Effects of Wildfire Events on California Radiation Oncology Clinics and Patients.

Purpose: The effect of climate-driven events, such as wildfires, on health care delivery and cancer care is a growing concern. Patients with cancer undergoing radiation therapy are particularly vulnerable to treatment interruptions, which have a direct effect on survival. We report the results of a study characterizing the effect of wildfires on radiation oncology clinics and their patients. Methods and Materials: A survey of California radiation oncologists was used to evaluate emergency preparedness and the effect of wildfires on the delivery of radiation therapy services between 2017 and 2022. Descriptive statistics and Pearson's χ2 tests were performed to investigate potential relationships between provider characteristics, practice settings, and perceptions of the effect of wildfire events. California Department of Forestry and Fire Protection data were employed to map the geographic distribution of wildfires to clinic locations. Results: Response rate was 12.3% (51/415 radiation oncologists), representing 25% of clinics (43/176) in 41% (24/58) of California counties. Sixty-one percent (31/51) of respondents reported being affected by a wildfire, 2 of which are rural clinics (100%, 2/2) and 29 are (59%, 29/49) metropolitan practices. Of these, 18% (9/51) reported a clinic closure, and 29% (15/51) reported staffing shortages. Respondents reported effects on patients, including having to evacuate (55%, 28/51), cancel/reschedule treatments (53%, 27/51), and experiencing physical, mental, or financial hardship due to wildfires (45%, 23/51). Respondents described effects on clinical operations, including being forced to transfer patients (24%, 12/51), transportation interruptions (37%, 19/51), regional/community evacuations (35%, 18/51), and physical/mental health effects (27%, 14/51) on clinic personnel. Less than half of the respondents (47%, 24/51) reported their workplace had a wildfire emergency preparedness plan. Additionally, geographic analysis revealed that 100% (176/176) of clinics were located within 25 miles of a wildfire. Conclusions: This study highlights the effects of wildfires on radiation oncology clinics and patients and underscores the need for emergency preparedness planning to minimize the consequences of such disasters.

Development and clinical implementation of simple needle attachment post placement interstitial template (SNAPP-IT) enabling a shorter, more direct needle path while preserving tumor visualization.

PURPOSE: Historical gynecologic interstitial brachytherapy templates block direct tumor visualization during needle placement, presenting an opportunity for clinical innovation to develop a novel interstitial template allowing direct tumor visualization during needle insertion. METHODS AND MATERIALS: We designed and implemented a novel interstitial template, simple needle attachment post placement interstitial template (SNAPP-IT), that allowed direct visualization of the target vaginal tumor during interstitial needle placement while maintaining the ability to individually secure needles to the template, allow a vaginal cylinder, suture holes for securing to the perineum, MRI compatibility and sterilizable for repeat use. Procedure outcomes including procedure time, needle path lengths, and plan dosimetry were prospectively captured in a patient database. RESULTS: Forty gynecologic interstitial brachytherapy cases were recorded (20 SNAPP-IT, 20 traditional templates). Needle insertion depth was reduced using the SNAPP-IT in comparison with traditional interstitial templates (11.8 cm vs. 3.6 cm, p < 0.0001). The average CTV volume was 25.6 cc for SNAPP-IT and 20.7 cc for traditional; both methods averaged a similar number of needles (15.8, 15.6). Dosimetric constraints were similarly met in both treatment groups. Procedures performed using the SNAPP-IT were shorter compared with those performed with traditional interstitial devices (83.4 minutes vs. 100.7 minutes) and there were no post-operative infections in the SNAPP-IT group. CONCLUSIONS: Implementation of a novel gynecologic interstitial brachytherapy template (SNAPP-IT) reduced procedure times, allowed direct tumor visualization, and decreased needle insertion depth. SNAPP-IT provides a useful alternative approach for vaginal interstitial brachytherapy, may increase brachytherapist efficiency with complex procedures and potentially expands access to interstitial brachytherapy.

SUPPORT: SUrvey of Parental Leave POlicies of RadiaTion Oncology Programs and Residency Applicants.

