Tumor-associated mononuclear cells in the tumor bed of triple-negative breast cancer associate with clinical outcomes in the post-neoadjuvant chemotherapy setting.

PURPOSE: To evaluate the clinical role of tumor-associated macrophages, including foamy (FM) and hemosiderin-laden macrophages (HLM) in the tumor bed (TB) of triple-negative breast cancer (TNBC) post-neoadjuvant chemotherapy (NACT). METHODS: We conducted a pathologic review of 129 women, diagnosed with TNBC between 2002 and 2016 at our institute. The residual cancer burden (RCB) was calculated. We estimated the percentage of tumor-infiltrating lymphocytes (TILs) in the core needle biopsy (CNB), and FM, HLM, and TILs (in TB) [the combined cells are designated as tumor-associated mononuclear cells (TAMNC)]. The information on patient demographics, chemotherapy regimen, recurrence-free survival (RFS), and overall survival (OS) was extracted from the medical records. RESULTS: Pathologic complete response (pCR) was achieved in 34.1% of the women. TILs (10% increment in CNB) only were associated with pCR in the multivariable analysis [odds ratio 1.04 (1.02, 1.06) (p = 0.0003)]. Immune cells associated with better OS included TAMNC (≤ 30%) [hazard ratio (HR) 4.32 (1.93, 9.66) (p = 0.0004)], and FM (0%) [HR 2.30 (1.06, 4.98) (p = 0.036)]. While increased HLM (10% increment) was statistically significant with HR 0.93 and 95% CI (0.88 to 0.98) (p = 0.0061), using a cutoff of 0%, HLM (0%: negative vs. ≥ 1%: positive) achieved only borderline significance with HR 2.05 (0.98, 4.31) (p = 0.058). Similarly, these immune cells were also associated with better RFS: TAMNC (≤ 30%) [HR 4.57 (2.04, 10.21) (p = 0.0002)], FM (0%) [HR 2.80 (1.23, 6.35) (p = 0.014)], and HLM (0%) [HR 2.34 (1.07, 5.11) (p = 0.03)]. TILs (in TB) were not associated with any clinical outcomes. CONCLUSIONS: Although TILs may play a role in the response to NACT, they may not be critical to the prognosis after NACT. Instead, FM and HLM may assume this role. More studies are warranted.

The Advantage of Proton Therapy in Hypothalamic-Pituitary Axis and Hippocampus Avoidance for Children with Medulloblastoma.

PURPOSE: Craniospinal irradiation (CSI) improves clinical outcomes at the cost of long-term neuroendocrine and cognitive sequelae. The purpose of this pilot study was to determine whether hypothalamic-pituitary axis (HPA) and hippocampus avoidance (HPA-HA) with intensity-modulated proton therapy (IMPT) can potentially reduce this morbidity compared with standard x-ray CSI. MATERIALS AND METHODS: We retrospectively evaluated 10 patients with medulloblastoma (mean, 7 years; range, 4-14 years). Target volumes and organs at risk were delineated as per our local protocol and the ACNS0331 atlas. An experienced neuroradiologist verified the HPA and hippocampus contours. The primary objective was CSI and boost clinical target volume (CTV) covering 95% of the volume (D95) > 99% coverage with robustness. Described proton therapy doses in grays are prescribed using a biological effectiveness relative to photon therapy of 1.1. The combined prescribed dose in the boost target was 54 Gy. Secondary objectives included the HPA and hippocampus composite average dose (Dmean ≤ 18 Gy). For each patient, volumetric modulated arc radiotherapy (VMAT) and tomotherapy (TOMO) plans existed previously, and a new plan was generated with 3 cranial and 1 or 2 spinal beams for pencil-beam scanning delivery. Statistical comparison was performed with 1-way analysis of variance. RESULTS: Compared with standard CSI, HPA-HA CSI had statistically significant decreases in the composite doses received by the HPA (32.2 versus 17.9 Gy; P < .001) and hippocampi (39.8 versus 22.8 Gy; P < .001). The composite HPA Dmean was lower in IMPT plans (17.9 Gy) compared with that of VMAT (21.8 Gy) and TOMO (21.2 Gy) plans (P = .05). Hippocampi composite Dmean was also lower in IMPT plans (21 Gy) compared with that of VMAT (27.5 Gy) and TOMO (27.2 Gy) plans (P = .02). The IMPT CTV D95 coverage was lower in IMPT plans (52.8 Gy) compared with that of VMAT (54.6 Gy) and TOMO (54.6 Gy) plans (P < .001) The spared mean volume was only 1.35% (19.8 cm3) of the whole-brain CTV volume (1476 cm3). CONCLUSION: We found that IMPT has the strong potential to reduce the dose to the HPA and hippocampus, compared with standard x-ray CSI while maintaining target coverage. A prospective clinical trial is required to establish the safety, efficacy, and toxicity of this novel CSI approach.

