Breast Radiation Therapy Survivorship and Cancer Support Groups: an Opportunity for Community Engagement and Education Through the Addressing Breast Cancer Dermatologic Side Effects (ABCDEs) Program.

Breast cancer is the most commonly diagnosed cancer and the second leading cause of cancer deaths in women in the USA. To serve under-insured breast cancer patients in South Texas, we designed a patient education program to improve health literacy of secondary dermatologic changes after completing radiation therapy. A needs assessment survey was distributed to better understand the patients' stage of treatment, experiences with radiation-induced dermatologic side effects, and over-the-counter skin products and home remedies used. Of the 33 patients that participated in this program, nearly all patients (93.94%, n = 31) are either currently undergoing treatment or have completed treatment. Of the 31 individuals, 74.19% of patients (n = 23) have completed treatment at least 9-12 months ago, 22.58% (n = 7) are currently receiving chemotherapy, and 3.23% (n = 1) are currently undergoing radiation therapy. Among the dermatologic side effects, patients experienced changes to skin color, redness, and burns/burning sensation at the greatest severity. The top products used by survey participants were prescription-strength topical corticosteroids (65.63%) followed by oral analgesics (28.13%) and compression sleeves (25.00%). Aloe vera (15.63%) was the most used complementary and alternative therapeutic treatment. By surveying experiences of radiation-induced dermatologic side effects in predominantly under-resourced and minority communities, we can better tailor patient education programs to reflect patients' experiences. Overall, this program can enhance clinicians' insight on under-resourced patient experiences to improve health literacy and dispel common misconceptions surrounding breast cancer treatment, management, and survivorship.

Network Localization of Unconscious Visual Perception in Blindsight.

OBJECTIVE: Blindsight is a disorder where brain injury causes loss of conscious but not unconscious visual perception. Prior studies have produced conflicting results regarding the neuroanatomical pathways involved in this unconscious perception. METHODS: We performed a systematic literature search to identify lesion locations causing visual field loss in patients with blindsight (n = 34) and patients without blindsight (n = 35). Resting state functional connectivity between each lesion location and all other brain voxels was computed using a large connectome database (n = 1,000). Connections significantly associated with blindsight (vs no blindsight) were identified. RESULTS: Functional connectivity between lesion locations and the ipsilesional medial pulvinar was significantly associated with blindsight (family wise error p = 0.029). No significant connectivity differences were found to other brain regions previously implicated in blindsight. This finding was independent of methods (eg, flipping lesions to the left or right) and stimulus type (moving vs static). INTERPRETATION: Connectivity to the ipsilesional medial pulvinar best differentiates lesion locations associated with blindsight versus those without blindsight. Our results align with recent data from animal models and provide insight into the neuroanatomical substrate of unconscious visual abilities in patients. ANN NEUROL 2022;91:217-224.

Blood-Borne Lipopolysaccharide Is Rapidly Eliminated by Liver Sinusoidal Endothelial Cells via High-Density Lipoprotein.

During Gram-negative bacterial infections, excessive LPS induces inflammation and sepsis via action on immune cells. However, the bulk of LPS can be cleared from circulation by the liver. Liver clearance is thought to be a slow process mediated exclusively by phagocytic resident macrophages, Kupffer cells (KC). However, we discovered that LPS disappears rapidly from the circulation, with a half-life of 2-4 min in mice, and liver eliminates about three quarters of LPS from blood circulation. Using microscopic techniques, we found that ∼75% of fluor-tagged LPS in liver became associated with liver sinusoidal endothelial cells (LSEC) and only ∼25% with KC. Notably, the ratio of LSEC-KC-associated LPS remained unchanged 45 min after infusion, indicating that LSEC independently processes the LPS. Most interestingly, results of kinetic analysis of LPS bioactivity, using modified limulus amebocyte lysate assay, suggest that recombinant factor C, an LPS binding protein, competitively inhibits high-density lipoprotein (HDL)-mediated LPS association with LSEC early in the process. Supporting the previous notion, 3 min postinfusion, 75% of infused fluorescently tagged LPS-HDL complex associates with LSEC, suggesting that HDL facilitates LPS clearance. These results lead us to propose a new paradigm of LSEC and HDL in clearing LPS with a potential to avoid inflammation during sepsis.