Purpose: Recruitment to radiation oncology training programs has recently declined, and gender inequities persist in radiation oncology. Policies that promote inclusivity, such as the updated American College of Graduate Medical Education parental leave policy establishing minimum parental leave requirements, may support recruitment to radiation oncology. Methods and Materials: We surveyed 2021-2022 radiation oncology residency applicants and program directors (PDs) about program-specific parental leave policies, transparency of parental leave information during the residency application and interview process, and perceptions of the effect of parenthood on residency training, career advancement, and well-being. Results: Of 89 radiation oncology PDs, 29 (33%) completed the survey. Of 154 residency applicants (current fourth-year medical students, international applicants, or postdoctoral fellows) surveyed, 62 (40%) completed the survey. Most applicants planned to start a family during residency (53%) and reported perceived flexibility to start a family influenced their decision to pursue radiation oncology over other career specialties (55%). Many applicants viewed time in residency (nonresearch, 22%), in research (33%), and as early career faculty (24%) as the best time to start a family. A small number of applicants used program-specific parental leave policy information in determining their rank list (11%), and many applicants sought information regarding fertility health care benefits (55%). Many applicants obtained parental leave information verbally, despite expressing a preference for objective means (slide deck, 63%; website, 50%; or handout, 42%) of information sharing. PDs were all supportive of a 6-week maternity leave policy (100% agree or strongly agree with the policy) and did not feel parental leave would negatively affect a resident's ability to pursue an academic (100%) or private practice career (100%). Conclusions: Many radiation oncology residency applicants plan to start families during training, seek and value program-specific parental leave information and health benefits, and prefer objective means of information sharing. These findings likely reflect those who have strong views of parental leave policies.

Effect of Radiation Schedule on Transportation-Related Carbon Emissions: A Case Study in Rectal Cancer.

Purpose: The health care sector is a major contributor of worldwide greenhouse gas (GHG) emissions. Indirect emissions, including those associated with transportation, make up 82% of the US health care sector's environmental footprint. Radiation therapy (RT) treatment regimens present an opportunity for environmental health care-based stewardship owing to the high incidence of cancer diagnosis, significant utilization of RT, and myriad treatment days required for curative regimens. Because the use of short-course RT (SCRT) in the treatment of rectal cancer has demonstrated noninferior clinical outcomes compared with conventional, long-course RT (LCRT), we investigate the environmental and health equity-related outcomes. Methods and Materials: Patients treated with curative, preoperative RT for newly diagnosed rectal cancer at our institution between 2004 and 2022 and living in-state were included. Travel distance was estimated using patients' reported home address. Associated GHG emissions were calculated and reported in carbon dioxide equivalents (CO2e). Results: Of 334 patients included, the total distance traveled for the treatment course was significantly greater in patients treated with LCRT versus SCRT (median, 1417 vs 319 miles; P < .001). Total CO2e emissions for those undergoing LCRT (n = 261) and SCRT (n = 73) were 665.3 kg CO2e and 149.9 kg CO2e, respectively, per treatment course (P < .001), with a net difference of 515.4 kg CO2e. Relatively, this suggests that LCRT is associated with 4.5 times greater GHG emissions from patient transportation. Conclusions: Using treatment of rectal cancer as proof-of-principle, we advocate for the inclusion of environmental considerations in the creation of climate-resilient oncologic RT practices, especially in the context of equivocal clinical outcomes between RT fractionation schedules.

Long-term Outcomes of Diffuse or Recurrent Tenosynovial Giant Cell Tumor Treated with Postoperative External Beam Radiation Therapy.

