Clinicopathologic analysis of a large series of microinvasive breast cancers.

Clinical management of microinvasive breast cancer (Tmic) remains controversial. Although metastases are infrequent in Tmic carcinoma patients, surgical treatment typically includes lymph node sampling. The objective of this study was to determine the rate and predictors of lymph node metastases, recurrence, and survival in a large series of Tmic breast carcinomas. Consecutive cases of Tmic were identified within our health care system from 2001 to 2015. We reviewed results of lymph node sampling and other pathologic factors including hormone receptor/HER2 status, associated in situ tumor size/grade, margin status, number of invasive foci, surgical/adjuvant therapies, and recurrence/survival outcomes. In this cohort, 294 Tmic cases were identified with mean follow-up of 4.6 years. Of 260 patients who underwent axillary staging, lymph node metastases were identified in 1.5% (all of which were ductal type). All Tmic cases with positive lymph node metastases had associated DCIS with size > 5 cm (5.3-8.5 cm) compared to a median DCIS tumor size of 2.5 cm (0.2-19.0 cm) for the entire cohort. No lymph node metastases were seen with microinvasive lobular carcinoma. During the follow-up period, there were no regional/distant recurrences or breast cancer-associated deaths in a mean follow-up period of 4.6 years. Two patients developed subsequent ipsilateral breast cancer (DCIS) in a different quadrant than the original Tmic. Clinical behavior of microinvasive breast cancer in this series is similar to DCIS. Lymph node metastases are uncommon and were only seen with ductal type microinvasive carcinoma. Our data suggest limited benefit for routine node sampling and support management of Tmic similar to DCIS, particularly for patients with DCIS < 5 cm in size.

Large mutational target size for rapid emergence of bacterial persistence.

Phenotypic heterogeneity displayed by a clonal bacterial population permits a small fraction of cells to survive prolonged exposure to antibiotics. Although first described over 60 y ago, the molecular mechanisms underlying this behavior, termed persistence, remain largely unknown. To systematically explore the genetic basis of persistence, we selected a library of transposon-mutagenized Escherichia coli cells for survival to multiple rounds of lethal ampicillin exposure. Application of microarray-based genetic footprinting revealed a large number of loci that drastically elevate persistence frequency through null mutations and domain disruptions. In one case, the C-terminal disruption of methionyl-tRNA synthetase (MetG) results in a 10,000-fold higher persistence frequency than wild type. We discovered a mechanism by which null mutations in transketolase A (tktA) and glycerol-3-phosphate (G3P) dehydrogenase (glpD) increase persistence through metabolic flux alterations that increase intracellular levels of the growth-inhibitory metabolite methylglyoxal. Systematic double-mutant analyses revealed the genetic network context in which such persistent mutants function. Our findings reveal a large mutational target size for increasing persistence frequency, which has fundamental implications for the emergence of antibiotic tolerance in the clinical setting.

Unusual Case of Missed Penile Metastases on 68 Ga-PSMA PET/CT.

ABSTRACT: A 75-year-old man with a history of previously treated localized prostate cancer and prostate-specific antigen of 4.86 ng/mL was referred for a 68 Ga-prostate-specific membrane antigen PET/CT. PET imaging was reported to be negative. After subsequent review and re-read of the scan, prostate-specific membrane antigen imaging revealed uptake along the penile shaft (SUV max of 14.7). MRI was compatible with tumor. Penile metastases from prostate cancer, although uncommon, do occur and readers are encouraged to distinguish penile metastatic uptake from residual urine in the urethra.

Prediction of Resistance to 177Lu-PSMA Therapy by Assessment of Baseline Circulating Tumor DNA Biomarkers.

177Lu-PSMA-617 and 177Lu-PSMA I&T (collectively termed 177Lu-PSMA) are currently being used for the treatment of selected metastatic castration-resistant prostate cancer (mCRPC) patients with PSMA PET-positive disease, but biomarkers for these agents remain incompletely understood. Methods: Pretreatment circulating tumor DNA (ctDNA) samples were collected from 44 mCRPC patients receiving 177Lu-PSMA treatment. Prostate-specific antigen responders and nonresponders were assessed relative to the ctDNA findings at baseline. Results: The ctDNA findings indicated that nonresponders were more likely to have gene amplifications than were responders (75% vs. 39.2%, P = 0.03). In particular, amplifications in FGFR1 (25% vs. 0%, P = 0.01) and CCNE1 (31.2% vs. 0%, P = 0.001) were more likely to be present in nonresponders. CDK12 mutations were more likely to be present in nonresponders (25% vs. 3.6%, P = 0.05). Conclusion: Our analyses indicate that ctDNA assays may contain specific biomarkers predictive of response or resistance for 177Lu-PSMA-treated mCRPC patients. Additional confirmatory studies are required before clinicians can use these findings to make personalized treatment decisions.