Children with appendicitis on the US-Mexico border have socioeconomic challenges and are best served by a freestanding children's hospital.

INTRODUCTION: The US-Mexico border is medically underserved. Recent political changes may render this population even more vulnerable. We hypothesized that children on the border present with high rates of perforated appendicitis due to socioeconomic barriers. METHODS: A prospective survey was administered to children presenting with appendicitis in El Paso, Texas. Primary outcomes were rate of perforation and reason for diagnostic delay. We evaluated the association between demographics, potential barriers to care, risk of perforation and risk of misdiagnosis using logistic regression. p < 0.05 was considered significant. RESULTS: 98 patients participated from October 2016 to February 2017. 96 patients (98%) were Hispanic and 81 (82%) had Medicaid or were uninsured. 11 patients (11%) resided in Mexico or Guatemala. Patients were less likely to receive a CT and more likely to receive an ultrasound if they presented to a freestanding children's hospital (p = 0.01). 37 patients (38%) presented with perforation, of which 19 (52%) were the result of practitioner misdiagnosis. Patients who presented to a freestanding children's hospital were less likely to be misdiagnosed than patients presenting to other facilities (p = 0.05). Children who underwent surgery in a freestanding children's hospital had the shortest length of stay after adjusting for perforation status and potential confounders (p < 0.01). CONCLUSION: Children with low socioeconomic status did not have difficulty accessing care on the USA-Mexico border, but they were commonly misdiagnosed. Children were less likely to receive a CT, more likely to be correctly diagnosed and length of stay was shorter when patients presented to a freestanding children's hospital.

FcγRIIb on liver sinusoidal endothelium clears small immune complexes.

It has long been known that the ITIM-bearing IgG Fc receptor (FcγRIIb, RIIb) is expressed on liver sinusoidal endothelial cells (LSEC) and that the liver is the major site of small immune complex (SIC) clearance. Thus, we proposed that RIIb of LSEC eliminates blood-borne SIC, thereby controlling immune complex-mediated autoimmune disease. Testing this hypothesis, we found most RIIb of the mouse, fully three-quarters, to be expressed in liver. Moreover, most (90%) liver RIIb was expressed in LSEC, the remainder in Kupffer cells. An absent FcRγ in LSEC implied that RIIb is the sole FcγR expressed. Testing the capacity of liver RIIb to clear blood-borne SIC, we infused mice intravenously with radio-iodinated SIC made of OVA and rabbit IgG anti-OVA. Tracking decay of SIC from the blood, we found the RIIb knockout strain to be severely deficient in eliminating SIC compared with the wild-type strain, terminal half-lives being 6 and 1.5 h, respectively. RIIb on LSEC, a major scavenger, keeps SIC blood concentrations low and minimizes pathologic deposition of inflammatory immune complex.

Treatment of localized hepatocellular carcinoma: resection vs. ablation vs. radiation.

Hepatocellular carcinoma (HCC) is a common malignancy with many patients presenting with local disease. As of date, the use of radiation is not included in the commonly utilized Barcelona Clinic Liver Cancer (BCLC) classification but is in the National Comprehensive Cancer Network guidelines. Radiation can volumetrically cover the entire tumor and with novel technologic advances can be administered non-invasively with excellent clinical outcomes with few adverse events. The gold standard for localized early HCC (such as BCLC-A) is resection or transplantation. In patients who are not candidates for surgical treatment, locoregional therapy should be considered as an optimal therapy for these patients. Tumor ablation techniques such as microwave ablation (MWA) and radiofrequency ablation (RFA) are excellent tools to control local disease or bridge to transplantation. Should these not be possible though then ablation with external beam radiation is also capable of yielding comparable local control and serve as a bridge to transplant without worse rates of adverse events. For tumors that meet Milan criteria for transplantation, in comparison to transarterial chemoembolization (TACE), there is considerable randomized evidence demonstrating better local control, less adverse events, better progression-free survival (PFS), and less costly. It can be utilized as a bridge in Barcelona liver class B. For larger localized tumors though (extrahepatic disease or vascular invasion like BCLC-C), stereotactic body radiation therapy (SBRT) is shown via a randomized clinical trial to have a survival benefit, local control benefit, and no worse adverse events compared to systemic therapy. In this setting, it should be considered the local consolidation standard of care.

