A Milky Way-like barred spiral galaxy at a redshift of 3.

The majority of massive disk galaxies in the local Universe show a stellar barred structure in their central regions, including our Milky Way1,2. Bars are supposed to develop in dynamically cold stellar disks at low redshift, as the strong gas turbulence typical of disk galaxies at high redshift suppresses or delays bar formation3,4. Moreover, simulations predict bars to be almost absent beyond z = 1.5 in the progenitors of Milky Way-like galaxies5,6. Here we report observations of ceers-2112, a barred spiral galaxy at redshift zphot ≈ 3, which was already mature when the Universe was only 2 Gyr old. The stellar mass (M★ = 3.9 × 109 M⊙) and barred morphology mean that ceers-2112 can be considered a progenitor of the Milky Way7-9, in terms of both structure and mass-assembly history in the first 2 Gyr of the Universe, and was the closest in mass in the first 4 Gyr. We infer that baryons in galaxies could have already dominated over dark matter at z ≈ 3, that high-redshift bars could form in approximately 400 Myr and that dynamically cold stellar disks could have been in place by redshift z = 4-5 (more than 12 Gyrs ago)10,11.

Confirmation and refutation of very luminous galaxies in the early Universe.

During the first 500 million years of cosmic history, the first stars and galaxies formed, seeding the Universe with heavy elements and eventually reionizing the intergalactic medium1-3. Observations with the James Webb Space Telescope (JWST) have uncovered a surprisingly high abundance of candidates for early star-forming galaxies, with distances (redshifts, z), estimated from multiband photometry, as large as z ≈ 16, far beyond pre-JWST limits4-9. Although such photometric redshifts are generally robust, they can suffer from degeneracies and occasionally catastrophic errors. Spectroscopic measurements are required to validate these sources and to reliably quantify physical properties that can constrain galaxy formation models and cosmology10. Here we present JWST spectroscopy that confirms redshifts for two very luminous galaxies with z > 11, and also demonstrates that another candidate with suggested z ≈ 16 instead has z = 4.9, with an unusual combination of nebular line emission and dust reddening that mimics the colours expected for much more distant objects. These results reinforce evidence for the early, rapid formation of remarkably luminous galaxies while also highlighting the necessity of spectroscopic verification. The large abundance of bright, early galaxies may indicate shortcomings in current galaxy formation models or deviations from physical properties (such as the stellar initial mass function) that are generally believed to hold at later times.

Challenges and opportunities for early phase clinical trials of novel drug-radiotherapy combinations: recommendations from NRG Oncology, the American Society for Radiation Oncology (ASTRO), the American College of Radiology (ACR), the Sarah Cannon Research Institute, and the American College of Radiation Oncology (ACRO).

NRG Oncology's Developmental Therapeutics and Radiation Therapy Subcommittee assembled an interdisciplinary group of investigators to address barriers to successful early phase clinical trials of novel combination therapies involving radiation. This Policy Review elucidates some of the many challenges associated with study design for early phase trials combining radiotherapy with novel systemic agents, which are distinct from drug-drug combination development and are often overlooked. We also advocate for potential solutions that could mitigate or eliminate some of these barriers, providing examples of specific clinical trial designs that could help facilitate efficient and effective evaluation of novel drug-radiotherapy combinations.

Annual Fecal Occult Blood Testing can be Safely Suspended for up to 5 Years After a Negative Colonoscopy in Asymptomatic Average-Risk Patients.