Prevention of a wrong-location misadministration through the use of an intradepartmental incident learning system.

PURPOSE: A series of examples are presented in which potential errors in the delivery of radiation therapy were prevented through use of incident learning. These examples underscore the value of reporting near miss incidents. METHODS: Using a departmental incident learning system, eight incidents were noted over a two-year period in which fields were treated "out-of-sequence," that is, fields from a boost phase were treated, while the patient was still in the initial phase of treatment. As a result, an error-prevention policy was instituted in which radiation treatment fields are "hidden" within the oncology information system (OIS) when they are not in current use. In this way, fields are only available to be treated in the intended sequence and, importantly, old fields cannot be activated at the linear accelerator control console. RESULTS: No out-of-sequence treatments have been reported in more than two years since the policy change. Furthermore, at least three near-miss incidents were detected and corrected as a result of the policy change. In the first two, the policy operated as intended to directly prevent an error in field scheduling. In the third near-miss, the policy operated "off target" to prevent a type of error scenario that it was not directly intended to prevent. In this incident, an incorrect digitally reconstructed radiograph (DRR) was scheduled in the OIS for a patient receiving lung cancer treatment. The incorrect DRR had an isocenter which was misplaced by approximately two centimeters. The error was a result of a field from an old plan being scheduled instead of the intended new plan. As a result of the policy described above, the DRR field could not be activated for treatment however and the error was discovered and corrected. Other quality control barriers in place would have been unlikely to have detected this error. CONCLUSIONS: In these examples, a policy was adopted based on incident learning, which prevented several errors, at least one of which was potentially severe. These examples underscore the need for a rigorous, systematic incident learning process within each clinic. The experiences reported in this technical note demonstrate the value of near-miss incident reporting to improve patient safety.

Embracing the Practical Aspects of Theranostics With Prostate-Specific Membrane Antigen-Targeted Lutetium-177.

Treatment options for men with metastatic castration-resistant prostate cancer are rapidly changing. In addition to novel anti-androgens and taxane-based chemotherapy, radiopharmaceuticals are having an increasing role. Although calcium-mimetic theranostics have been in use for years, newer approaches use molecularly targeted radiation therapy by conjugating isotopes to prostate-specific membrane antigen (PSMA) and in so doing directly target prostate cancer cells; 177Lutetium-PSMA-617 is perhaps the best-known member of this new class. Expanding our capacity to deliver targeted beta-emitters requires additional planning and equipment. Having delivered close to 200 doses of 177Lutetium-PSMA-617 at our center, we offer practical advice about patient selection, radiation safety, treatment administration, and toxicity monitoring. Although this blueprint is not the only way to expand a theranostics program beyond Radium-223, we offer our institutional experience with 177Lutetium-PSMA-617 as an example to programs seeking to expand their radiopharmaceutical programs. We must rise to meet the patient-driven demand for these innovative and effective therapies.

Safety strategies in an academic radiation oncology department and recommendations for action.

BACKGROUND: Safety initiatives in the United States continue to work on providing guidance as to how the average practitioner might make patients safer in the face of the complex process by which radiation therapy (RT), an essential treatment used in the management of many patients with cancer, is prepared and delivered. Quality control measures can uncover certain specific errors such as machine dose miscalibration or misalignments of the patient in the radiation treatment beam. However, they are less effective at uncovering less common errors that can occur anywhere along the treatment planning and delivery process, and even when the process is functioning as intended, errors still occur. PRIORITIZING RISKS AND IMPLEMENTING RISK-REDUCTION STRATEGIES: Activities undertaken at the radiation oncology department at the Johns Hopkins Hospital (Baltimore) include Failure Mode and Effects Analysis (FMEA), risk-reduction interventions, and voluntary error and near-miss reporting systems. A visual process map portrayed 269 RT steps occurring among four subprocesses-including consult, simulation, treatment planning, and treatment delivery. Two FMEAs revealed 127 and 159 possible failure modes, respectively. Risk-reduction interventions for 15 "top-ranked" failure modes were implemented. Since the error and near-miss reporting system's implementation in the department in 2007, 253 events have been logged. However, the system may be insufficient for radiation oncology, for which a greater level of practice-specific information is required to fully understand each event. CONCLUSIONS: The "basic science" of radiation treatment has received considerable support and attention in developing novel therapies to benefit patients. The time has come to apply the same focus and resources to ensuring that patients safely receive the maximal benefits possible.