PURPOSE: Tenosynovial giant cell tumor (TGCT) is a rare proliferative disorder of synovial membrane that previously was known as pigmented villonodular synovitis. Primary treatment involves surgical resection; however, complete removal of all disease involvement is difficult to achieve. Radiation may be useful to reduce the risk of recurrence. We report and update our institutional experience treating diffuse and recurrent TGCT with postsurgical external beam radiation therapy. METHODS AND MATERIALS: We performed a retrospective chart review of 30 patients with TGCT from 2003 to 2019 treated with radiation therapy. Each patient was evaluated for demographics, radiation treatment parameters, surgical management, complications, and outcome. RESULTS: With mean follow-up of 82 months (range, 3-211), 24 patients (80%) who underwent surgery followed by radiation therapy did not experience any further relapse, and all 30 patients achieved local control (100%) with additional salvage therapy after radiation therapy. The most common site of disease was the knee (n = 22, 73%), followed by the ankle (n = 5, 16%) and the hand (n = 3, 10%). Seven patients (24%) presented at time of initial diagnosis and 23 (76%) presented with recurrent disease after surgical resection, with an average of 2.6 surgical procedures before radiation therapy. After resection, 18 of 30 patients (67%) demonstrated residual TGCT by imaging. The median radiation therapy dose delivered was 36 Gy (range, 34-36 Gy) in 1.8 to 2.5 Gy/fractions for 4 weeks. In the assessment of posttreatment joint function, 26 sites (86%) exhibited excellent or good function, 2 (7%) fair, and 2 poor (7%) as determined by our scoring system. There were no cases of radiation-associated malignancy. CONCLUSIONS: Among patients with diffuse or recurrent TGCT, postsurgical external beam radiation therapy provided excellent local control and good functional status, with minimal treatment-related complications. Postsurgical radiation therapy is a well-tolerated noninvasive treatment that should be considered after maximal cytoreductive resection to prevent disease progression and recurrence.

Paraneoplastic Neurologic Symptoms in a Pediatric Patient with Hodgkin Lymphoma.

Neurological paraneoplastic syndromes are exceedingly rare, and often difficult to recognize clinically. Paraneoplastic achalasia is a condition characterized by new-onset dysphagia that is unrelated to tumor burden, most often due to the development of auto-immune antibodies targeting esophageal tissue. Due to the rarity of this condition, diagnosis is often delayed, leading to increased time to treatment. Here we report a case of a rare paraneoplastic achalasia in a female child with EBV + Hodgkin lymphoma (HL), review literature describing paraneoplastic achalasia, and discuss treatment strategies for improving clinical outcome in these patients.

Intratumoral injection reduces toxicity and antibody-mediated neutralization of immunocytokine in a mouse melanoma model.

BACKGROUND: Some patients with cancer treated with anticancer monoclonal antibodies (mAbs) develop antidrug antibodies (ADAs) that recognize and bind the therapeutic antibody. This response may neutralize the therapeutic mAb, interfere with mAb effector function or cause toxicities. We investigated the potential influence of ADA to modify the tumor-binding capability of a tumor-reactive 'immunocytokine' (IC), namely, a fusion protein (hu14.18-IL2) consisting of a humanized, tumor-reactive, anti-GD2 mAb genetically linked to interleukin 2. We characterize the role of treatment delivery of IC (intravenous vs intratumoral) on the impact of ADA on therapeutic outcome following IC treatments in an established antimelanoma (MEL) regimen involving radiotherapy (RT) +IC. METHODS: C57BL/6 mice were injected with human IgG or the hu14.18-IL2 IC to develop a mouse anti-human antibody (MAHA) response (MAHA+). In vitro assays were performed to assess ADA binding to IC using sera from MAHA+ and MAHA- mice. In vivo experiments assessed the levels of IC bound to tumor in MAHA+ and MAHA- mice, and the influence of IC route of delivery on its ability to bind to B78 (GD2+) MEL tumors. RESULTS: MAHA is inducible in C57BL/6 mice. In vitro assays show that MAHA is capable of inhibiting the binding of IC to GD2 antigen on B78 cells, resulting in impaired ADCC mediated by IC. When B78-bearing mice are injected intravenously with IC, less IC binds to B78-MEL tumors in MAHA+ mice than in MAHA- mice. In contrast, when IC is injected intratumorally in tumor-bearing mice, the presence of MAHA does not detectibly impact IC binding to the tumor. Combination therapy with RT+IT-IC showed improved tumor regression compared with RT alone in MAHA+ mice. If given intratumorally, IC could be safely readministered in tumor-bearing MAHA+ mice, while intravenous injections of IC in MAHA+ mice caused severe toxicity. Histamine levels were elevated in MAHA+ mice compared with MAHA- mice after reintroduction of IC. CONCLUSIONS: Intratumoral injection may be a means of overcoming ADA neutralization of therapeutic activity of tumor-reactive mAbs or ICs and may reduce systemic toxicity, which could have significant translational relevance.

In situ Vaccine Plus Checkpoint Blockade Induces Memory Humoral Response.