Effects of the Brief Simha Kriya Breathing Practice for Health Care Workers During the COVID-19 Pandemic.

Introduction: During the COVID-19 pandemic, health care workers (HCWs) experienced increased anxiety, depression, loneliness, and other mental health issues. HCWs need additional resources to cope with the mental health impact of their work. Yoga techniques could be helpful strategies to manage different stressors during times of uncertainty. Methods: This prospective, single-arm, trial examined the effects of a brief pranayama yoga practice on the wellbeing of HCWs during the height of COVID-19. HCWs were recruited through announcements and institutional websites at a large major cancer center in the southern United States. A short, prerecorded, 5-min breathwork video intervention called "Simha Kriya" was provided to participants, and they were encouraged to practice one to two times daily for 4 weeks. Participants completed self-report instruments at baseline and weeks 1 and 4, including: (1) Perceived Stress Scale (PSS); (2) Brief Resilient Coping Scale (BRCS); and (3) a questionnaire assessing the experience of COVID-19 among HCWs that had five subscales. HCWs also conducted a measure of breath holding time. Paired sample t-tests and mixed-effects analysis of variance models examined changes over time. Results: One hundred participants consented to the study, with 88 female, 60 white, 39 worked remotely, and 27 were clinical staff. Sixty-nine participants provided data at week 1 and 56 at week 4. Participants' adherence to the breathing exercises between weeks 1 and 4 was similar, with a mean of six times per week. At week 4, there were significant decreases in the COVID-19 Distress score (p < 0.0001) and COVID-19 Disruption (p = 0.013), yet no changes in the PSS. There were also significant increases in COVID-19 Stress Management (p = 0.0001) and BRCS scores (p = 0.012), but no changes in Perceived Benefits of COVID-19 and no changes in breath holding time. Discussion: Brief yoga-based breathing practices helped reduce pandemic-specific stress, improved resilience, and stress management skills in HCWs. Trial Registration Number: NCT04482647.

Rapid and efficient clearance of blood-borne virus by liver sinusoidal endothelium.

The liver removes quickly the great bulk of virus circulating in blood, leaving only a small fraction to infect the host, in a manner characteristic of each virus. The scavenger cells of the liver sinusoids are implicated, but the mechanism is entirely unknown. Here we show, borrowing a mouse model of adenovirus clearance, that nearly all infused adenovirus is cleared by the liver sinusoidal endothelial cell (LSEC). Using refined immunofluorescence microscopy techniques for distinguishing macrophages and endothelial cells in fixed liver, and identifying virus by two distinct physicochemical methods, we localized adenovirus 1 minute after infusion mainly to the LSEC (∼90%), finding ∼10% with Kupffer cells (KC) and none with hepatocytes. Electron microscopy confirmed our results. In contrast with much prior work claiming the main scavenger to be the KC, our results locate the clearance mechanism to the LSEC and identify this cell as a key site of antiviral activity.

FcRn in the yolk sac endoderm of mouse is required for IgG transport to fetus.

In adults, the nonclassical MHC class I molecule, FcRn, binds both IgG and albumin and rescues both from a degradative fate, endowing both proteins with high plasma concentrations. FcRn also transports IgG from mother to young during gestation. Anticipating that a detailed understanding of gestational IgG transport in the mouse may give us a useful model to understand FcRn function in the human placenta, we have studied FcRn in the mouse yolk sac placenta in detail. Analyzing day 19-20 fetuses of the three FcRn genotypes resulting from matings of FcRn(+/-) parents, we found that FcRn(-/-) fetuses showed negligible IgG concentrations (1.5 microg/ml), whereas IgG concentrations in FcRn(+/-) fetuses were about a half (176 microg/ml) that of FcRn(+/+) fetuses (336 microg/ml), indicating that FcRn is responsible for virtually all IgG transport from mother to fetus. Immunofluorescence and immunoblotting studies indicated that FcRn is expressed in the endoderm of the yolk sac placenta but not in other cells of the yolk sac placenta or in the chorioallantoic placenta. IgG was found in the endoderm of both FcRn(+/+) and FcRn(-/-) yolk sac placentas and in the mesenchyme of FcRn(+/+) but was missing from the mesenchyme of FcRn(-/-) yolk sac placentas, indicating that IgG enters the endoderm constitutively but is moved out of the endoderm by FcRn. The similarities of these results to human placental FcRn expression and function are striking.