Prophylactic external beam radiation therapy for keloid prevention in thyroid surgery patients.

BACKGROUND: Poor cosmesis, secondary to keloid or hypertrophic scar, following thyroid surgery may cause considerable patient distress and be a significant challenge to treat. In this case series we examined the efficacy of prophylactic external beam radiation therapy (EBRT) for prevention of keloid formation in keloid-prone patients undergoing thyroid surgery. While much has been published about documenting the efficacy in reducing keloid formation following keloid excision, very little literature exists documenting prophylactic use related to surgeries with the goal of prevent de novo keloid formation. METHODS: We retrospectively evaluated a series of ten patients, who underwent a prophylactic EBRT for keloid prevention after thyroid surgery between January 2013 and February 2019. Patient demographics, primary diagnosis, surgical procedure, EBRT dosage, and post-operative visit records were reviewed. RESULTS: All ten patients who received EBRT for keloid prophylaxis following a thyroid surgery were female. Half of the patients were African Americans, 40% Caucasians, and 10% Hispanic. The mean age was 46.40±15.63 years with BMI of 31.5±5.5 kg/m2. Radiation was initiated within 6 hours of the surgery with an average radiation dose per session of 5.7±1.7 Gy. The total average EBRT dose delivered was 17.4±4.2 Gy. Mean follow-up period was 13 months post-thyroidectomy, with the longest follow-up at 23 months. One patient, who underwent a lateral neck dissection in addition to thyroid surgery, developed hypertrophic scar in less than 10% of her incision length. Nine other patients (90%) showed no post-surgical keloid nor hypertrophic scar formation and patients were satisfied with postsurgical cosmesis. CONCLUSIONS: We examined the efficacy of prophylactic EBRT in keloid-prone patients undergoing thyroid surgery. Prophylactic EBRT following thyroid surgery is effective in achieving a satisfactory cosmetic outcome in patients at high risk for keloid formation.

Increasing Readiness for Early Integrated Palliative Oncology Care: Development and Initial Evaluation of the EMPOWER 2 Intervention.

CONTEXT: Early integrated palliative care improves quality of life, but palliative care programs are underutilized. Psychoeducational interventions explaining palliative care may increase patients' readiness for palliative care. OBJECTIVES: To 1) collaborate with stakeholders to develop the EMPOWER 2 intervention explaining palliative care, 2) examine acceptability, 3) evaluate feasibility and preliminary efficacy. METHODS: The research was conducted at a North American cancer center and involved 21 stakeholders and 10 patient-participants. Investigators and stakeholders iteratively developed the intervention. Stakeholders rated acceptability of the final intervention. Investigators implemented a pre-post trial to examine the feasibility of recruiting 10 patients with metastatic cancer within one month and with a ≥50% consent rate. Preliminary efficacy outcomes were changes in palliative care knowledge and attitudes. RESULTS: Using feedback from four stakeholder meetings, we developed a multimedia intervention tailored to three levels of health-literacy. The intervention provides knowledge and reassurance about the purpose and nature of palliative care, addressing cognitive and emotional barriers to utilization. Stakeholders rated the intervention and design process highly acceptable (3.78/4.00). The pilot met a priori feasibility criteria (10 patients enrolled in 14 days; 83.3% consent rate). The intervention increased palliative care knowledge by 83.1% and improved attitudes by 18.9 points on a 0 to 51 scale (Ps < 0.00001). CONCLUSIONS: This formative research outlines the development of a psychoeducational intervention about palliative care. The intervention is acceptable, feasible, and demonstrated promising pilot test results. This study will guide clinical teams in improving patients' readiness for palliative care and inform the forthcoming EMPOWER 3 randomized clinical trial.

