Recent Publications by CFE Educators

BACKGROUND

Malignant peripheral nerve sheath tumor (MPNST) is an aggressive and poorly understood malignant neoplasm. Even in the setting of multimodal therapy, the clinical course of MPNST is frequently marked by metastatic conversion and poor overall prognosis, with optimal treatment paradigms for this rare tumor unknown.

METHODS

We reviewed the medical records and histopathology of 54 consecutive patients who were treated at University of California San Francisco between 1990 and 2018.

RESULTS

Our cohort consisted of 24 male and 30 female patients (median age 38 years). Fédération Nationale des Centres de Lutte Contre Le Cancer (FNCLCC) sarcoma grading criteria segregated patients into groups with differences in overall survival (OS) ( = .02). Increasing Ki-67 labeling index was associated with poor OS (hazard ratio [HR] 1.36 per 10%, = .0002). Unsupervised hierarchical clustering-based immunohistochemical staining patterns identified 2 subgroups of tumors with differences in H3K27me3, Neurofibromin, S100, SOX10, p16, and EGFR immunoreactivity. In our cohort, cluster status was associated with improved locoregional failure-free rate ( = .004) in response to radiation.

CONCLUSIONS

Our results lend support to the FNCLCC sarcoma grading criteria as a prognostic scheme for MPNST, although few cases of grade 1 were included. Further, we identify increased Ki-67 labeling as a strong predictor of poor OS from MPNST. Finally, we identify a subset of MPNSTs with a predictive immunohistochemical profile that has improved local control with adjuvant radiotherapy. These data provide insights into the grading and therapy for patients with MPNST, although further studies are needed for independent validation.

OBJECTIVE

To capture the perspective of prospective urology applicants experiencing unique challenges in the context of COVID-19.

METHODS

A voluntary, anonymous survey was distributed online, assessing the impact of COVID-19 on a large sample of US medical students planning to apply to urology residencies. Themes of (1) specialty discernment, (2) alterations to medical education, and (3) the residency application process were explored.

RESULTS

A total of 238 medical students, 87% third and fourth years, responded to the survey. While 85% indicated that the pandemic had not deterred their specialty choice, they noted substantial impacts on education, including 82% reporting decreased exposure to urology. Nearly half of students reported changes to required rotations and 35% reported changes to urology-specific rotations at their home institutions. Students shared concerns about suspending in-person experiences, including the impact on letters of recommendation (68% "very concerned) and program choice (73% "very concerned"). Looking to the possibility of virtual interactions, students identified the importance of small group and one-on-one communication with residents (83% "very important") and opportunities to learn about hospital facilities (72% "very important").

CONCLUSION

Despite the impacts of COVID-19 on medical education, prospective urology applicants appear to remain confident in their specialty choice. Students' biggest concerns involve disruption of away rotations, including impacts on obtaining letters of recommendation and choosing a residency program.

OBJECTIVES

To evaluate long-term chronic sialadenitis symptoms in patients without sialolithiasis following sialendoscopy-assisted salivary duct surgery (SASDS) compared to a control group managed conservatively.

STUDY DESIGN

Prospective cohort study.

SETTING

Tertiary care center.

METHODS

Thirty-six patients (52 glands) with chronic sialadenitis without sialolithiasis completed the Chronic Obstructive Sialadenitis Symptoms (COSS) questionnaire at presentation and at 3-month time intervals thereafter for 1 year. Lower COSS scores represent lower symptom severity. We compared 27 patients who underwent SASDS to 9 control patients who elected conservative management.

RESULTS

COSS gland-specific scores from 38 SASDS-treated glands (cases) and 14 control glands were similar at baseline. At 6 to 12 months (mean, 8.4 months), the surgically treated group had significantly lower scores and a greater score reduction from baseline compared to controls (mean score change [95% confidence interval] cases: 20.7 points [15.7-25.8]; controls: 11.7 points [4.9-18.4]; = .04). There was a significant difference in scores between the 2 groups over time ( .001). A greater proportion (72%) of cases reported partial or complete resolution of overall sialadenitis symptoms at 6 to 12 months compared to the controls (22%, .05).