Intensity-Modulated Proton Therapy for Nasopharynx Cancer: 2-year Outcomes from a Single Institution.

PURPOSE: Advances in radiotherapy have improved tumor control and reduced toxicity in the management of nasopharyngeal carcinoma (NPC). Local failure remains a problem for some patients with advanced primary tumors, and toxicities are significant given the large treatment volume and tumor proximity to critical structures, even with modern photon-based radiotherapy. Proton therapy has unique dosimetric advantages, and recent technological advances now allow delivery of intensity-modulated proton therapy (IMPT), which can potentially improve the therapeutic ratio in NPC. We report our 2-year clinical outcomes with IMPT for NPC. MATERIALS AND METHODS: We retrospectively reviewed treatment records of patients with NPC treated with IMPT at our center. Demographics, dosimetry, tumor response, local regional control (LRC), distant metastasis, overall survival, and acute and late toxicity outcomes were reviewed. Analyses were performed with descriptive statistics and Kaplan-Meier method. Toxicity was graded per Common Terminology Criteria for Adverse Events (version 4.0). RESULTS: Twenty-six patients were treated from 2015 to 2020. Median age was 48 years (range, 19-73 years), 62% (n = 16) had T3-T4 disease, 92% (n = 24) were node positive, 92% (n = 24) had stage III-IV disease, and 69% (n = 18) had positive results for Epstein-Barr virus. Dose-painted pencil-beam IMPT was used. Most patients (85%; 22 of 26) were treated with 70 Gy(RBE) in 33 fractions once daily; 4 (15%) underwent hyperfractionated accelerated treatment twice daily. All received concurrent cisplatin chemotherapy; 7 (27%) also received induction chemotherapy. All patients (100%) completed the planned radiotherapy, and no acute or late grade 4 or 5 toxicities were observed. At median follow-up of 25 months (range, 4-60), there were 2 local regional failures (8%) and 3 distant metastases (12%). The Kaplan-Meier 2-year LRC, freedom from distant metastasis, and overall survival were 92%, 87%, and 85% respectively. CONCLUSION: IMPT is feasible in locally advanced NPC with early outcomes demonstrating excellent LRC and favorable toxicity profile. Our data add to the growing body of evidence supporting the clinical use of IMPT for NPC.

A Combined Neutron and Proton Regimen for Advanced Salivary Tumors: Early Clinical Experience.

Background and objective  Fast neutron radiotherapy (NRT) is a high linear energy transfer (LET) particle therapy that offers a local control (LC) advantage over low-LET X-rays in the treatment of advanced and unresectable salivary gland malignancies. However, in tumors approximating the base of skull (BOS), target volumes may be underdosed to minimize toxicity to the central nervous system (CNS). In this setting, a proton beam boost to the underdosed part of the tumor may improve LC. We report our early experience with a hybrid neutron-proton approach in patients with BOS involvement. Materials and methods We retrospectively reviewed 29 patients with locally advanced and unresectable salivary gland tumors involving the BOS between 2014-2018. The median age of the patients was 56 years, with the majority of them having adenoid cystic carcinomas (ACC) (79%) with advanced T4a/b disease (86%), pathologic perineural invasion (PNI) (55.2%), and orbital invasion (34.5%). Five patients (17.2%) were cases of re-irradiation. Surgical resection was attempted in 15 patients (51.7%), of which none achieved negative margins. The median neutron dose was 18.4 neutron Gray (nGy) with a sequential proton boost (PB) with a median dose of 25 Gy [relative biological effectiveness (RBE)] (range: 16-45 Gy). Toxicity was graded per the Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. Descriptive statistics and the Kaplan-Meier method were used. Results At a median follow-up of 18.9 months [interquartile range (IQR): 6.1-32.5], the entire cohort's overall survival (OS) was 93.1%, progression-free survival (PFS) was 79.3%, and LC was 89.7%. Among patients who were not re-irradiated (n=24), the most commonly recorded acute grade 3 toxicities were mucositis (50%) and dermatitis (37.5%). There was no documented acute grade 4/5 events. Late grade 3/4 events included trismus (n=1), hearing loss (n=2), visual loss (n=6), and bone necrosis (n=1). There were no reported late grade 5 events in de novo patients. Conclusion In this challenging cohort with a poor prognosis, early outcomes for a hybrid neutron-proton approach were found to be promising. Further studies involving longer follow-ups with a larger cohort of patients are required to validate our findings.