OBJECTIVES: Annual fecal occult blood testing (FOBT) is often continued in patients who have had a recent negative colonoscopy, despite recommendations to the contrary. This prospective study aimed to determine the proportion of patients with a positive FOBT who had adenomas and cancers on colonoscopy stratified according to the duration of time since the last negative colonoscopy. METHODS: A total of 1,119 asymptomatic average-risk patients ≥50 years of age referred for a positive FOBT were prospectively identified and stratified by the duration of time since the last colonoscopy (never, >10 years, 5-10 years, or <5 years). The proportion of patients in each category with adenomas of any size, adenomas ≥10 mm, advanced neoplasms, and cancers was assessed. RESULTS: The mean age (68.9±9.6 years), sex (95.2% male), and race (48.1% white, 32.1% black, 15.6% Hispanic, and 4.2% other) did not differ between the four groups. Overall, adenomas of any size were detected in 42.8% of patients, adenomas ≥10 mm in 14.7%, advanced neoplasms in 20.7%, and cancers in 7.3%. Advanced neoplasms were detected in 30.4% of patients who have never had a colonoscopy, 27% in those who have had one greater than 10 years prior, 10.0% in 5-10 years prior, and 1.1% in less than 5 years prior. CONCLUSIONS: In asymptomatic average-risk patients with a negative colonoscopy within the last 5 years, the prevalence of adenomas is low, and no patient was diagnosed with cancer. These findings support the CDC recommendations to suspend annual FOBT for up to 5 years after a negative colonoscopy.

Multi-institutional, randomized, double-blind, placebo-controlled trial to assess the efficacy of a mucoadhesive hydrogel (MuGard) in mitigating oral mucositis symptoms in patients being treated with chemoradiation therapy for cancers of the head and neck.

BACKGROUND: The objective of this trial was to determine how a mucoadhesive hydrogel (MuGard), a marketed medical device, would fare when tested with the strictness of a conventional multi-institutional, double-blind, randomized, placebo-controlled study format. METHODS: A total of 120 subjects planned to receive chemoradiation therapy (CRT) for treatment of head and neck cancers were randomized to receive either MuGard or sham control rinse (SC) during CRT. Subjects completed the validated Oral Mucositis Daily Questionnaire. Weight, opiate use, and World Health Organization (WHO) oral mucositis (OM) scores were recorded. Subjects who dosed at least once daily during the first 2.5 weeks of CRT were included in the efficacy analysis. RESULTS: Of 120 subjects enrolled, 78 (SC, N=41; MuGard, N=37) were eligible for efficacy analysis. Both cohorts were similar in demographics, baseline characteristics, primary tumor type, and planned CRT regimen. MuGard effectively mitigated OM symptoms as reflected by area under the curve of daily patient-reported oral soreness (P=.034) and WHO scores on the last day of radiation therapy (P=.038). MuGard was also associated with nonsignificant trends related to therapeutic benefit including opioid use duration, and OM scores (WHO criteria) at CRT week 4. Rinse compliance was identical between cohorts. No significant adverse events were reported, and the adverse event incidence was similar between cohorts. CONCLUSIONS: Testing MuGard, a rinse marketed as a device, in a standard clinical trial format demonstrated its superiority to SC in mitigating OM symptoms, delaying OM progression, and its safety and tolerability.

The promise of combining radiation therapy and immunotherapy: morbidity and toxicity.

Radiation therapy and immunotherapy in partnership may have the capability of delivering a therapeutic effect exceeding the sum of its parts. The possible relationship has been demonstrated in murine models and has been extended to a variety of clinical trials. Though the standard notion of whole body radiation therapy is immunosuppressive, there is growing evidence toward the contrary for focal radiation therapy. Furthermore, if immunotherapeutic techniques can retune the immune system against cancerous cells, they should have obvious benefits for advanced treatments moving forward. Herein, we explore the promise in combining radiation therapy and immunotherapy with distinct focus on potential morbidities and toxicities through analysis of completed clinical trials.

Hemibody Irradiation for Bone Metastases: A Systematic Review and Meta-Analysis.

