Role of HIF-1α in the Responses of Tumors to Radiotherapy and Chemotherapy.

Tumor microenvironment is intrinsically hypoxic with abundant hypoxia-inducible factors-1α (HIF-1α), a primary regulator of the cellular response to hypoxia and various stresses imposed on the tumor cells. HIF-1α increases radioresistance and chemoresistance by reducing DNA damage, increasing repair of DNA damage, enhancing glycolysis that increases antioxidant capacity of tumors cells, and promoting angiogenesis. In addition, HIF-1α markedly enhances drug efflux, leading to multidrug resistance. Radiotherapy and certain chemotherapy drugs evoke profound anti-tumor immunity by inducing immunologic cell death that release tumor associated antigens together with numerous pro-immunological factors, leading to priming of cytotoxic CD8+ T cells and enhancing the cytotoxicity of macrophages and NK cells. Radiotherapy and chemotherapy of tumors significantly increase HIF-1α activity in tumor cells. Unfortunately, HIF-1α effectively promotes various immune suppressive pathways including secretion of immune suppressive cytokines, activation of myeloid-derived suppressor cells (MIDSCs), activation of regulatory T cells (Tregs), inhibition of T cells priming and activity, and upregulation of immune checkpoints. Consequently, the anti-tumor immunity elevated by radiotherapy and chemotherapy is counterbalanced or masked by the potent immune suppression promoted by HIF-1α. Effective inhibition of HIF-1α may significantly increase the efficacy of radiotherapy and chemotherapy by increasing radiosensitivity and chemosensitivity of tumor cells and also by upregulating anti-tumor immunity.

A Patient-Specific correspondence model to track tumor location in thorax during radiation therapy.

PURPOSE: We present a patient-specific model to estimate tumor location in the thorax during radiation therapy using chest surface displacement as the surrogate signal. METHODS: Two types of data are used for model construction: Four-dimensional computed tomography (4D-CT) images of the patient and the displacement of two points on the patient's skin on the thoracic area. Principal component analysis is used to fit the correspondence model. This model incorporates the recorded surrogate signals during radiation delivery as input and delivers the 3D trajectory of the tumor as output. We evaluated the accuracy of the proposed model on a respiratory phantom and five lung cancer patients. RESULTS: For the respiratory phantom, the location of the center of the sphere during treatment was calculated in three directions: Left-Right (LR), Anterior-Posterior (AP) and, Superior-Inferior (SI). The error of localization was less than 1 mm in the LR and AP directions and less than 2 mm in the SI direction. The location of the tumor center for two of the patients, and the location of the apex of the diaphragm for the other three, was calculated in three directions. For all patients, the localization error in the LR and AP directions was less than 1.1 mm for two fractions and the maximum localization error in the SI direction was 6.4 mm. CONCLUSIONS: This work presents a feasibility study of utilizing surface displacement data to locate the tumor in the thorax during radiation treatment. Future work will validate the model on a larger patient population.

Comparison of peripheral leukocyte parameters in patients receiving conventionally and hypofractionated radiotherapy schemes for the treatment of newly diagnosed glioblastoma.

Introduction: Treatment for glioblastomas, aggressive and nearly uniformly fatal brain tumors, provide limited long-term success. Immunosuppression by myeloid cells in both the tumor microenvironment and systemic circulation are believed to contribute to this treatment resistance. Standard multi-modality therapy includes conventionally fractionated radiotherapy over 6 weeks; however, hypofractionated radiotherapy over 3 weeks or less may be appropriate for older patients or populations with poor performance status. Lymphocyte concentration changes have been reported in patients with glioblastoma; however, monocytes are likely a key cell type contributing to immunosuppression in glioblastoma. Peripheral monocyte concentration changes in patients receiving commonly employed radiation fractionation schemes are unknown. Methods: To determine the effect of conventionally fractionated and hypofractionated radiotherapy on complete blood cell leukocyte parameters, retrospective longitudinal concentrations were compared prior to, during, and following standard chemoradiation treatment. Results: This study is the first to report increased monocyte concentrations and decreased lymphocyte concentrations in patients treated with conventionally fractionated radiotherapy compared to hypofractionated radiotherapy. Discussion: Understanding the impact of fractionation on peripheral blood leukocytes is important to inform selection of dose fractionation schemes for patients receiving radiotherapy.

Evaluation of Various Polishing Systems for Lithium Disilicate Glass-Ceramics.