Image-Guided Intensity-Modulated Radiation Therapy for IgG4-Related Ophthalmic Disease.

BACKGROUND: IgG4-related ophthalmic disease is a rare, newly recognized entity with high failure rates on first-line therapy of systemic corticosteroids and no other proven management options. Case Presentation. Here, we present the clinical course of a patient with IgG4 ophthalmic disease who achieved a favorable response from radiotherapy. Our patient initially presented with a history of recurrent painful flares of orbital inflammation, a pathologic diagnosis follicular lymphoid hyperplasia from a right lacrimal gland biopsy, and MRI imaging noting expansion of the lateral rectus muscle of the right eye. Initial treatment with dacryoadenectomy and multiple courses of corticosteroids failed to keep his symptoms at bay. Further evaluation revealed florid IgG4 staining. In this context, he was evaluated for image-guided intensity-modulated radiotherapy (IG-IMRT) to the orbit to 20 Gy in 10 fractions. His ophthalmic symptoms resolved. CONCLUSIONS: This treatment experience suggests radiotherapy may be a favorable option for symptom relief in patients with IgG4-related ophthalmic disease not controlled by corticosteroids.

Epidural and Paraspinal Abscess Presenting as Acute Low Back Pain.

A 56-year-old man sought care from a primary care physician (PCP) 5 days after lifting a heavy box produced acute, isolated lumbar pain. The PCP diagnosed a lumbar disc herniation and referred the patient to physical therapy without diagnostic imaging. Due to the presence of multiple red flags leading up to and during examination, the patient was transferred to the emergency department for further evaluation. Magnetic resonance imaging revealed a spinal epidural abscess with an associated multiloculated abscess within the adjacent left paraspinal muscles. J Orthop Sports Phys Ther 2019;49(6):482. doi:10.2519/jospt.2019.8456.

Nonautistic motor stereotypies: clinical features and longitudinal follow-up.

To characterize further the clinical features and long-term outcomes among children with motor stereotypies who do not manifest mental retardation or pervasive developmental disorders, a review of clinical records and semistructured telephone interviews were undertaken. The identified clinical cohort consisted of 100 typically developing children with motor stereotypies. The mean length of follow-up was 6.8 +/- 4.6 years. At most recent follow-up, movements had continued in 94% of the sample (62% for >5 years). Only six children reported complete cessation of movements, with four (3 of 4 with head nodding) doing so >1 year after their initial diagnosis. Thus the course of motor stereotypies, especially in children with arm/hand movements, appears chronic. Nearly half the children in this cohort exhibit other comorbidities, including attention-deficit-hyperactivity disorder (30%), tics (18%), and obsessive-compulsive behaviors/obsessive-compulsive disorder (10%). Twenty-five percent of children with motor stereotypies reported positive family histories of motor stereotypies, suggesting an underlying genetic abnormality. Finally, evidence is emerging that the clinical course of children who exhibit head nodding may differ from those whose motor stereotypy predominantly involves the hands and arms.

Tic disorders: neural circuits, neurochemistry, and neuroimmunology.

The neuroanatomy and neurochemistry underlying tic disorders are thought to involve corticostriatothalamocortical circuits and dysregulation of their component neurotransmitter systems. Tourette syndrome is a tic disorder that begins in childhood and follows a waxing and waning course of tic severity. Although it is generally believed to have a genetic component, its etiology has not been fully elucidated. The clinical entity pediatric autoimmune neuropsychiatric disorders associated with streptococcal infection (PANDAS) has led some to suggest that the pathophysiology of tics in some individuals might involve a postinfectious autoimmune component. We review the neural circuits and neurochemistry of Tourette syndrome and evaluate the evidence for and against a role for autoimmunity in the expression of tics.

Corticosteroids as potential mechanism regulating variability in reproductive success in monogamous oldfield mice (Peromyscus polionotus).