Hemibody irradiation (HBI) is a radiation therapy technique that involves treating one-half of the patient's skeletal system in a single radiation field. It is mostly given as upper hemibody irradiation (UHBI), lower hemibody irradiation (LHBI), or sequential UHBI and LHBI. It is used to treat extensive bone metastases from solid tumors. It was primarily utilized in the 1980s and 1990s and has since fallen out of favor. However, it is a potentially cost-effective treatment for widespread bone metastases. To determine its efficacy, we performed a meta-analysis of all available published articles on the efficacy of HBI to relieve pain from bone metastases. Twenty-seven articles involving 1318 patients were identified and analyzed. Our findings show that 80% of the patients had complete or partial pain relief and 29% had complete pain relief. The trials were of poor quality, but the results showed minimal heterogeneity in the response rates. These response rates are consistent with those seen with focal irradiation of bone metastases and for radionuclide treatment of bone metastases. The toxicity of the treatments decreased when delivered with modern treatment techniques. In light of this, we propose that this technique warrants re-evaluation with modern treatment methods.

Strong damped Lyman-α absorption in young star-forming galaxies at redshifts 9 to 11.

Primordial neutral atomic gas, mostly composed of hydrogen, is the raw material for star formation in galaxies. However, there are few direct constraints on the amount of neutral atomic hydrogen (H i) in galaxies at early cosmic times. We analyzed James Webb Space Telescope (JWST) near-infrared spectroscopy of distant galaxies, at redshifts ≳8. From a sample of 12 galaxies, we identified three that show strong damped Lyman-α absorption due to H i in their local surroundings. The galaxies are located at spectroscopic redshifts of 8.8, 10.2, and 11.4, corresponding to 400 to 600 million years after the Big Bang. They have H i column densities ≳1022 cm-2, which is an order of magnitude higher than expected for a fully neutral intergalactic medium, and constitute a gas-rich population of young star-forming galaxies.

Building on sipuleucel-T for immunologic treatment of castration-resistant prostate cancer.

BACKGROUND: Sipuleucel-T is an autologous cellular immunotherapy approved by the US Food and Drug Administration for the treatment of asymptomatic or minimally symptomatic metastatic castration-resistant prostate cancer. Its mechanism of action is based on stimulation of the patient's own immune system to target prostate cancer. Peripheral blood mononuclear cells, including antigen-presenting cells and T cells, are obtained from patients via leukapheresis and treated ex vivo with PA2024, a fusion protein consisting of prostatic acid phosphatase/granulocyte-macrophage colony-stimulating factor antigen. METHODS: Data relating to the potential pharmacodynamic biomarkers associated with sipuleucel-T activity are reviewed, as well as considerations for patient selection and for sequencing sipuleucel-T with other prostate cancer treatments. Possible directions for future development are also discussed, including treatment of less advanced prostate cancer populations, combination treatment, and immune modulation. RESULTS: Data from three randomized, double-blind, placebo-controlled phase III clinical trials of sipuleucel-T in patients with metastatic castration-rresistant prostate cancer have shown improvement in overall survival vs control. Here, we review its developing role in prostate cancer therapy and future directions for development. CONCLUSIONS: There is potential to build on sipuleucel-T to further advance immunotherapy of prostate cancer.

Synergy of IL-21 and IL-15 in regulating CD8+ T cell expansion and function.

Interleukin (IL)-21 is the most recently recognized of the cytokines that share the common cytokine receptor gamma chain (gamma(c)), which is mutated in humans with X-linked severe combined immunodeficiency. We now report that IL-21 synergistically acts with IL-15 to potently promote the proliferation of both memory (CD44high) and naive (CD44low) phenotype CD8+ T cells and augment interferon-gamma production in vitro. IL-21 also cooperated, albeit more weakly, with IL-7, but not with IL-2. Correspondingly, the expansion and cytotoxicity of CD8+ T cells were impaired in IL-21R-/- mice. Moreover, in vivo administration of IL-21 in combination with IL-15 boosted antigen-specific CD8+ T cell numbers and resulted in a cooperative effect on tumor regression, with apparent cures of large, established B16 melanomas. Thus, our studies reveal that IL-21 potently regulates CD8+ T cell expansion and effector function, primarily in a synergistic context with IL-15.

