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PURPOSE: The impact of age on optimal management of glioblastoma remains unclear. A recent combined analysis of two randomised trials, GEINO14-01 and EX-TEM, found no benefit from extending post-radiation temozolomide in newly diagnosed glioblastoma. Here, we explore the impact of age. METHODS: Relevant intergroup statistics were used to identify differences in tumour, treatment and outcome characteristics based on age with elderly patients (EP) defined as age 65 years and over. Survival was estimated using the Kaplan Meier method. RESULTS: Of the combined 205 patients, 57 (28%) were EP. Of these, 95% were ECOG 0-1 and 65% underwent macroscopic resection compared with 97% and 61% of younger patients (YP) respectively. There were numerically less MGMT-methylated (56% vs. 63%, p = 0.4) and IDH-mutated (4% vs. 13%, p = 0.1) tumours in EP vs. YP. Following surgery, EP were more likely to receive short course chemoradiation (17.5% vs. 6%, p = 0.017). At recurrence, EP tended to receive or best supportive care (28.3% vs. 15.4%, p = 0.09) or non-surgical options (96.2% vs. 84.6%, p = 0.06), but were less likely to receive bevacizumab (23.1% vs. 49.5%, p < 0.01). Median PFS was similar at 9.3months in EP and 8.5months in YP, with similar median OS at 20months. CONCLUSION: In this trial population of predominantly fit EP, survival was similar to YP despite a proportion receiving less aggressive therapy at diagnosis and recurrence. Advancing age does not appear to be an adverse prognostic factor for glioblastoma when patients are fit for treatment, and a less aggressive approach in selected patients may not compromise outcomes.
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Neoplasias Encefálicas , Glioblastoma , Humanos , Glioblastoma/terapia , Glioblastoma/mortalidade , Idoso , Neoplasias Encefálicas/terapia , Neoplasias Encefálicas/mortalidade , Masculino , Feminino , Pessoa de Meia-Idade , Idoso de 80 Anos ou mais , Temozolomida/uso terapêutico , Adulto , Antineoplásicos Alquilantes/uso terapêutico , Fatores Etários , Terapia Combinada , Resultado do Tratamento , Gerenciamento ClínicoRESUMO
PURPOSE: After standard treatment for glioblastoma, perfusion MRI remains challenging for differentiating tumor progression from post-treatment changes. Our objectives were (1) to correlate rCBV values at diagnosis and at first tumor progression and (2) to analyze the relationship of rCBV values at tumor recurrence with enhancing volume, localization of tumor progression, and time elapsed since the end of radiotherapy in tumor recurrence. METHODS: Inclusion criteria were (1) age > 18 years, (2) histologically confirmed glioblastoma treated with STUPP regimen, and (3) tumor progression according to RANO criteria > 12 weeks after radiotherapy. Co-registration of segmented enhancing tumor VOIs with dynamic susceptibility contrast perfusion MRI was performed using Olea Sphere software. For tumor recurrence, we correlated rCBV values with enhancing tumor volume, with recurrence localization, and with time elapsed from the end of radiotherapy to progression. Analyses were performed with SPSS software. RESULTS: Sixty-four patients with glioblastoma were included in the study. Changes in rCBV values between diagnosis and first tumor progression were significant (p < 0.001), with a mean and median decreases of 32% and 46%, respectively. Mean rCBV values were also different (p < 0.01) when tumors progressed distally (radiation field rCBV values of 1.679 versus 3.409 distally). However, changes and, therefore, low rCBV values after radiotherapy in tumor recurrence were independent of time. CONCLUSION: Chemoradiation alters tumor perfusion and rCBV values may be decreased in the setting of tumor progression. Changes in rCBV values with respect to diagnosis, with low rCBV in tumor progression, are independent of time but related to the site of recurrence.