Radiation-induced brain injury in patients with meningioma treated with proton or photon therapy.

INTRODUCTION: Radiation therapy is often used to treat meningioma with adverse features or when unresectable. Proton therapy has advantages over photon therapy in reducing integral dose to the brain. This study compared the incidence of radiological and clinical adverse events after photon versus proton therapy in the treatment of meningioma. METHODS: A retrospective review was conducted on patients with meningioma treated with proton or photon therapy at two high-volume tertiary cancer centers. Patients with a history of prior radiation therapy (RT) or less than 3 months of follow-up were excluded. Post-RT imaging changes were categorized into abnormal T2 signal intensities (T2 changes) or abnormal T1 post-contrast and T2 signal intensities (T1c+T2 changes) on magnetic resonance imaging (MRI). Clinical outcomes of adverse events and survival were compared between the proton and photon therapies. RESULTS: Among the total of 77 patients, 38 patients received proton therapy and 39 patients received photon therapy. The median age at diagnosis was 55 years and median follow-up was 2.2 years. No significant differences in symptomatic adverse events were observed between the two groups: grade ≥ 2 adverse events were seen in 4 (10.5%) patients in the proton group and 3 (7.7%) patients in the photon group (p = 0.67). The 2-year cumulative incidences of T2 changes were 38.3% after proton therapy and 47.7% after photon therapy (p = 0.53) and the 2-year cumulative incidences of T1c+T2 changes were 26.8% after proton therapy and 5.3% after photon therapy (p = 0.02). One patient experienced grade ≥ 4 adverse event in each group (p = 0.99). Estimated 2-year progression-free survival was 79.5% (proton therapy 76.0% vs. photon therapy 81.3%, p = 0.66) and 2-year overall survival was 89.7% (proton therapy 86.6% vs. photon therapy 89.3%, p = 0.65). CONCLUSIONS: Following RT, high rates of T2 changes were seen in meningioma patients regardless of treatment modality. Proton therapy was associated with significantly higher rates of T1c+T2 changes compared with photon therapy, but severe adverse events were uncommon in both groups and survival outcomes were comparable between the two groups. Future studies will aim at correlating the MRI changes with models that can be incorporated into RT planning to avoid toxicity.

A Dose-Response Relationship to Radiotherapy for Cutaneous Lesions of Langerhans Cell Histiocytosis.

Langerhans cell histiocytosis (LCH) is a rare disease, afflicting approximately 4.6 and 1-2 per 1 million children and adults, respectively. While LCH can involve numerous organ systems such as the lung or bone, it is uncommon for the disease to be limited to the skin. Radiotherapy has an established role for osseous lesions. However, the efficacy and dose for nonosseous manifestations of the disease are not well described. In the current case report, we detail a 49-year-old adult male with skin-limited LCH requiring palliative radiotherapy (RT) to numerous sites for pain control. The patient was initially diagnosed and treated with single agent cytarabine for approximately 6 months. Despite treatment, he had little symptomatic response of his cutaneous lesions. We delivered a single dose of 8 Gray (Gy) to 3 separate skin lesions, including the bilateral groin, right popliteal region, and right axillary lesion, which resulted in pain reduction and partial response at four-month follow-up. Subsequently, we decided to treat the left axillary untreated lesion to a higher dose of 24 Gy in 12 fractions. At four-month follow-up, the left axilla RT resulted in complete clinical response and improved pain control compared to the right axilla. Following RT treatments, the patient was found to have a BRAF mutation, and vemurafenib was initiated. Further follow-up with positron emissions tomography demonstrated complete metabolic response in numerous disease areas, including both axillae. Based on this case report's findings, a higher radiotherapy dose may be more effective for treating cutaneous LCH.

Proton Therapy for Locally Advanced Oropharyngeal Cancer: Initial Clinical Experience at the University of Washington.