The major histocompatibility complex-related Fc receptor for IgG (FcRn) binds albumin and prolongs its lifespan.

The inverse relationship between serum albumin concentration and its half-life suggested to early workers that albumin would be protected from a catabolic fate by a receptor-mediated mechanism much like that proposed for IgG. We show here that albumin binds FcRn in a pH dependent fashion, that the lifespan of albumin is shortened in FcRn-deficient mice, and that the plasma albumin concentration of FcRn-deficient mice is less than half that of wild-type mice. These results affirm the hypothesis that the major histocompatibility complex-related Fc receptor protects albumin from degradation just as it does IgG, prolonging the half-lives of both.

When cognitive evaluation does not disclose a neurologic disorder: experience of a university behavioral neurology clinic.

OBJECTIVE: We examined clinical features, referral patterns, and diagnostic outcome of patients receiving cognitive evaluation in a behavioral neurology clinic who had no neurologic disorder. BACKGROUND: Cognitive complaints may indicate Alzheimer Disease (AD) or many other conditions. Accurate early evaluation of these complaints is critical, and appropriate subspecialty clinic referral has public health policy implications. METHOD: This retrospective medical records review included 342 consecutive patients seen at the Neurobehavior Clinic of the University of Colorado Hospital from July 2006 through June 2008. All patients received an initial diagnosis by a clinic attending and subsequent consensus diagnosis by 3 subspecialists board certified in Behavioral Neurology & Neuropsychiatry. RESULTS: Among the 342 patients, 68% had a neurologic disorder, the most common of which was probable AD (17%). The remainder had nonneurologic diagnoses: 20% had a psychiatric diagnosis, 7% had no neuropsychiatric disorder, and 5% had a medical diagnosis. Of those with nonneurologic diagnoses, 65% were referred by primary care providers, and the most common symptom was memory loss (72%). In the psychiatric subgroup, depression was the most frequent diagnosis (56%). All normal individuals had concern about cognitive decline. In the medical subgroup, medication effect was the most frequent diagnosis (50%). CONCLUSIONS: Probable AD was the most common neurologic diagnosis, but 32% of the referred patients had no neurologic disorder, and most of these individuals had a psychiatric cause for cognitive complaints. These results highlight the need for policies promoting more effective use of subspecialty clinics dedicated to neurologic disorders of cognition.

Phase II Trial of Ipilimumab with Stereotactic Radiation Therapy for Metastatic Disease: Outcomes, Toxicities, and Low-Dose Radiation-Related Abscopal Responses.

Ipilimumab is effective for patients with melanoma, but not for those with less immunogenic tumors. We report a phase II trial of ipilimumab with concurrent or sequential stereotactic ablative radiotherapy to metastatic lesions in the liver or lung (NCT02239900). Ipilimumab (every 3 weeks for 4 doses) was given with radiotherapy begun during the first dose (concurrent) or 1 week after the second dose (sequential) and delivered as 50 Gy in 4 fractions or 60 Gy in 10 fractions to metastatic liver or lung lesions. In total, 106 patients received ≥1 cycle of ipilimumab with radiation. Median follow-up was 10.5 months. Median progression-free survival time was 2.9 months (95% confidence interval, 2.45-3.40), and median overall survival time was not reached. Rates of clinical benefit of nonirradiated tumor volume were 26% overall, 28% for sequential versus 20% for concurrent therapy (P = 0.250), and 31% for lung versus 14% for liver metastases (P = 0.061). The sequential lung group had the highest rate of clinical benefit at 42%. There were no differences in treatment-related adverse events between groups. Exploratory analysis of nontargeted lesions revealed that lesions receiving low-dose radiation were more likely to respond than those that received no radiation (31% vs. 5%, P = 0.0091). This phase II trial of ipilimumab with stereotactic radiotherapy describes satisfactory outcomes and low toxicities, lending support to further investigation of combined-modality therapy for metastatic cancers.