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Neoplasias Encefálicas , Glioblastoma , Humanos , Adulto , Pessoa de Meia-Idade , Glioblastoma/diagnóstico por imagem , Glioblastoma/radioterapia , Neoplasias Encefálicas/diagnóstico por imagem , Neoplasias Encefálicas/radioterapia , Recidiva Local de Neoplasia/diagnóstico por imagem , Meios de Contraste , Quimiorradioterapia , Imageamento por Ressonância Magnética/métodosRESUMO
OBJECTIVE: This systematic review aims to evaluate the optimal treatment for male infertility resulting from Anabolic Androgenic Steroids (AAS) abuse. METHODS: A systematic review was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. Studies that compared different protocols for the recovery of spermatogenesis in patients after AAS use were included. RESULTS: 13 studies investigating different protocols to restore spermatogenesis in patients with AAS abuse met the inclusion criteria. The available agents that showed restoration of spermatogenesis include injectable gonadotropins, selective estrogen receptor modulators, and aromatase inhibitors, but their use is still poorly described in the literature. CONCLUSIONS: Clinicians need to be aware of the detrimental effects of AAS on spermatogenesis. AAS-associated infertility may be reversible, but sperm production may take over a year to normalize. Both conservative and aggressive treatment can boost spermatogenesis with positive results. Further understanding of male reproductive endocrinology and high-quality data on the field of restoration of spermatogenesis after AAS abuse are warranted.
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Anabolizantes , Androgênios , Humanos , Masculino , Esteróides Androgênicos Anabolizantes , Anabolizantes/efeitos adversos , Sêmen , Congêneres da Testosterona/efeitos adversos , EspermatogêneseRESUMO
PURPOSE: The optimal duration of post-radiation temozolomide in newly diagnosed glioblastoma remains unclear, with no published phase III randomised trials. Standard-of-care stipulates 6 months. However, in routine care, it is often extended to 12 months, despite lacking robust supporting data. METHODS: GEINO14-01 (Spain) and EX-TEM (Australia) studies enrolled glioblastoma patients without progression at the end of 6 months post-radiation temozolomide. Participants were randomised 1:1 to six additional months of temozolomide or observation. Primary endpoint was 6-month progression free survival from date of randomisation (6mPFS). Secondary endpoints included overall survival (OS) and toxicity. 204 patients were required to detect an improvement in 6mPFS from 50 to 60% (80% power). Neither study recruited sufficient patients. We performed a combined analysis of individual patient data. RESULTS: 205 patients were recruited: 159 in GEINO14-01 (2014-2018) and 46 in EX-TEM (2019-2022). Median follow-up was 20.0 and 14.5 months. Baseline characteristics were balanced. There was no significant improvement in 6mPFS (57.2% vs 64.0%, OR0.75, p = 0.4), nor across any subgroups, including MGMT methylated; PFS (HR0.92, p = 0.59, median 7.8 vs 9.7 months); or OS (HR1.03, p = 0.87, median 20.1 vs 19.4 months). During treatment extension, 64% experienced any grade adverse event, mainly fatigue and gastrointestinal (both 54%). Only a minority required treatment changes: 4.5% dose delay, 7.5% dose reduction, 1.5% temozolomide discontinuation. CONCLUSION: For glioblastoma patients, extending post-radiation temozolomide from 6 to 12 months is well tolerated but does not improve 6mPFS. We could not identify any subset that benefitted from extended treatment. Six months should remain standard-of-care.
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Neoplasias Encefálicas , Glioblastoma , Humanos , Temozolomida/uso terapêutico , Glioblastoma/tratamento farmacológico , Glioblastoma/radioterapia , Estudos Prospectivos , Dacarbazina/efeitos adversos , Intervalo Livre de Doença , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/radioterapia , Antineoplásicos Alquilantes/efeitos adversosRESUMO
Developing better treatments that work for the majority of patients with brain metastasis (BM) is highly necessary. Complementarily, avoiding those therapeutic procedures that will not benefit a specific patient is also very relevant. In general, existing therapies for patients with BM could be improved in terms of molecular stratification and therapeutic efficacy. By questioning the benefit of whole brain radiotherapy as provided nowadays and the lack of biomarkers detecting radioresistance, we identified S100A9 and receptor for advanced glycation end-products (RAGE) as a liquid biopsy biomarker and a potential target for a radiosensitizer, respectively. Both of them are being clinically tested as part of the first comprehensive molecular strategy to personalized radiotherapy in BM.