OBJECTIVE: The aim of this study was to investigate the surface roughness of lithium disilicates (LS2s) polished using various polishing systems. MATERIALS AND METHODS: Two types of LS2 (A, Amber Mill and E, IPS e.max CAD) were polished using LS2-specific polishing systems (L-Edenta, L-Jota), a zirconia-specific polishing system (Z-Jota), and a conventional ceramic polishing system (P-Shofu) (n = 8 per group). The compositions of different polishing systems were analyzed using EDS. Surface roughness was measured using confocal laser scanning microscopy and analyzed using EDS and SEM. ANOVA and Tukey's tests were used for the statistical analyses (p = 0.05). RESULTS: The polishing systems were mainly composed of C, O, and Si. The L-Jota group exhibited rougher surfaces than the other groups. Amber Mill exhibited higher surface roughness than IPS e.max CAD (p⟨0.001). Among the polishing systems, the L-Jota group presented the highest roughness value (pp⟨0.001). The surface roughness of the AL-Jota group was higher than that of the other groups. CONCLUSIONS: A sufficiently smooth surface can be achieved without a LS2-specific polishing system. Further, the same polishing system can have different effects depending on the type of LS2.

Biological Principles of Stereotactic Body Radiation Therapy (SBRT) and Stereotactic Radiation Surgery (SRS): Indirect Cell Death.

PURPOSE: To review the radiobiological mechanisms of stereotactic body radiation therapy stereotactic body radiation therapy (SBRT) and stereotactic radiation surgery (SRS). METHODS AND MATERIALS: We reviewed previous reports and recent observations on the effects of high-dose irradiation on tumor cell survival, tumor vasculature, and antitumor immunity. We then assessed the potential implications of these biological changes associated with SBRT and SRS. RESULTS: Irradiation with doses higher than approximately 10 Gy/fraction causes significant vascular injury in tumors, leading to secondary tumor cell death. Irradiation of tumors with high doses has also been reported to increase the antitumor immunity, and various approaches are being investigated to further elevate antitumor immunity. The mechanism of normal tissue damage by high-dose irradiation needs to be further investigated. CONCLUSIONS: In addition to directly killing tumor cells, high-dose irradiation used in SBRT and SRS induces indirect tumor cell death via vascular damage and antitumor immunity. Further studies are warranted to better understand the biological mechanisms underlying the high efficacy of clinical SBRT and SRS and to further improve the efficacy of SBRT and SRS.

Indirect cell death and the LQ model in SBRT and SRS.

High-dose hypofractionated SBRT and SRS indirectly kills substantial fractions of tumor cells via causing vascular damage. The LQ formula may work well for certain clinical cases of SBRT and SRS when the indirect/additional tumor cell death secondary to vascular damage is small. However, when the indirect cell death is extensive, the LQ model will underestimate the clinical outcome of SBRT and SRS.

Dysphagia prevalence and associated survival differences in older patients with lung cancer: A SEER-Medicare population-based study.

INTRODUCTION: The impact of dysphagia in persons with lung cancer is unknown. The objective of this study is to measure the prevalence and survival differences associated with dysphagia in older adults with lung cancer. MATERIALS AND METHODS: Linked SEER cancer registries - Medicare data, 1991-2009 was utilized to identify 201,674 persons with lung cancer. Most were male (53%), had regional or distant disease (74%), and were aged <80 years (82%). The pre-existing prevalence of dysphagia was identified using claims codes before the lung cancer diagnosis. Survival was analyzed using Kaplan Meier curves and Cox proportional hazard models. RESULTS: 8517 (4%) had dysphagia prior to their lung cancer diagnoses. Younger age, worse disease stage, more comorbidities, and hospital rurality were associated with higher likelihood of dysphagia. Patients with dysphagia had worse survival (median survival 8 months [95%CI 7,9]) than those without dysphagia (median survival 12 months [95%CI 11,13]). After adjusting for sociodemographic, clinical, and disease characteristics, dysphagia was still associated with worse survival (Hazard ratio of death 1.34, [95%CI 1.28-1.35], p ≤ .0001). DISCUSSION AND CONCLUSIONS: This is the first Medicare claims-based study of older adults with lung cancer and dysphagia. Pre-existing dysphagia occurred in approximately 1 in 25 patients with lung cancer and was associated with worse survival. Determining the best methods to evaluate and treat dysphagia in patients with lung cancer is an important avenue for future studies.

Falsely Undetectable Prostate-Specific Antigen (PSA) Due to Presence of an Inhibitory Serum Factor: A Case Report and Review of Pertinent Literature.