Beta 2-microglobulin deficient mice catabolize IgG more rapidly than FcRn- alpha-chain deficient mice.

FcRn, a nonclassical MHC-I protein bound to beta 2-microglobulin (beta 2m), diverts IgG and albumin from an intracellular degradative fate, prolonging the half-lives of both. While knockout mouse strains lacking either FcRn-alpha-chain (AK) or beta 2m (BK) show much shorter half-lives of IgG and albumin than normal mice, the plasma IgG half-life in the BK and AK strains is different, being shorter in the BK strain. Since beta 2m does not affect the IgG production rate, we tested whether an additional beta 2m-associated mechanism protects IgG from catabolism. First, we compared the fractional disappearance rate in plasma of an intravenous dose of radioiodinated IgG in a mouse strain deficient in both FcRn-alpha-chain and beta 2m (ABK), in the two parental knockout strains (AK and BK), and in the background wild-type (WT) strain. We found that IgG survived longer in the beta 2m-expressing AK strain than in the beta 2m-lacking ABK and BK strains, whereas the IgG half-lives between the ABK and BK strains were identical. Then we compared endogenous concentrations of four typical plasma proteins among the four strains and found that steady-state plasma concentrations of both IgG and albumin were higher in the AK strain than in either the BK or the ABK strain. These results suggest that a beta 2m-associated effect other than FcRn prolongs the survival of both IgG and albumin, although leaky gene transcription in the AK strain cannot be ruled out.

Radiation and Anti-Cancer Vaccines: A Winning Combination.

The emerging combination of radiation therapy with vaccines is a promising new treatment plan in the fight against cancer. While many cancer vaccines such as MUC1, p53 CpG oligodeoxynucleotide, and SOX2 may be great candidates for antitumor vaccination, there still remain many investigations to be done into possible vaccine combinations. One fruitful partnership that has emerged are anti-tumor vaccines in combination with radiation. Radiation therapy was previously thought to be only a tool for directly or indirectly damaging DNA and therefore causing cancer cell death. Now, with much preclinical and clinical data, radiation has taken on the role of an in situ vaccine. With both cancer vaccines and radiation at our disposal, more and more studies are looking to combining vaccine types such as toll-like receptors, viral components, dendritic-cell-based, and subunit vaccines with radiation. While the outcomes of these combinatory efforts are promising, there is still much work to be covered. This review sheds light on the current state of affairs in cancer vaccines and how radiation will bring its story into the future.

Accuracy and Precision of an Optoacoustic Prototype in Determining Endotracheal Tube Position in Children.

BACKGROUND: Confirmation of endotracheal tube (ETT) tip position and timely identification and correction of malposition is an essential component of care for endotracheally intubated and mechanically ventilated children. We evaluated the ability of a prototype optoacoustic medical device to determine ETT tip position. We hypothesized that the precision of optoacoustic assessment of ETT tip position would be comparable to chest radiography. METHODS: We recruited children aged newborn to 16 y who were admitted to the pediatric ICU requiring tracheal intubation and undergoing a chest radiograph for clinical purposes. After positioning each child on a chest radiograph plate, a sterile optical fiber, temporarily inserted through the ETT, emitted laser pulses perpendicular to the fiber and to the ETT, generating acoustic (ultrasound) waves in overlying tissue when the tip of the fiber passed beneath an acoustic sensor in the sternal notch. The distance from the ETT tip to the peak acoustic signal was used to calculate the distance from the ETT tip to the carina, which was compared with the same distance calculated by the radiologist reading the chest radiograph. Pearson's correlation coefficient, paired t tests, a Bland-Altman plot were used to compare the measures (P < .05 was considered statistically significant). RESULTS: Twenty-six subjects were enrolled: 15 (57.7%) were male, median (interquartile range) age, weight, and height were 9 months (4-24), 9.6 kg (5.7-13.0), and 75 cm (62-90), respectively. All ETTs were cuffed (internal diameter range 3.0-5.0 mm). The relationship between optoacoustic and chest radiograph measurements was strong (r = 0.91, P < .001). Bias was 0.1 cm with narrow limits of agreement between measures (0.58 cm and 0.76 cm). CONCLUSIONS: The optoacoustic prototype accurately determined ETT tip position and was comparable in precision to chest radiograph.