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Calgranulina B , Neoplasias , Humanos , Receptor para Produtos Finais de Glicação Avançada/metabolismo , BiomarcadoresRESUMO
The assembly/disassembly of biological macromolecules plays an important role in their biological functionalities. Although the dynamics of tubulin polymers and their super-assembly into microtubule structures is critical for many cellular processes, details of their cyclical polymerization/depolymerization are not fully understood. Here, we use a specially designed light scattering technique to continuously examine the effects of temperature cycling on the process of microtubule assembly/disassembly. We observe a thermal hysteresis loop during tubulin assembly/disassembly, consistently with earlier reports on the coexistence of tubulin and microtubules as a phase transition. In a cyclical process, the structural hysteresis has a kinetic component that depends on the rate of temperature change but also an intrinsic thermodynamic component that depends on the protein topology, possibly related to irreversible processes. Analyzing the evolution of such thermal hysteresis loops over successive cycles, we found that the assembly/disassembly ceases after some time, which is indicative of protein aging leading to its inability to self-assemble after a finite number of temperature cycles. The emergence of assembly-incompetent tubulin could have major consequences for human pathologies related to microtubules, including aging, neurodegenerative diseases and cancer.
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Phase transitions of liposomes are normally studied by differential scanning calorimetry. A suspension of liposomes is subjected to an increase (decrease) of temperature and when heat is absorbed (released), the liposomes transit from a gel (liquid) to a liquid (gel) phase. This endothermic (exothermic) process takes place at a temperature called the melting temperatureTm, which is distinctive of the type of lipids forming the vesicles. The vesicles, though, also modify their size in the transition. Indeed, the thickness of the membranes decreases (increases) because carbon tails misalign (align). Concomitant with the modifications in the membrane thickness, the diameter (D) of the liposomes changes too. Therefore, when they are inspected by light, the scattered signal carries information from such dilatation (contraction) process. We performed careful experiments using dynamic light scattering as a function of temperature to detect the size changes of different liposomes. Gaussian fits of the derivatives of theDvsTcurves coincide within 1% with thermograms, which hints to the possibility of performing thermodynamic studies of lipid systems employing light.
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Lipossomos , Fosfatidilcolinas , Varredura Diferencial de Calorimetria , Temperatura Alta , Luz , Lipossomos/química , Fosfatidilcolinas/química , Temperatura , TermodinâmicaRESUMO
Recent advances in molecular profiling, have reclassified medulloblastoma, an undifferentiated tumor of the posterior fossa, in at least four diseases, each one with differences in prognosis, epidemiology and sensibility to different treatments. The recommended management of a lesion with radiological characteristics suggestive of MB includes maximum safe resection followed by a post-surgical MR < 48 h, LCR cytology and MR of the neuroaxis. Prognostic factors, such as presence of a residual tumor volume > 1.5 cm2, presence of micro- or macroscopic dissemination, and age > 3 years as well as pathological (presence of anaplastic or large cell features) and molecular findings (group, 4, 3 or p53 SHH mutated subgroup) determine the risk of relapse and should guide adjuvant management. Although there is evidence that both high-risk patients and to a lesser degree, standard-risk patients benefit from adjuvant craneoespinal radiation followed by consolidation chemotherapy, tolerability is a concern in adult patients, leading invariably to dose reductions. Treatment after relapse is to be considered palliative and inclusion on clinical trials, focusing on the molecular alterations that define each subgroup, should be encouraged. Selected patients can benefit from surgical rescue or targeted radiation or high-dose chemotherapy followed by autologous self-transplant. Even in patients that are cured by chemorradiation presence of significant sequelae is common and patients must undergo lifelong follow-up.