BACKGROUND Few cases of falsely undetectable PSA due to the presence of an inhibitory serum factor have been reported in the world literature. We present a case of falsely low-to-undetectable PSA with data from a serum dilution series, the current literature on biochemical assay interference, and the implications for prostate cancer salvage treatment. CASE REPORT A 63-year-old man was treated with prostatectomy for high-risk prostate cancer and was found to have a rising PSA after approximately 3 years following surgery. He subsequently transferred his care to a different health system and was found to have an undetectable PSA. He was eventually found to have an elevated PSA once again after the particular assay at this institution was changed. He thus received salvage prostate radiotherapy and androgen deprivation therapy. CONCLUSIONS While falsely low PSA results cannot be explained by the presence of serum heterophile antibodies, competitive antibody interference against the immunoassay reagents or anti-PSA antibodies are possible explanations for the results of the dilution experiments performed in this case study. We suggest that unexpected PSA testing results should raise concern for assay interference and warrant further clinical workup.

Reoxygenation and Repopulation of Tumor Cells after Ablative Hypofractionated Radiotherapy (SBRT and SRS) in Murine Tumors.

In this work, we investigated the change in tumor microenvironment caused by semi-ablative high-dose irradiation and its implication on tumor cell survival, reoxygenation of hypoxic cells and repopulation in FSaII tumors grown subcutaneously in the hind legs of C3H mice. Tumors were exposed to 10-30 Gy of X-ray radiation in a single exposure, and the vascularity and blood perfusion were assessed based on the levels of CD31 expression and Hoechst 33342 perfusion, respectively. The tumor hypoxia was assessed by staining for pimonidazole adduct formation and the expression of hypoxia-inducible factor-1α (HIF-1α) and carbonic anhydrase 9 (CA9). Tumor cell survival was determined using in vivo-in vitro excision assay method. The proportion of hypoxic cells in the tumor was determined from the surviving cell fraction in tumors exposed to a test dose under aerobic and hypoxic conditions. Radiation expsoure markedly reduced the functional vascularity and blood perfusion, and profoundly increased the expression of HIF-1α and CA9 pointing to an increase in tumor hypoxia. The overall clonogenic cell survival progressively decreased during 2-5 days postirradiation, most likely due to the radiation-induced vascular dysfunction. In turn, the proportion of surviving hypoxic cells decreased over several days postirradiation, presumably due to reoxygenation of hypoxic cells. The oxygen supplied through small fractions of blood vessels that survived the high-dose exposure, together with a reduction of oxygen consumption due to massive cell death, appeared to be the cause of the reoxygenation of hypoxic cells. The surviving tumor cells then subsequently repopulated. The findings from this study using a murine tumor model suggest that the efficacy of stereotactic body radiotherapy (SBRT) and stereotactic radiosurgery (SRS) may be significantly improved by allowing an inter-fraction time for reoxygenation while avoiding repopulation.

Editor's Choice- Sedation in the coronary intensive care unit: An adapted algorithm for critically ill cardiovascular patient.

In the current era, cardiovascular intensive care units care for more complex patients who are far sicker than historical post-myocardial infarction patients, and sedation has become a common intervention in these units. Current sedation best practices derive mainly from non-cardiac units which limits their generalization to the critically ill cardiac patient. Thus, a great variability in sedation protocols, especially the selection of sedative agents, is commonly seen in daily practice across cardiac units. We present an updated review on sedation in cardiovascular critical care medicine with emphasis on the hemodynamic impact. The goal of this review is to generate a general sedation algorithm specific for the cardiac patient.

Early and multiple PSA bounces can occur following high-dose prostate stereotactic body radiation therapy: Subset analysis of a phase 1/2 trial.