CONCLUSION

Compared to patients electing for conservative management, patients with sialadenitis without sialolithasis treated with SASDS had improved symptom scores and a greater reduction of symptom severity after 6 months. With SASDS, patients had higher rates of significant overall symptom improvement. In evaluating chronic sialadenitis, assessment at multiple time points is necessary to capture the intermittent and cyclical pattern of obstructive symptoms.

PURPOSE

Transforming growth factor β (TGFβ) promotes cell survival by endorsing DNA damage repair and mediates an immunosuppressive tumor microenvironment. Thus, TGFβ activation in response to radiation therapy is potentially targetable because it opposes therapeutic control. Strategies to assess this potential in the clinic are needed.

METHODS AND MATERIALS

We evaluated positron emission tomography (PET) to image Zr -fresolimumab, a humanized TGFβ neutralizing monoclonal antibody, as a means to detect TGFβ activation in intracranial tumor models. Pathway activity of TGFβ was validated by immunodetection of phosphorylated SMAD2 and the TGFβ target, tenascin. The contribution of TGFβ to radiation response was assessed by Kaplan-Meier survival analysis of mice bearing intracranial murine tumor models GL261 and SB28 glioblastoma and brain-adapted 4T1 breast cancer (4T1-BrA) treated with TGFβ neutralizing monoclonal antibody, 1D11, and/or focal radiation (10 Gy).

RESULTS

Zr-fresolimumab PET imaging detected engineered, physiological, and radiation-induced TGFβ activation, which was confirmed by immunostaining of biological markers. GL261 glioblastoma tumors had a greater PET signal compared with similar-sized SB28 glioblastoma tumors, whereas the widespread PET signal of 4T1-BrA intracranial tumors was consistent with their highly dispersed histologic distribution. Survival of mice bearing intracranial tumors treated with 1D11 neutralizing antibody alone was similar to that of mice treated with control antibody, whereas 1D11 improved survival when given in combination with focal radiation. The extent of survival benefit of a combination of radiation and 1D11 was associated with the degree of TGFβ activity detected by PET.

CONCLUSIONS

This study demonstrates that Zr-fresolimumab PET imaging detects radiation-induced TGFβ activation in tumors. Functional imaging indicated a range of TGFβ activity in intracranial tumors, but TGFβ blockade provided survival benefit only in the context of radiation treatment. This study provides further evidence that radiation-induced TGFβ activity opposes therapeutic response to radiation.

BACKGROUND

Breast cancer treatment is based on estrogen receptors (ERs), progesterone receptors (PRs), and human epidermal growth factor receptor 2 (HER2). At the time of metastasis, receptor status can be discordant from that at initial diagnosis. The purpose of this study was to determine the incidence of discordance and its effect on survival and subsequent treatment in patients with breast cancer brain metastases (BCBM).

METHODS

A retrospective database of 316 patients who underwent craniotomy for BCBM between 2006 and 2017 was created. Discordance was considered present if the ER, PR, or HER2 status differed between the primary tumor and the BCBM.

RESULTS

The overall receptor discordance rate was 132/316 (42%), and the subtype discordance rate was 100/316 (32%). Hormone receptors (HR, either ER or PR) were gained in 40/160 (25%) patients with HR-negative primary tumors. HER2 was gained in 22/173 (13%) patients with HER2-negative primary tumors. Subsequent treatment was not adjusted for most patients who gained receptors-nonetheless, median survival (MS) improved but did not reach statistical significance (HR, 17-28 mo, P = 0.12; HER2, 15-19 mo, P = 0.39). MS for patients who lost receptors was worse (HR, 27-18 mo, P = 0.02; HER2, 30-18 mo, P = 0.08).

CONCLUSIONS

Receptor discordance between primary tumor and BCBM is common, adversely affects survival if receptors are lost, and represents a missed opportunity for use of effective treatments if receptors are gained. Receptor analysis of BCBM is indicated when clinically appropriate. Treatment should be adjusted accordingly.

KEY POINTS

1. Receptor discordance alters subtype in 32% of BCBM patients.2. The frequency of receptor gain for HR and HER2 was 25% and 13%, respectively.3. If receptors are lost, survival suffers. If receptors are gained, consider targeted treatment.