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Neoplasias Cerebelares/diagnóstico , Neoplasias Cerebelares/terapia , Meduloblastoma/diagnóstico , Meduloblastoma/terapia , Adulto , Antineoplásicos/efeitos adversos , Antineoplásicos/uso terapêutico , Neoplasias Cerebelares/genética , Neoplasias Cerebelares/patologia , Cisplatino/efeitos adversos , Terapia Combinada/métodos , Medicina Baseada em Evidências , Humanos , Oncologia , Meduloblastoma/genética , Meduloblastoma/patologia , Terapia de Alvo Molecular/métodos , Recidiva Local de Neoplasia/terapia , Cuidados Paliativos , Complicações Pós-Operatórias/etiologia , Prognóstico , Radioterapia/efeitos adversos , Retratamento/métodos , Sociedades Médicas , Espanha , Vincristina/efeitos adversosRESUMO
Urothelial bladder cancer (UC) is the most common malignancy involving the urinary system and represents a significant health problem. Immunotherapy has been used for decades for UC with intravesical bacillus Calmette-Guérin (BCG) set as the standard of care for non-muscle-invasive bladder cancer (NMIBC). The advent of immune checkpoint inhibitors (ICIs) has completely transformed the treatment landscape of bladder cancer enabling to expand the treatment strategies. Novel ICIs have successfully shown improved outcomes on metastatic disease to such an extent that the standard of care paradigm has changed leading to the development of different trials with the aim of determining whether ICIs may have a role in early disease. The localized muscle-invasive bladder cancer (MIBC) scenario remains challenging since the recurrence rate continues to be high despite all therapeutic efforts. This article will review the current experience of ICIs in the neoadjuvant setting of UC, the clinical trials landscape and finally, an insight of what to expect in the immediate and mid-term future.
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Neoplasias da Bexiga Urinária/terapia , Humanos , Imunoterapia/métodos , Terapia Neoadjuvante/métodos , Invasividade Neoplásica/prevenção & controle , Recidiva Local de Neoplasia/imunologia , Recidiva Local de Neoplasia/terapiaRESUMO
BACKGROUND: Bromodomain and extra-terminal (BET) proteins are epigenetic readers that regulate expression of genes involved in oncogenesis. CC-90010 is a novel, oral, reversible, small-molecule BET inhibitor. PATIENTS AND METHODS: CC-90010-ST-001 (NCT03220347; 2015-004371-79) is a phase I dose-escalation and expansion study of CC-90010 in patients with advanced or unresectable solid tumors and relapsed/refractory (R/R) non-Hodgkin's lymphoma (NHL). We report results from the dose escalation phase, which explored 11 dose levels and four dosing schedules, two weekly (2 days on/5 days off; 3 days on/4 days off), one biweekly (3 days on/11 days off), and one monthly (4 days on/24 days off). The primary objectives were to determine the safety, maximum tolerated dose (MTD) and/or recommended phase II dose (RP2D) and schedule. Secondary objectives were to evaluate signals of early antitumor activity, pharmacokinetics, and pharmacodynamics. RESULTS: This study enrolled 69 patients, 67 with solid tumors and two with diffuse large B-cell lymphoma (DLBCL). The median age was 57 years (range, 21-80) and the median number of prior regimens was four (range, 1-9). Treatment-related adverse events (TRAEs) were mostly mild and manageable; grade 3/4 TRAEs reported in more than two patients were thrombocytopenia (13%), anemia, and fatigue (4% each). Six patients had dose-limiting toxicities. MTDs were 15 mg (2 days on/5 days off), 30 mg (3 days on/11 days off), and 45 mg (4 days on/24 days off). The RP2D and schedule selected for expansion was 45 mg (4 days on/24 days off). As of 8 October 2019, one patient with grade 2 astrocytoma achieved a complete response, one patient with endometrial carcinoma had a partial response, and six patients had prolonged stable disease ≥11 months. CONCLUSIONS: CC-90010 is well tolerated, with single-agent activity in patients with heavily pretreated, advanced solid tumors.
