Biological effects of intraoperative radiation therapy: histopathological changes and immunomodulation in breast cancer patients.

Introduction: Intraoperative radiation therapy (IORT) delivers a single accelerated radiation dose to the breast tumor bed during breast-conserving surgery (BCS). The synergistic biologic effects of simultaneous surgery and radiation remain unclear. This study explores the cellular and molecular changes induced by IORT in the tumor microenvironment and its impact on the immune response modulation. Methods: Patients with hormone receptor (HR)-positive/HER2-negative, ductal carcinoma in situ (DCIS), or early-stage invasive breast carcinoma undergoing BCS with margin re-excision were included. Histopathological evaluation and RNA-sequencing in the re-excision tissue were compared between patients with IORT (n=11) vs. non-IORT (n=11). Results: Squamous metaplasia with atypia was exclusively identified in IORT specimens (63.6%, p=0.004), mimicking DCIS. We then identified 1,662 differentially expressed genes (875 upregulated and 787 downregulated) between IORT and non-IORT samples. Gene ontology analyses showed that IORT was associated with the enrichment of several immune response pathways, such as inflammatory response, granulocyte activation, and T-cell activation (p<0.001). When only considering normal tissue from both cohorts, IORT was associated with intrinsic apoptotic signaling, response to gamma radiation, and positive regulation of programmed cell death (p<0.001). Using the xCell algorithm, we inferred a higher abundance of γδ T-cells, dendritic cells, and monocytes in the IORT samples. Conclusion: IORT induces histological changes, including squamous metaplasia with atypia, and elicits molecular alterations associated with immune response and intrinsic apoptotic pathways. The increased abundance of immune-related components in breast tissue exposed to IORT suggests a potential shift towards active immunogenicity, particularly immune-desert tumors like HR-positive/HER2-negative breast cancer.

Does Residual Invasive Disease in Wide Local Excision after Diagnosis with Partial Biopsy Technique Influence Survival in Melanoma? Matched-Pair Analysis of Multicenter Selective Lymphadenectomy Trial I and II.

BACKGROUND: Current guidelines recommend excisional/complete biopsy for melanoma diagnosis, owing to high rates of residual disease found at wide local excision (WLE) after partial biopsy techniques. We sought to determine any survival disadvantage associated with the presence of residual invasive melanoma in the WLE after diagnosis with a partial biopsy technique. STUDY DESIGN: Data were examined from Multicenter Selective Lymphadenectomy Trials I and II (MSLT-I and -II), 2 large melanoma trials. Patients diagnosed with excisional/complete biopsy were excluded. Clinicopathologic characteristics, melanoma-specific survival (MSS), distant disease-free survival (DDFS), and disease-free survival (DFS) of those with residual invasive melanoma in the definitive WLE and those with no residual melanoma were compared. Matched pairing was used to reduce variability between groups. RESULTS: From 1994 through 2014, 3,939 patients were enrolled in these trials and 874 (22%) were diagnosed using partial biopsy techniques. Of these, 399 (46%) had residual tumor in the WLE. Only 6 patients had residual tumor in their WLE resulting in T-upstaging of their tumor. Match-pairing formed two cohorts (1:1) of patients with and without residual invasive tumor after WLE. A total of 514 patients were paired; 288 (56%) males, 148 (28.8%) aged 60 or older, 192 (37.4%) with truncal melanomas, 214 (41.6%) had Breslow thickness 2 mm or greater, and 376 (73.2%) had positive sentinel nodes. Kaplan-Meier analysis showed no statistical difference in 10-year MSS (73.6% ± 3.3% vs 73.9% ± 3.7%, p = 0.891), DDFS (68.7% ± 3.4% vs 65.3% ± 4.0%, p = 0.548), or DFS (59.6% ± 3.7% vs 59.4% ± 3.9%, p = 0.783). CONCLUSIONS: Survival in patients with primary melanoma does not appear to be worse in patients who undergo a partial biopsy technique and are later found to have residual invasive tumor in the WLE specimen.

Nasal septal perforation from bevacizumab: a discussion of outcomes, management, and pharmacovigilance.

To date, the published literature describes 18 reports of nasal septal perforation in cancer patients with the administration of bevacizumab. This complication was detected during post-marketing surveillance of bevacizumab. How should patients who develop this complication be managed? This discussion summarizes suggestions for management of bevacizumab-associated nasal septal perforation and, as relevant to healthcare providers, discusses some of the practical aspects of post-marketing pharmacovigilance.

Bevacizumab-induced nasal septal perforation: incidence of symptomatic, confirmed event(s) in colorectal cancer patients.

PURPOSE: In breast cancer patients, Mailliez and others described that 5 of 70 patients (7%) developed a bevacizumab-induced nasal septal perforation. However, to date, no studies have reported such rates in colorectal cancer patients, who derive a survival advantage with this drug. METHODS: This study examined the incidence of bevacizumab-induced, clinically symptomatic, otolaryngology specialist-confirmed nasal septal perforation among 100 patients who had been consecutively-treated for metastatic colorectal cancer. RESULTS: The incidence of nasal septal perforation was 1% (95% confidence intervals: -0.95% to 2.95%). This single adverse event was successfully managed conservatively. Within the whole group, 94 had been treated with bevacizumab at 5 mg/kg every two weeks, except for four patients treated at higher doses. The median number of bevacizumab doses (range) was seven (1-96). Concomitant chemotherapy had been prescribed to all patients, consisting of oxaliplatin, 5-fluorouracil, leucovorin, as per one of the FOLFOX regimens (44 patients); irinotecan, 5-fluorouracil, leucovorin, as per the FOLFIRI regimen (13 patients); both these regimens and no other (five patients); or a different regimen (38 patients). CONCLUSION: Nasal septal perforation from bevacizumab occurs infrequently among colorectal cancer patients.