PURPOSE: We hypothesized that high-dose stereotactic body radiation therapy (SBRT) would lead to faster time to nadir and lower nadir values compared with conventional radiation therapy experiences. We now report prostate-specific antigen (PSA) kinetics following high-dose SBRT in patients treated with radiation alone. METHODS AND MATERIALS: Ninety-one patients were enrolled on the phase 1/2 dose escalation study of SBRT for localized prostate cancer. All patients with at least 36 months of follow-up and without hormone therapy were included in this analysis (n = 47). Treatment response parameters evaluated include time to nadir, nadir value, occurrence of PSA bounces (rise of ≥0.2 ng/mL followed by a subsequent fall), magnitude of bounces, duration of bounces, and correlation of bounces with clinical outcomes. RESULTS: Median follow-up was 42 months (range, 36-78 months). Treatment dose levels were 45 Gy (n = 10), 47.5 Gy (n = 8), and 50 Gy (n = 29) in 5 fractions. Biochemical control rate was 98%. Median PSA at follow-up was 0.10 ± 0.20 ng/mL. Median time to nadir was 36 ± 11 months. A total of 24/47 (51.1%) patients had ≥1 PSA bounce. Median magnitude of PSA rise during bounce was 0.50 ± 1.2 ng/mL. Median time to first bounce was 9 ± 7.0 months. Median bounce duration was 3 ± 2.3 months for the first bounce and 6 ± 5.2 months for subsequent bounces. Prostate volumes <30 mL were associated with a decreased likelihood of bounce (P = .0202), and increasing prostate volume correlated with increasingly likelihood of having ≥2 bounces (P = .027). Patients reaching PSA nadir of ≤0.1 ng/mL were less likely to experience any bounce (P = .0044). CONCLUSIONS: Compared with other SBRT experiences, our study demonstrated a higher PSA bounce rate, a similar or shorter median time to bounce, and a very low nadir. Prostate volume appears correlated with bounce.

Stereotactic body radiation therapy for low and intermediate risk prostate cancer-Results from a multi-institutional clinical trial.

BACKGROUND: We report the outcome of a phase I/II clinical trial of stereotactic body radiation therapy (SBRT) for low (LR) and select intermediate risk (IR) prostate cancer (PCa) patients. PATIENTS AND METHODS: Eligible patients included men with prostate adenocarcinoma with Gleason score 6 with PSA ≤ 20 or Gleason 7 with PSA ≤ 15 and clinical stage ≤ T2b. For the phase I portion of the study patients in cohorts of 15 received 45, 47.5, or 50 Gray (Gy) in five fractions. Since the maximally tolerated dose was not met in the phase I study, an additional 47 patients received 50 Gy in five fractions in the phase II study. Toxicity using Common Toxicity Criteria for Adverse Events v. 3.0, quality of life, and outcome data was collected. RESULTS: A total of 91 patients are included for analysis; 63.7% had NCCN IR and 36.3% had LR PCa. At a median follow up of 54 months the actuarial freedom from biochemical failure was 100% at 3 years and 98.6% at 5 years. Actuarial distant metastasis free survival was 100% at 3 and 5 years. Overall survival was 94% at 3 years and 89.7% at 5 years with no deaths attributed to PCa. Acute and late urinary grade ≥ III toxicity occurred in 0% and 5.5% of patients, respectively. Gastrointestinal (GI) acute and late toxicity of grade ≥ III occurred in 2% and 7% of patients, respectively. A total of four men experienced grade IV toxicity (three GI, one genitourinary). CONCLUSION: SBRT treatment results in excellent biochemical control rates at 5 years for LR and IR PCa patients although doses greater than 47.5 Gy in five fractions led to increased severe late toxicity.

Management of Unplanned Excision for Soft-Tissue Sarcoma With Preoperative Radiotherapy Followed by Definitive Resection.

BACKGROUND AND OBJECTIVES: The purpose of this study was to review the outcomes after preoperative radiotherapy and definitive surgery for patients who initially had inadvertent excision for sarcoma. MATERIALS AND METHODS: Treatment records of 44 consecutive patients, who initially underwent unplanned excision of soft-tissue sarcoma between January 2004 and January 2012, were reviewed. All patients had clinically localized disease before treatment and received preoperative external-beam radiotherapy followed by definitive oncologic surgery at our institution. RESULTS: The median follow-up was 36 months. Residual tumor after preoperative radiotherapy and wound bed excision was identified in 39% (17/44) of the cases. Kaplan-Meier estimates for 5-year local control, recurrence-free survival, and overall survival are 95% (95% confidence interval [CI], 80-99), 86% (95% CI, 69-94), and 94% (95% CI, 79-99) respectively. Perioperative morbidity occurred in 25% of patients (11/44.) All patients with perioperative wound complications had lower extremity sarcomas. CONCLUSIONS: Optimal management for unplanned excision of soft-tissue sarcoma is unknown. Our institution has adopted the approach of preoperative radiotherapy, followed by definitive surgery. In our series of 44 patients, local control was excellent at 95%, with perioperative complications seen only in patients with lower extremity sarcomas, suggesting that this is a reasonable approach to manage inadvertently resected sarcoma.

Indirect Tumor Cell Death After High-Dose Hypofractionated Irradiation: Implications for Stereotactic Body Radiation Therapy and Stereotactic Radiation Surgery.