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Antineoplásicos , Linfoma Difuso de Grandes Células B , Linfoma não Hodgkin , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/efeitos adversos , Humanos , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Linfoma não Hodgkin/tratamento farmacológico , Dose Máxima Tolerável , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/tratamento farmacológico , Adulto JovemRESUMO
El presente artículo indaga la aparición de dos instituciones de control de la higiene pública en Chile entre los años 1879 y 1920: los protomedicatos y lazaretos. El objeto de estudio utiliza como caso la presencia de la viruela en La Araucanía. Se abordan las características y contexto que adquirió la instalación de estos dispositivos que permitieron al Estado de Chile operacionalizar el asunto de la higiene pública, lo que interpeló a los profesionales de la salud para avanzar a mayores niveles de perfeccionamiento del ejercicio profesional de la medicina. El Estado liberal positivista de fines de siglo XIX comprendió que el tema de la higiene no era solamente una cuestión de responsabilidad individual, sino que tenía una dimensión social, pública y medio ambiental. No sólo había personas que eran higiénicas, sino también ambientes higiénicos y antihigiénicos. Por tanto, se estudia la higiene, el tribunal del protomedicato, la hoja sanitaria, lazaretos, médicos y vacunadores; quienes estuvieron en permanente tensión con las autoridades del gobierno central debido a los insuficientes recursos proporcionados por el Estado para la atención de los enfermos contagiados con viruela. El estudio se orienta desde una metodología cualitativa con un diseño historiográfico con alcances descriptivos densos. Se han utilizado fuentes primarias y secundarias disponibles en archivos en Chile y Alemania. Los resultados evidencian que la presencia de viruela apareció violentamente en el centro sur de Chile en la segunda mitad del siglo XIX y permaneció en la Araucanía hasta la primera mitad del siglo XX. La violencia con que se desarrolló la viruela generó miedo e incertidumbre afectando a personas de diferentes clases sociales, y tuvo como una de sus causas principales las precarias condiciones de salubridad de la población.
This article investigates the emergence of two institutions for the control of public hygiene in Chile between 1879 and 1920: colleges of royal physicians and isolation hospitals using the case of smallpox in La Araucanía, a region located in the South of Chile. We cover the characteristics and context of these institutions that allowed the State of Chile to address the problems of public hygiene and to prompt health professionals to professionalize the practice of medicine. The liberal positivist state of the late nineteenth century understood that the issue of hygiene was not only a matter of individual responsibility but had a social, public, and environmental dimension. People practiced hygiene alongside the existence of hygienic and anti-hygienic environments. Therefore, hygiene, the royal colleges of physicians, health records, isolation hospitals, doctors, and vaccinators are studied. All of these components of the health care system of the time were in permanent tension with the central government authorities due to the insufficient resources provided by the state for the care of infected patients with smallpox. The study follows a qualitative methodology with a descriptive historiographic design. We used archival primary and secondary sources available in Chile and Germany. The results show that the presence of smallpox appeared ferociously in South-Central Chile in the second half of the 19th century and remained in La Araucanía until the first half of the 20th century. The extent to which smallpox spread, spawning fear and insecurity in people of different social classes, had as one of its leading causes the precarious conditions of health and hygiene of the population.
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Humanos , História do Século XIX , História do Século XX , Varíola/prevenção & controle , Varíola/transmissão , Varíola/epidemiologia , Higiene/história , Chile/epidemiologia , Atenção à Saúde , Hospitais de Isolamento/históriaRESUMO
We present a novel long-range surface plasmon polariton (LRSPP) device consisting of a suspended dielectric matrix in which an electrically active, millimeter-long metallic waveguide is embedded. We show that, by opening an air gap under the lower cladding, the influence of the substrate is suppressed and the symmetry of the thermo-optical distribution around the LRSPP waveguide is preserved over extended ranges of applied electrical current with minimal optical losses. Experimental results show that, compared to a standard nonsuspended structure, our device allows either the induction of a phase change that is three times larger, for a fixed electrical power, or, equivalently, a scaling down of the device to one-tenth of its original length, for a fixed phase change.
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We discuss the specific features of fiber-based implementations of optical sensing techniques based on spatiotemporal coherence-gated dynamic light scattering (DLS). This sensing approach has a number of unique capabilities such as an effective isolation of single scattering, a large sensitivity, and high collection efficiency, and it can also operate over a wide range of optical regimes while providing means for proper ensemble averaging. We review a number of applications in which these specific characteristics permit recovering information beyond the capabilities of traditional light-scattering-based techniques.