PURPOSE: Proton therapy can potentially improve the therapeutic ratio over conventional radiation therapy for oropharyngeal squamous cell cancer (OPSCC) by decreasing acute and late toxicity. We report our early clinical experience with intensity-modulated proton therapy (IMPT). MATERIALS AND METHODS: We retrospectively reviewed patients with OPSCC treated with IMPT at our center. Endpoints include local regional control (LRC), progression-free survival (PFS), overall survival (OS), tumor response, and toxicity outcomes. Toxicity was graded as per the Common Terminology Criteria for Adverse Events v4.03. Descriptive statistics and Kaplan-Meier method were used. RESULTS: We treated 46 patients from March 2015 to August 2017. Median age was 58 years, 93.5% were male, 67% were nonsmokers, 98% had stage III-IVB disease per the 7th edition of the AJCC [American Joint Committee on Cancer] Cancer Staging Manual, and 89% were p16 positive. Twenty-eight patients received definitive IMPT to total dose of 70 to 74.4 Gy(RBE), and 18 patients received postoperative IMPT to 60 to 66 Gy(RBE) following transoral robotic surgery (TORS). Sixty-four percent of patients received concurrent systemic therapy. There were no treatment interruptions or observed acute grade 4 or 5 toxicities. Eighteen patients had percutaneous endoscopic gastrostomy (PEG) tube placement; the majority (14) were placed prophylactically. The most common grade 3 acute toxicities were dermatitis (76%) and mucositis (72%). The most common late toxicity was grade 2 xerostomia (30%). At a median follow-up time of 19.2 months (interquartile range [IQR], 11.2-28.4), primary complete response was 100% and nodal complete response was 92%. One patient required a salvage neck dissection owing to an incomplete response at 4 months. There were no recorded local regional or marginal recurrences, PFS was 93.5%, and OS was 95.7%. CONCLUSION: Our early results for IMPT in OPSCC are promising with no local regional or marginal recurrences and a favorable toxicity profile. Our data add to a body of evidence that supports the clinical use of IMPT. Randomized comparative trials are encouraged.

Functional cranio-spinal irradiation: A hippocampal and hypothalamic-pituitary axis sparing radiation technique using two IMRT modalities.

Cranio-spinal irradiation (CSI) treatment of embryonal tumors is associated with long-term endocrine and neuro-cognitive sequelae. As an example, the radiation regiment for standard risk medulloblastoma is 23.4 Grays (Gy) CSI followed by a boost of 30.6Gy to the tumor bed. We hypothesize that a novel CSI technique, which we named "Functional" CSI (F-CSI) can reduce the dose to the hypothalamic-pituitary axis (HPA) and hippocampi compared to standard CSI (S-CSI) without sacrificing coverage. In this study, we compared the efficacy of Volumetric Modulated Arc Therapy (VMAT) and Helical Tomotherapy (HT) in delivering this novel CSI technique. Plans were constructed from 10 patients with embryonal tumors previously treated at our institution. Target volumes and organs at risk were delineated as per our local protocol and the ACNS0331 Atlas. The HPA and hippocampi contours were verified by an experienced neuro-radiologist. Primary objective was to achieve a D95% to the prescribed dose of 23.4Gy for CSI and 30.6Gy for the boost. Dmean ≤18Gy was assigned to the HPA and hippocampi. A two-sided t-test was used for comparison. F-CSI in both modalities were able to achieve the D95% target coverage. Hot spots (D2%) were lower with HT for both the CSI component (p = 0.03) and boost component (p < 0.01). VMAT was able to achieve better conformality (p < 0.01). Compared to S-CSI, both F-CSI modalities were able to achieve a significant decrease in dose to the HPA and Hippocampi. The average S-CSI HPA and Hippocampi Dmean were 23.9Gy and 23.8Gy. In contrast, respective F-CSI Dmean were 13.9Gy and 17.2Gy in VMAT and 15Gy and 15.9Gy in HT. The average composite (F-CSI plus boost) Dmean to the HPA and hippocampi often exceeded 18Gy. Compared to S-CSI, F-CSI with VMAT and HT were capable of achieving acceptable coverage while sparing the HPA and hippocampi. However, the addition of the boost component often exceeded the mean dose of 18Gy. This may be overcome with more conformal modalities for the boost phase such as stereotactic radiotherapy or proton therapy.

Clinical Monte Carlo versus Pencil Beam Treatment Planning in Nasopharyngeal Patients Receiving IMPT.