PURPOSE: The purpose of this study was to reveal the biological mechanisms underlying stereotactic body radiation therapy (SBRT) and stereotactic radiation surgery (SRS). METHODS AND MATERIALS: FSaII fibrosarcomas grown subcutaneously in the hind limbs of C3H mice were irradiated with 10 to 30 Gy of X rays in a single fraction, and the clonogenic cell survival was determined with in vivo--in vitro excision assay immediately or 2 to 5 days after irradiation. The effects of radiation on the intratumor microenvironment were studied using immunohistochemical methods. RESULTS: After cells were irradiated with 15 or 20 Gy, cell survival in FSaII tumors declined for 2 to 3 days and began to recover thereafter in some but not all tumors. After irradiation with 30 Gy, cell survival declined continuously for 5 days. Cell survival in some tumors 5 days after 20 to 30 Gy irradiation was 2 to 3 logs less than that immediately after irradiation. Irradiation with 20 Gy markedly reduced blood perfusion, upregulated HIF-1α, and increased carbonic anhydrase-9 expression, indicating that irradiation increased tumor hypoxia. In addition, expression of VEGF also increased in the tumor tissue after 20 Gy irradiation, probably due to the increase in HIF-1α activity. CONCLUSIONS: Irradiation of FSaII tumors with 15 to 30 Gy in a single dose caused dose-dependent secondary cell death, most likely by causing vascular damage accompanied by deterioration of intratumor microenvironment. Such indirect tumor cell death may play a crucial role in the control of human tumors with SBRT and SRS.

Stereotactic Body Radiation Therapy for Prostate Cancer: Review of Experience of a Multicenter Phase I/II Dose-Escalation Study.

INTRODUCTION: Stereotactic body radiation therapy (SBRT) is an area of active investigation for treatment of prostate cancer. In our phase I dose-escalation study, maximum-tolerated dose (MTD) was not reached, and subsequently phase II study has been completed. The purpose of this article is to review our experiences of dose-escalated SBRT for localized prostate cancer. METHODS AND MATERIALS: Patients enrolled to phase I/II study from 2006 to 2011 were reviewed. Prescription dose groups were 45, 47.5, and 50 Gray (Gy) in five fractions over 2.5 weeks. Toxicity and quality of life questionnaire data were collected and analyzed. Descriptive statistics were obtained in the form of means, medians, and ranges for the continuous variables, and frequencies and percentages for the categoric variables. RESULTS: Ninety-one patients were enrolled from five institutions. Median follow-up for prostate specific antigen (PSA) evaluation was 42 months. PSA control remains at 99%. While the MTD was not reached in the phase I study, excess high grade rectal toxicity (10.6%) was noted in the phase II study. The 13 patients treated to 50 Gy in the phase I study that did not have high grade rectal toxicity, in retrospect met these parameters and have not had further events on longer follow-up. CONCLUSION: Prostate specific antigen control rate, even for patients with intermediate risk, is thus far excellent at these dose levels. This study provides a platform for exploration of SBRT based clinical trials aimed at optimizing outcome for intermediate and high risk patients. High grade toxicities specifically related to the rectum were observed in a small but meaningful minority at the highest dose level. Dose constraints based on physiologic parameters have been defined to mitigate this risk, and strategies to minimize rectal exposure to such doses are being explored.

Emergence of stereotactic body radiation therapy and its impact on current and future clinical practice.

Stereotactic body radiation therapy (SBRT) is generally a tumor-ablative radiation modality using essential technologies capable of accurately and precisely damaging the target with a high dose while geometrically sparing innocent normal tissues. The intent, conduct, and tissue biology are all dramatically distinct from conventionally fractionated radiotherapy such that new understanding is required for its optimization. It is most practical, tolerable, and tumoricidal in its most potent form treating tumors in the lung and liver. However, it is increasingly being used for tumors adjacent to bowels and nervous tissue, albeit with somewhat less ablative potency. Its strengths include high rates of tumor eradication via a noninvasive, convenient outpatient treatment. Its weakness relates to the possibility of causing difficult-to-manage toxicity (eg, ulceration, stenosis, fibrosis, and even necrosis) that may occur considerably later after treatment, particularly in the vicinity of the body's many tubular structures (eg, organ hila, bowel). However, clinical trials in a variety of organs and sites have shown SBRT to result in good outcomes in properly selected patients. Given its short course, lack of need for recovery, and favorable overall toxicity profile, there is great hope that SBRT will find a prominent place in the treatment of metastatic cancer as a consolidative partner with systemic therapy. With considerable published experience, available required technologies and training, and many patients in need of local therapy, SBRT has found a place in the routine cancer-fighting arsenal.