Removal of homeostatic cytokine sinks by lymphodepletion enhances the efficacy of adoptively transferred tumor-specific CD8+ T cells.

Depletion of immune elements before adoptive cell transfer (ACT) can dramatically improve the antitumor efficacy of transferred CD8+ T cells, but the specific mechanisms that contribute to this enhanced immunity remain poorly defined. Elimination of CD4+CD25+ regulatory T (T reg) cells has been proposed as a key mechanism by which lymphodepletion augments ACT-based immunotherapy. We found that even in the genetic absence of T reg cells, a nonmyeloablative regimen substantially augmented CD8+ T cell reactivity to self-tissue and tumor. Surprisingly, enhanced antitumor efficacy and autoimmunity was caused by increased function rather than increased numbers of tumor-reactive T cells, as would be expected by homeostatic mechanisms. The gammaC cytokines IL-7 and IL-15 were required for augmenting T cell functionality and antitumor activity. Removal of gammaC cytokine-responsive endogenous cells using antibody or genetic means resulted in the enhanced antitumor responses similar to those seen after nonmyeloablative conditioning. These data indicate that lymphodepletion removes endogenous cellular elements that act as sinks for cytokines that are capable of augmenting the activity of self/tumor-reactive CD8+ T cells. Thus, the restricted availability of homeostatic cytokines can be a contributing factor to peripheral tolerance, as well as a limiting resource for the effectiveness of tumor-specific T cells.

Improved survival in patients with lymph node-positive gastric cancer who received preoperative radiation: an analysis of the Surveillance, Epidemiology, and End Results database.

BACKGROUND: Several trials have been conducted to determine the feasibility of preoperative radiotherapy (RT) for gastric cancer. However, the absolute benefit from radiotherapy remains to be defined. In this study, the authors examined the use of preoperative RT (Pre-RT) and postoperative RT (PORT) in patients with gastric cancer from the Surveillance, Epidemiology, and End Results (SEER) database. METHODS: The overall survival of patients who had nonmetastatic, resected gastric cancer between 2000 and 2006 was analyzed from the SEER database. Kaplan-Meier survival curves comparing Pre-RT, PORT, and no RT (No-RT) were analyzed using the log-rank test. A multivariate analysis (MVA) was conducted using Cox proportional hazards regression. RESULTS: The authors identified 10,251 patients. There was no survival benefit for patients who received Pre-RT or PORT compared with No-RT patients for the entire cohort. Conversely, among lymph node-positive patients, there was a significant survival benefit from both Pre-RT and PORT compared with No-RT (log-rank test: PORT, P < .0001; Pre-RT, P = .0261). The median survival and 5-year overall survival among lymph node-positive patients were 22 months and 24%, respectively, for Pre-RT;29 months and 34%, respectively, for PORT; and 19 months and 20%, respectively, for No-RT. MVA demonstrated that Pre-RT, PORT, and removing ≥ 15 lymph nodes were independent predictors of improved survival, whereas tumor classification, lymph node status, tumor size, and tumor location were independent predictors of death. CONCLUSIONS: The current results supported the use of Pre-RT in select patients with gastric cancer. However, additional trials will be needed to confirm these findings.

The confluence of stereotactic ablative radiotherapy and tumor immunology.

Stereotactic radiation approaches are gaining more popularity for the treatment of intracranial as well as extracranial tumors in organs such as the liver and lung. Technology, rather than biology, is driving the rapid adoption of stereotactic body radiation therapy (SBRT), also known as stereotactic ablative radiotherapy (SABR), in the clinic due to advances in precise positioning and targeting. Dramatic improvements in tumor control have been demonstrated; however, our knowledge of normal tissue biology response mechanisms to large fraction sizes is lacking. Herein, we will discuss how SABR can induce cellular expression of MHC I, adhesion molecules, costimulatory molecules, heat shock proteins, inflammatory mediators, immunomodulatory cytokines, and death receptors to enhance antitumor immune responses.