In a syngeneic murine melanoma (MEL) model, we recently reported an in situ vaccination response to combined radiation (RT) and intra-tumoral (IT) injection of anti-GD2 hu14. 18-IL2 immunocytokine (IC). This combined treatment resulted in 71% complete and durable regression of 5-week tumors, a tumor-specific memory T cell response, and augmented response to systemic anti-CTLA-4 antibody checkpoint blockade. While the ability of radiation to diversify anti-tumor T cell response has been reported, we hypothesize that mice rendered disease-free (DF) by a RT-based ISV might also exhibit a heightened B cell response. C57BL/6 mice were engrafted with 2 × 106 GD2+ B78 MEL and treated at a target tumor size of ~200 mm3 with 12 Gy RT, IT-IC on day (D)6-D10, and anti-CTLA-4 on D3, 6, and 9. Serum was collected via facial vein before tumor injection, before treatment, during treatment, after becoming DF, and following rejection of subcutaneous 2 × 106 B78 MEL re-challenge on D90. Flow cytometry demonstrated the presence of tumor-specific IgG in sera from mice rendered DF and rejecting re-challenge with B78 MEL at D90 after starting treatment. Consistent with an adaptive endogenous anti-tumor humoral memory response, these anti-tumor antibodies bound to B78 cells and parental B16 cells (GD2-), but not to the unrelated syngeneic Panc02 or Panc02 GD2+ cell lines. We evaluated the kinetics of this response and observed that tumor-specific IgG was consistently detected by D22 after initiation of treatment, corresponding to a time of rapid tumor regression. The amount of tumor-specific antibody binding to tumor cells (as measured by flow MFI) did not correlate with host animal prognosis. Incubation of B16 MEL cells in DF serum, vs. naïve serum, prior to IV injection, did not delay engraftment of B16 metastases and showed similar overall survival rates. B cell depletion using anti-CD20 or anti-CD19 and anti-B220 did not impact the efficacy of ISV treatment. Thus, treatment with RT + IC + anti-CTLA-4 results in adaptive anti-tumor humoral memory response. This endogenous tumor-specific antibody response does not appear to have therapeutic efficacy but may serve as a biomarker for an anti-tumor T cell response.

Protective Epitope Discovery and Design of MUC1-based Vaccine for Effective Tumor Protections in Immunotolerant Mice.

Human mucin-1 (MUC1) is a highly attractive antigen for the development of anticancer vaccines. However, in human clinical trials of multiple MUC1 based vaccines, despite the generation of anti-MUC1 antibodies, the antibodies often failed to exhibit much binding to tumor presumably due to the challenges in inducing protective immune responses in the immunotolerant environment. To design effective MUC1 based vaccines functioning in immunotolerant hosts, vaccine constructs were first synthesized by covalently linking the powerful bacteriophage Qß carrier with MUC1 glycopeptides containing 20-22 amino acid residues covering one full length of the tandem repeat region of MUC1. However, IgG antibodies elicited by these first generation constructs in tolerant human MUC1 transgenic (Tg) mice did not bind tumor cells strongly. To overcome this, a peptide array has been synthesized. By profiling binding selectivities of antibodies, the long MUC1 glycopeptide was found to contain immunodominant but nonprotective epitopes. Critical insights were obtained into the identity of the key protective epitope. Redesign of the vaccine focusing on the protective epitope led to a new Qß-MUC1 construct, which was capable of inducing higher levels of anti-MUC1 IgG antibodies in MUC1.Tg mice to react strongly with and kill a wide range of tumor cells compared to the construct containing the gold standard protein carrier, i.e., keyhole limpet hemocyanin. Vaccination with this new Qß-MUC1 conjugate led to significant protection of MUC1.Tg mice in both metastatic and solid tumor models. The antibodies exhibited remarkable selectivities toward human breast cancer tissues, suggesting its high translational potential.

Combining brachytherapy and immunotherapy to achieve in situ tumor vaccination: A review of cooperative mechanisms and clinical opportunities.

