poor LRRFS (p = 0.013) and DMFS (p = 0.021), while the International Federation Gynecology and Obstetrics (FIGO) stage (p = 0.043) was associated with LRRFS. CONCLUSION: Considering that adjuvant radiotherapy after surgical resection was effective to decrease loco-regional recurrence and most treatment failures were distant metastasis, multimodal therapy including surgery, radiotherapy, and chemotherapy might be an optimal treatment for uterine carcinosarcoma patients.

Photodynamic therapy for bilateral subfoveal choroidal neovascularization complicating stargardt macular dystrophy.

PURPOSE: To report the outcome of repeated photodynamic therapy (PDT) for a patient with choroidal neovascularization complicating Stargardt disease. METHODS: Interventional case report. RESULTS: A 41-year-old patient with Stargardt disease developed unilateral choroidal neovascularization treated multiple times with PDT over 2.5 years. At that time, she developed choroidal neovascularization in the fellow eye also treated with PDT. Despite poor interim vision, after >4 years of follow-up, final visual outcome was excellent. CONCLUSION: Our case provides further evidence that repeated PDT may be used for the treatment of choroidal neovascular membrane complicating Stargardt disease without deleterious effects up to 4 years after treatment.

Effects of upper eyelid blepharoplasty on ocular surface sensation and tear production.

BACKGROUND: To evaluate the effect of upper eyelid surgery on ocular surface sensation and tear production. METHODS: Prospective, interventional, consecutive case series. Patients undergoing upper eyelid blepharoplasty or blepharoptosis repair were evaluated with measurements of their corneal sensation and tear production using a Cochet-Bonnet esthesiometer and the Schirmer 1 test without anesthesia, respectively. Measurements were obtained preperatively, and at 1 day and 1 month postoperatively. RESULTS: Eleven patients (21 eyes) were enrolled in the study. There was a significant decrease in corneal sensation between the baseline and postperative day 1 (p < 0.01) and a significant increase between day 1 and month 1 after surgery (p < 0.01). There was no statistically significant difference in corneal sensation between the baseline and postoperative 1 month measurement (p > 0.05). There was no significant difference in tear production between baseline and postoperative day 1 (p > 0.05). There was a statistically significant increase in tear production between baseline and postoperative month 1 (p < 0.05). There was no significant correlation between corneal sensitivity and Schirmer 1 test preoperatively, at postoperative day 1, or at postoperative month 1 after surgery. INTERPRETATION: Upper eyelid surgery results in a temporary decrease in ocular surface sensation that returns to baseline after 1 month. Patients with pre-existing ocular surface dysfunction should consider aggressive treatments with lubricating drops and ointment, punctual occlusion, or anti-inflammatory therapy to accommodate the temporary effects on ocular surface sensation that result from upper eyelid surgery.

Embolization of type 2 endoleaks after endovascular repair of abdominal aortic aneurysms with use of cyanoacrylate with or without coils.

Translumbar embolization was used to treat 11 type 2 endoleaks in nine patients with the liquid embolic agent n-butyl cyanoacrylate (NBCA). Nine of the embolizations were performed with a combination of stainless-steel coils and NBCAJ and the other two were performed with NBCA alone. There was complete occlusion on initial computed tomographic (CT) angiography in six of nine patients (66%), including the two cases treated with NBCA alone. Persistent endoleak on initial CT angiography occurred in three of nine patients (33%). Two of these patients underwent successful repeated embolization with NBCA. Aneurysm size remained unchanged in four patients (44%), decreased in four patients (44%), and increased in one patient (11%). No complications occurred. Initial results with the use of NBCA for endoleak embolization are encouraging.

Device selection in the treatment of in-stent restenosis with and without radiation (from the Gamma Radiation Trials).

In-stent restenosis (ISR) is a major limitation of coronary stenting and is associated with high recurrence rates after intervention with all available devices. Intracoronary gamma (gamma) radiation was proved to reduce the recurrence rate after conventional therapy. The purpose of this study was to compare the different devices utilized for the treatment of ISR with and without gamma radiation. To search for the optimal device for the treatment of ISR, 685 patients from the radiation trials for ISR who were randomized to either iridium-192 gamma radiation (559 patients) or placebo (126 patients) following intervention were evaluated. Devices used included balloon percutaneous transluminal coronary angioplasty, excimer laser coronary angioplasty (ELCA), rotational atherectomy, and additional stent implantation. Baseline clinical and angiographic characteristics were similar between the gamma radiation and placebo groups. One- and 6-month clinical and angiographic outcomes were compared. The use of stenting compared with other devices was associated with increased late loss. Device selection used as adjunctive therapy did not influence the 30-day outcome. Patients treated with gamma radiation and placebo therapy had similar rates of composite major adverse coronary events (MACE) (death, Q-wave myocardial infarction, target vessel revascularization) (3% vs 2%, p = NS). At 6 months, MACE rates in irradiated patients were similar among POBA (29%), ELCA (28%), rotational atherectomy (18%), and additional stent implantation (30%, p = NS), and were significantly lower compared with placebo for the entire cohort and for each device subgroup. The overall recurrence rate of ISR was lower in patients treated with gamma radiation using iridium-192 compared with placebo. Device selection did not influence late clinical outcomes in irradiated and nonirradiated groups.