Male and female mammals undergo profound hormonal changes during pregnancy, some of which are sufficiently dramatic to influence offspring survival. In order to understand the proximate mechanisms regulating the variability in reproductive success within and between individuals, we monitored changes in fecal corticosteroid concentrations over the reproductive cycle in male and female oldfield mice (Peromyscus polionotus subgriseus) to test whether corticosteroid concentrations during pregnancy were associated with offspring survival. In females that successfully raised litters to weaning, fecal corticosteroid concentrations were low until mid-gestation and increased significantly towards term; in females that did not raise their pups to weaning, fecal corticosteroid concentrations were significantly higher at mid-gestation, and remained high until late gestation. The difference in fecal corticosteroid concentrations at mid-gestation between successful and unsuccessful females can be explained by the fact that successful females were lactating. Lactation has been associated with a down-regulation of the hypothalamic-pituitary-adrenal (HPA) axis and, accordingly, a decrease in plasma corticosterone (CORT) in several species, including humans. Males that successfully raised their litters had low fecal corticosteroid concentrations throughout their partner's pregnancy. Unsuccessful males, however, had significantly higher fecal corticosteroid concentrations at term than males that raised their pups to weaning. While these preliminary data require further investigation, we suggest that pre-partum fecal corticosteroid concentrations in males were responsible for the variability in reproductive success.

Ethical Issues in Patient Safety Research: A Systematic Review of the Literature.

As many as 1 in 10 patients is harmed while receiving hospital care in wealthy countries. The risk of health care-associated infection in some developing countries is as much as 20 times higher. In response, in many global regions, increased attention has turned to the implementation of a broad program of safety research, encompassing a variety of methods. Although important international ethical guidelines for research exist, literature has been emerging in the last 20 years that begins to apply such guidelines to patient safety research specifically. This paper provides a review of the literature related to ethics, oversight, and patient safety research; identifies issues highlighted in articles as being of ethical relevance; describes areas of consensus regarding how to respond to these ethical issues; and highlights areas where additional ethical analysis and discussion are needed to provide guidance to those in the field.

Novel imidazoline antimicrobial scaffold that inhibits DNA replication with activity against mycobacteria and drug resistant Gram-positive cocci.

Bacterial antimicrobial resistance is an escalating public health threat, yet the current antimicrobial pipeline remains alarmingly depleted, making the development of new antimicrobials an urgent need. Here, we identify a novel, potent, imidazoline antimicrobial compound, SKI-356313, with bactericidal activity against Mycobacterium tuberculosis and Gram-positive cocci, including vancomycin-resistant Enterococcus faecium (VRE) and methicillin-resistant Staphylococcus aureus (MRSA). SKI-356313 is active in murine models of Streptococcus pneumoniae and MRSA infection and is potently bactericidal for both replicating and nonreplicating M. tuberculosis. Using a combination of genetics, whole genome sequencing, and a novel target ID approach using real time imaging of core macromolecular biosynthesis, we show that SKI-356313 inhibits DNA replication and displaces the replisome from the bacterial nucleoid. These results identify a new antimicrobial scaffold with a novel mechanism of action and potential therapeutic utility against nonreplicating M. tuberculosis and antibiotic resistant Gram-positive cocci.

Physician attitudes and practices related to voluntary error and near-miss reporting.

PURPOSE: Incident learning systems are important tools to improve patient safety in radiation oncology, but physician participation in these systems is poor. To understand reporting practices and attitudes, a survey was sent to staff members of four large academic radiation oncology centers, all of which have in-house reporting systems. METHODS: Institutional review board approval was obtained to send a survey to employees including physicians, dosimetrists, nurses, physicists, and radiation therapists. The survey evaluated barriers to reporting, perceptions of errors, and reporting practices. The responses of physicians were compared with those of other professional groups. RESULTS: There were 274 respondents to the survey, with a response rate of 81.3%. Physicians and other staff agreed that errors and near-misses were happening in their clinics (93.8% v 88.7%, respectively) and that they have a responsibility to report (97% overall). Physicians were significantly less likely to report minor near-misses (P = .001) and minor errors (P = .024) than other groups. Physicians were significantly more concerned about getting colleagues in trouble (P = .015), liability (P = .009), effect on departmental reputation (P = .006), and embarrassment (P < .001) than their colleagues. Regression analysis identified embarrassment among physicians as a critical barrier. If not embarrassed, participants were 2.5 and 4.5 times more likely to report minor errors and major near-miss events, respectively. CONCLUSIONS: All members of the radiation oncology team observe errors and near-misses. Physicians, however, are significantly less likely to report events than other colleagues. There are important, specific barriers to physician reporting that need to be addressed to encourage reporting and create a fair culture around reporting.