Effective tumor treatment targeting a melanoma/melanocyte-associated antigen triggers severe ocular autoimmunity.

Nonmutated tissue differentiation antigens expressed by tumors are attractive targets for cancer immunotherapy, but the consequences of a highly effective antitumor immune response on self-tissue have not been fully characterized. We found that the infusion of ex vivo expanded adoptively transferred melanoma/melanocyte-specific CD8+ T cells that mediated robust tumor killing also induced autoimmune destruction of melanocytes in the eye. This severe autoimmunity was associated with the up-regulation of MHC class I molecules in the eye and high levels of IFN-gamma derived from both adoptively transferred CD8+ T cells and host cells. Furthermore, ocular autoimmunity required the presence of the IFN-gamma receptor on target tissues. Data compiled from >200 eyes and tumors in 10 independently performed experiments revealed a highly significant correlation (P < 0.0001) between the efficacy of tumor immunotherapy and the severity of ocular autoimmunity. Administration of high doses of steroids locally mitigated ocular autoimmunity without impairing the antitumor effect. These findings have particular importance for immunotherapies directed against self-antigens and highlight the need for targeting unique tumor antigens not expressed in critical tissues.

Immune evasion by murine melanoma mediated through CC chemokine receptor-10.

Human melanoma cells frequently express CC chemokine receptor (CCR)10, a receptor whose ligand (CCL27) is constitutively produced by keratinocytes. Compared with B16 murine melanoma, cells rendered more immunogenic via overexpression of luciferase, B16 cells that overexpressed both luciferase and CCR10 resisted host immune responses and readily formed tumors. In vitro, exposure of tumor cells to CCL27 led to rapid activation of Akt, resistance to cell death induced by melanoma antigen-specific cytotoxic T cells, and phosphatidylinositol-3-kinase (PI3K)-dependent protection from apoptosis induced by Fas cross-linking. In vivo, cutaneous injection of neutralizing antibodies to endogenous CCL27 blocked growth of CCR10-expressing melanoma cells. We propose that CCR10 engagement by locally produced CCL27 allows melanoma cells to escape host immune antitumor killing mechanisms (possibly through activation of PI3K/Akt), thereby providing a means for tumor progression.

Tumor regression and autoimmunity after reversal of a functionally tolerant state of self-reactive CD8+ T cells.

Many tumor-associated antigens are derived from nonmutated "self" proteins. T cells infiltrating tumor deposits recognize self-antigens presented by tumor cells and can be expanded in vivo with vaccination. These T cells exist in a functionally tolerant state, as they rarely result in tumor eradication. We found that tumor growth and lethality were unchanged in mice even after adoptive transfer of large numbers of T cells specific for an MHC class I-restricted epitope of the self/tumor antigen gp100. We sought to develop new strategies that would reverse the functionally tolerant state of self/tumor antigen-reactive T cells and enable the destruction of large (with products of perpendicular diameters of >50 mm2), subcutaneous, unmanipulated, poorly immunogenic B16 tumors that were established for up to 14 d before the start of treatment. We have defined three elements that are all strictly necessary to induce tumor regression in this model: (a) adoptive transfer of tumor-specific T cells; (b) T cell stimulation through antigen-specific vaccination with an altered peptide ligand, rather than the native self-peptide; and (c) coadministration of a T cell growth and activation factor. Cells, vaccination, or cyto-kine given alone or any two in combination were insufficient to induce tumor destruction. Autoimmune vitiligo was observed in mice cured of their disease. These findings illustrate that adoptive transfer of T cells and IL-2 can augment the function of a cancer vaccine. Furthermore, these data represent the first demonstration of complete cures of large, established, poorly immunogenic, unmanipulated solid tumors using T cells specific for a true self/tumor antigen and form the basis for a new approach to the treatment of patients with cancer.