PURPOSE: Pencil beam (PB) analytical algorithms have been the standard of care for proton therapy dose calculations. The introduction of Monte Carlo (MC) algorithms may provide more robust and accurate planning and can improve therapeutic benefit. We conducted a dosimetric analysis to quantify the differences between MC and PB algorithms in the clinical setting of dose-painted nasopharyngeal cancer intensity-modulated proton radiotherapy. PATIENTS AND METHODS: Plans of 14 patients treated with PB analytical algorithm optimized and calculated (PBPB) were retrospectively analyzed. The PBPB plans were recalculated using MC to generate PBMC plans and, finally, reoptimized and recalculated with MC to generate MCMC plans. The plans were compared across several dosimetric endpoints and correlated with documented toxicity. Robustness of the planning scenarios (PBPB, PBMC, MCMC) in the presence of setup and range uncertainties was compared. RESULTS: A median decrease of up to 5 Gy (P < .05) was observed in coverage of planning target volume high-risk, intermediate-risk, and low-risk volumes when PB plans were recalculated using the MC algorithm. This loss in coverage was regained by reoptimizing with MC, albeit with a slightly higher dose to normal tissues but within the standard tolerance limits. The robustness of both PB and MC plans remained similar in the presence of setup and range uncertainties. The MC-calculated mean dose to the oral avoidance structure, along with changes in global maximum dose between PB and MC dosimetry, may be associated with acute toxicity-related events. CONCLUSION: Retrospective analyses of plan dosimetry quantified a loss of coverage with PB that could be recovered under MC optimization. MC optimization should be performed for the complex dosimetry in patients with nasopharyngeal carcinoma before plan acceptance and should also be used in correlative studies of proton dosimetry with clinical endpoints.

Comparison of four techniques for spine stereotactic body radiotherapy: Dosimetric and efficiency analysis.

PURPOSE: The aim of this study is to compare the dosimetric differences between four techniques for spine stereotactic body radiotherapy (SBRT): CyberKnife (CK), volumetric modulated arc therapy (VMAT), and helical tomotherapy (HT) with dynamic jaws (HT-D) and fixed jaws (HT-F). MATERIALS/METHODS: Data from 10 patients were utilized. All patients were planned for 24 Gy in two fractions, with the primary objectives being: (a) restricting the maximum dose to the cord to ≤ 17 Gy and/or cauda equina to ≤ 20 Gy, and (b) to maximize the clinical target volume (CTV) to receive the prescribed dose. Treatment plans were generated by separate dosimetrists and then compared using velocity AI. Parameters of comparison include target volume coverage, conformity index (CI), gradient index (GI), homogeneity index (HI), treatment time (TT) per fraction, and monitor units (MU) per fraction. RESULTS: PTV D2 and D5 were significantly higher for CK compared to VMAT, HT-F, and HT-D (P < 0.001). The average volume of CTV receiving the prescription dose (CTV D95) was significantly less for VMAT compared to CK, HT-F and HT-D (P = 0.036). CI improved for CK (0.69), HT-F (0.66), and HT-D (0.67) compared to VMAT (0.52) (P = 0.013). CK (41.86) had the largest HI compared to VMAT (26.99), HT-F (20.69), and HT-D (21.17) (P < 0.001). GI was significantly less for CK (3.96) compared to VMAT (6.76) (P = 0.001). Likewise, CK (62.4 min, 14059 MU) had the longest treatment time and MU per fraction compared to VMAT (8.5 min, 9764 MU), HT-F (13 min, 10822 MU), and HT-D (13.5 min, 11418 MU) (P < 0.001). CONCLUSION: Both CK and HT plans achieved conformal target coverage while respecting cord tolerance. Dose heterogeneity was significantly larger in CK. VMAT required the least treatment time and MU output, but had the least steep GI, CI, and target coverage.

Effects on duration of post-operative ischemia and patterns of blood flow recovery in different conditions of mouse hind limb ischemia.

BACKGROUND: Current limitations to the experimentation on patients with peripheral arterial disease push the development of different preclinical strategies. We investigated both duration of ischemia and blood flow recovery in mouse models of partial femoral artery ligation. METHODS: Male BALB/c mice were used. The ligation over needle method involved placing a suture needle over the femoral artery, ligating over it and then removing the needle. The transfixation method involved transfixing the approximate center of the femoral artery and then tying the suture. Laser Doppler Perfusion Imaging was used to assess perfusion every 3rd day until 42 days after the procedure. RESULTS: Ligation over needle method: Immediately post procedure, mean perfusion was -71.87% ± 4.43. Then mean difference in perfusion remained below the base line reading on days 3, 6, 9, and 12. From day 15 on wards mean perfusion progressively improved remaining near base line. Transfixation Method: Immediately post procedure mean perfusion was -70.82% ± 4.73. Mean perfusion improved following the procedure on days 3 and 6; a plateau followed this on days 9, 12 and 15. From day 15 onwards perfusion progressively improved remaining well below base line until crossing it on day 36. CONCLUSION: The currently described models do not pose major improvements over previously described methods.