Penetrating trauma in children on the United States-Mexico border: Hispanic ethnicity is not a risk factor.

INTRODUCTION: The United States-Mexico border is perceived as dangerous by the media and current political leaders. Hispanic ethnicity, low socioeconomic status, male gender and adolescent age have previously been identified as risk factors for penetrating trauma (PT). METHODS: A retrospective review of PT was performed in a border region. Children 0-17 years old, admitted to the region's only level I trauma center between 2001 and 2016 were included. Standardized morbidity ratio was used to compare observed to expected morbidity. RESULTS: There were 417 PT admissions. 197 (47%) were non-accidental, 34 (8%) suicide attempts and 186 (45%) accidental. There were 12 homicides, 7 suicides and no accidental deaths. The region contains over 280,000 children, thus yielding a homicide rate of 0.26 per 100,000. The U.S. pediatric homicide rate was 2.6-4.0 over this period. Adolescents 13-17 years old accounted for 237 (57%) admissions, 152 (78%) of non-accidental admissions and 12 (63%) deaths. Most admissions (N = 321, 77%) and 15 of the deaths (79%) were males. Non-accidental injuries were more frequent in ZIP codes associated with low incomes. Hispanic patients accounted for 173 (88%) of non-accidental trauma. However, 40 (20%) non-accidental injuries occurred in Mexico and 157 (80%) injuries occurred in an 82% Hispanic region. Therefore, the standardized morbidity ratio for Hispanic ethnicity was 1.048 (CL 0.8-1.2, P = 0.6). CONCLUSION: On the United States-Mexico border, the pediatric homicide rate was less than 1/10 the national average. Male adolescents are at risk for non-accidental PT. In a Hispanic majority population, Hispanic ethnicity was not a risk factor for PT. It is possible that economic disparity, rather than race/ethnicity, is a risk factor for PT.

Radiation therapy and immunotherapy: what is the optimal timing or sequencing?

Radiotherapy is a component of the standard of care for many patients with locally advanced nonmetastatic tumors and increasingly those with oligometastatic tumors. Despite encouraging advances in local control and progression-free and overall survival outcomes, continued manifestation of tumor progression or recurrence leaves room for improvement in therapeutic efficacy. Novel combinations of radiation with immunotherapy have shown promise in improving outcomes and reducing recurrences by overcoming tumor immune tolerance and evasion mechanisms via boosting the immune system's ability to recognize and eradicate tumor cells. In this review, we discuss preclinical and early clinical evidence that radiotherapy and immunotherapy can improve treatment outcomes for locally advanced and metastatic tumors, elucidate underlying molecular mechanisms and address strategies to optimize timing and sequencing of combination therapy for maximal synergy.

Uncovering the immune tumor microenvironment in non-small cell lung cancer to understand response rates to checkpoint blockade and radiation.

The study of immunology has led to breakthroughs in treating non-small cell lung cancer (NSCLC). The recent approval of an anti-PD1 checkpoint drug for NSCLC has generated much interest in novel combination therapies that might provide further benefit for patients. However, a better understanding of which combinations may (or may not) work in NSCLC requires understanding the lung immune microenvironment under homeostatic conditions and the changes in that microenvironment in the setting of cancer progression and with radiotherapy. This review provides background information on immune cells found in the lung and the prognostic significance of these cell types in lung cancer. It also addresses current clinical directions for the combination of checkpoint inhibitors with radiation for NSCLC.