Nonsurgical options for hepatocellular carcinoma: evolving role of external beam radiotherapy.

BACKGROUND: Hepatocellular carcinoma (HCC) is the sixth most common cancer worldwide and thus poses a global concern. Its incidence is expected to increase in North America secondary to the increasing incidence of patients who develop hepatitis C. Patients who ultimately develop cirrhosis have an increased risk of developing hepatocellular carcinoma. METHODS: The authors focus on nonsurgical therapies for this disease with an exploration of how external beam radiotherapy can be used alone or with other modalities. The development of partial liver strategies secondary to an explosion in radiation treatment planning and delivery advances is reviewed. Integration of advanced technology has evolved from three-dimensional conformal treatment to intensity-modulated radiation therapy and image-guided radiation therapy, along with stereotactic body radiation therapy, tomotherapy, and proton beam therapy. RESULTS: Current data show a promising future for treatment strategies incorporating radiation with high rates of infield tumor control and low rates of radiation-induced liver disease. Radiation can be delivered in conjunction with transarterial catheter embolization for advanced-stage patients. External beam radiotherapy also has a role in the setting of patients with macrovascular tumor thrombus. CONCLUSIONS: Future directions include how to best synergize the effects of radiation strategies with novel agents, given the hypervascularity of HCC. Downstaging of larger lesions with these therapies to resectable or transplantable disease may lead to better outcomes for patients deemed inoperable at diagnosis, and definitive radiotherapy may offer cure to patients with smaller lesions.

Systemic therapy for advanced hepatocellular carcinoma: past, present, and future.

BACKGROUND: Although approximately 80% of hepatocellular carcinoma (HCC) cases occur in developing countries, the incidence of HCC in Western countries is on the rise due to the impact of hepatitis C. Challenges in developing effective therapies include the inherent chemoresistance of HCC, the pharmacologic challenges presented by a diseased liver, the presentation of most patients at advanced stages, and the difficulty in adequately measuring radiological response. While responses to traditional chemotherapeutic agents have been documented, significant survival benefit is debatable. METHODS: The authors review the results of published clinical trials of systemic therapy and immunotherapy that have impacted the present treatment of HCC. RESULTS: With recent progress in the elucidation of HCC molecular pathways, targeted agents show promise. The multikinase inhibitor sorafenib has provided survival benefit in patients with advanced HCC and well-preserved liver function. Sunitinib, bevacizumab, epidermal growth factor receptor inhibitors, and mammalian target of rapamycin (mTOR) inhibitors have shown activity in small patient cohorts. Immunotherapy appears to be a promising approach that can result in the regression of bulky, invasive cancer in some patients. CONCLUSIONS: New agents with a variety of mechanisms of activity offer promising therapeutic options for patients with advanced HCC.

Acquisition of full effector function in vitro paradoxically impairs the in vivo antitumor efficacy of adoptively transferred CD8+ T cells.

T cell differentiation is a progressive process characterized by phenotypic and functional changes. By transferring tumor-specific CD8+ T cells into tumor-bearing mice at various stages of differentiation, we evaluated their efficacy for adoptive immunotherapy. We found that administration of naive and early effector T cells, in combination with active immunization and IL-2, resulted in the eradication of large, established tumors. Despite enhanced in vitro antitumor properties, more-differentiated effector T cells were less effective for in vivo tumor treatment. Several events may underlie this paradoxical phenomenon: (a) downregulation of lymphoid-homing and costimulatory molecules; (b) inability to produce IL-2 and access homeostatic cytokines; and (c) entry into a proapoptotic and replicative senescent state. While the progressive acquisition of terminal effector properties is characterized by pronounced in vitro tumor killing, in vivo T cell activation, proliferation, and survival are progressively impaired. These findings suggest that the current methodology for selecting T cells for transfer is inadequate and provide new criteria for the generation and the screening of optimal lymphocyte populations for adoptive immunotherapy.