As immunotherapies continue to emerge as a standard component of treatment for a variety of cancers, the imperative for testing these in combination with other standard cancer therapies grows. Radiation therapy may be a particularly well-suited partner for many immunotherapies. By modulating immune tolerance and functional immunogenicity at a targeted tumor site, radiation therapy may serve as a method of in situ tumor vaccination. In situ tumor vaccination is a therapeutic strategy that seeks to convert a patient's own tumor into a nidus for enhanced presentation of tumor-specific antigens in a way that will stimulate and diversify an antitumor T cell response. The mechanisms whereby radiation may impact immunotherapy are diverse and include its capacity to simultaneously elicit local inflammation, temporary local depletion of suppressive lymphocyte lineages, enhanced tumor cell susceptibility to immune response, and immunogenic tumor cell death. Emerging data suggest that each of these mechanisms may display a distinct dose-response profile, making it challenging to maximize each of these effects using external beam radiation. Conversely, the highly heterogenous and conformal dose distribution achieved with brachytherapy may be optimal for enhancing the immunogenic capacity of radiation at a tumor site while minimizing off-target antagonistic effects on peripheral immune cells. Here, we review the immunogenic effects of radiation, summarize the clinical rationale and data supporting the use of radiation together with immunotherapies, and discuss the rationale and urgent need for further preclinical and clinical investigation specifically of brachytherapy in combination with immunotherapies. Harnessing these immunomodulatory effects of brachytherapy may offer solutions to overcome obstacles to the efficacy of immunotherapies in immunologically "cold" tumors while potentiating greater response in the context of immunologically "hot" tumors.

Antitumor Humoral and T Cell Responses by Mucin-1 Conjugates of Bacteriophage Qß in Wild-type Mice.

Mucin-1 (MUC1) is one of the top ranked tumor associated antigens. In order to generate effective anti-MUC1 immune responses as potential anticancer vaccines, MUC1 peptides and glycopeptides have been covalently conjugated to bacteriophage Qß. Immunization of mice with these constructs led to highly potent antibody responses with IgG titers over one million, which are among the highest anti-MUC1 IgG titers reported to date. Furthermore, the high IgG antibody levels persisted for more than six months. The constructs also elicited MUC1 specific cytotoxic T cells, which can selectively kill MUC1 positive tumor cells. The unique abilities of Qß-MUC1 conjugates to powerfully induce both antibody and cytotoxic T cell immunity targeting tumor cells bode well for future translation of the constructs as anticancer vaccines.

Chemical Synthesis of GM2 Glycans, Bioconjugation with Bacteriophage Qß, and the Induction of Anticancer Antibodies.

The development of carbohydrate-based antitumor vaccines is an attractive approach towards tumor prevention and treatment. Herein, we focused on the ganglioside GM2 tumor-associated carbohydrate antigen (TACA), which is overexpressed in a wide range of tumor cells. GM2 was synthesized chemically and conjugated with a virus-like particle derived from bacteriophage Qß. Although the copper-catalyzed azide-alkyne cycloaddition reaction efficiently introduced 237 copies of GM2 per Qß, this construct failed to induce significant amounts of anti-GM2 antibodies compared to the Qß control. In contrast, GM2 immobilized on Qß through a thiourea linker elicited high titers of IgG antibodies that recognized GM2-positive tumor cells and effectively induced cell lysis through complement-mediated cytotoxicity. Thus, bacteriophage Qß is a suitable platform to boost antibody responses towards GM2, a representative member of an important class of TACA: the ganglioside.

Significant Impact of Immunogen Design on the Diversity of Antibodies Generated by Carbohydrate-Based Anticancer Vaccine.

Development of an effective vaccine targeting tumor associated carbohydrate antigens (TACAs) is an appealing approach toward tumor immunotherapy. While much emphasis has been typically placed on generating high antibody titers against the immunizing antigen, the impact of immunogen design on the diversity of TACA-specific antibodies elicited has been overlooked. Herein, we report that the immunogen structure can significantly impact the breadth and the magnitude of humoral responses. Vaccine constructs that induced diverse TACA-binding antibodies provided much stronger recognition of a variety of Tn positive tumor cells. Optimization of the breadth of the antibody response led to a vaccine construct that demonstrated long lasting efficacy in a mouse tumor model. After challenged with the highly aggressive TA3Ha cells, mice immunized with the new construct exhibited a statistically significant improvement in survival relative to controls (0% vs 50% survival; p < 0.0001). Furthermore, the surviving mice developed long-term immunity against TA3Ha. Thus, both the magnitude and the breadth of antibody reactivity should be considered when designing TACA-based antitumor vaccines.