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BACKGROUND AND PURPOSE: Multifocal glioblastomas (ie, glioblastomas with multiple foci, unconnected in postcontrast pretreatment T1-weighted images) represent a challenge in clinical practice due to their poor prognosis. We wished to obtain imaging biomarkers with prognostic value that have not been found previously. MATERIALS AND METHODS: A retrospective review of 1155 patients with glioblastomas from 10 local institutions during 2006-2017 provided 97 patients satisfying the inclusion criteria of the study and classified as having multifocal glioblastomas. Tumors were segmented and morphologic features were computed using different methodologies: 1) measured on the largest focus, 2) aggregating the different foci as a whole, and 3) recording the extreme value obtained for each focus. Kaplan-Meier, Cox proportional hazards, correlations, and Harrell concordance indices (c-indices) were used for the statistical analysis. RESULTS: Age (P < .001, hazard ratio = 2.11, c-index = 0.705), surgery (P < .001, hazard ratio = 2.04, c-index = 0.712), contrast-enhancing rim width (P < .001, hazard ratio = 2.15, c-index = 0.704), and surface regularity (P = .021, hazard ratio = 1.66, c-index = 0.639) measured on the largest focus were significant independent predictors of survival. Maximum contrast-enhancing rim width (P = .002, hazard ratio = 2.05, c-index = 0.668) and minimal surface regularity (P = .036, hazard ratio = 1.64, c-index = 0.600) were also significant. A multivariate model using age, surgery, and contrast-enhancing rim width measured on the largest foci classified multifocal glioblastomas into groups with different outcomes (P < .001, hazard ratio = 3.00, c-index = 0.853, median survival difference = 10.55 months). Moreover, quartiles with the highest and lowest individual prognostic scores based on the focus with the largest volume and surgery were identified as extreme groups in terms of survival (P < .001, hazard ratio = 18.67, c-index = 0.967). CONCLUSIONS: A prognostic model incorporating imaging findings on pretreatment postcontrast T1-weighted MRI classified patients with glioblastoma into different prognostic groups.
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Neoplasias Encefálicas/classificação , Neoplasias Encefálicas/patologia , Glioblastoma/classificação , Glioblastoma/patologia , Adulto , Idoso , Neoplasias Encefálicas/diagnóstico por imagem , Feminino , Glioblastoma/diagnóstico por imagem , Humanos , Imageamento por Ressonância Magnética/métodos , Masculino , Pessoa de Meia-Idade , Prognóstico , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Análise de SobrevidaRESUMO
AIM: To define recommendations that permit safe management of antineoplastic medication, minimise medication errors and improve the safety of cancer patients undergoing treatment. METHODS: By reviewing the literature and consulting the websites of various health organisations and agencies, an expert committee from the Spanish Society of Hospital Pharmacy and the Spanish Society of Medical Oncology defined a set of safe practices covering all stages of providing cancer therapy to patients. The Spanish Society of Oncology Nursing revised and endorsed the final list. RESULTS: In total, 68 recommendations arranged in five sections were defined. They include issues concerning the training of health professionals, the technological resources needed, treatment planning, informing the patient and his/her family, the processes of prescribing, preparing, dispensing and administering cancer therapy (orally, parenterally or intrathecally), assessing patient adherence and treatment toxicity. CONCLUSIONS: It is essential for healthcare establishments to implement specific measures designed to prevent medication errors, in order to ensure the safety of cancer patients treated with antineoplastic medication.
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Antineoplásicos/uso terapêutico , Oncologia/normas , Conduta do Tratamento Medicamentoso/normas , Segurança do Paciente/normas , Antineoplásicos/efeitos adversos , Humanos , Oncologia/organização & administração , Erros de Medicação/prevenção & controle , Neoplasias/tratamento farmacológico , Enfermagem Oncológica/organização & administração , Serviço de Farmácia Hospitalar/organização & administração , EspanhaRESUMO
When dealing with dynamic scattering systems, being able to collect strong signals while maintaining a high signal-to-noise ratio (SNR) is critical. It is well known that a spatially coherent measurement provides the largest SNR, while a partially coherent one provides better means for proper spatial averaging. In this Letter, we present a robust implementation of a fiber-based, single-mode, common-path interferometer assisted by multimode interference. We show that light can be efficiently collected from larger coherent regions while keeping a high SNR that is comparable to that of a pure single-mode arrangement. Additionally, our implementation allows having both a stable local oscillator encoding information on the fiber-medium interface and a linear dependence on scattering density. These two attributes, in turn, permit accessing the effective optical properties of the dynamic complex system.
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Greenhouse warming is a predicted consequence of the Chicxulub impact, but supporting data are sparse. This shortcoming compromises understanding of the impact's effects, and it has persisted due to an absence of sections that both contain suitable material for traditional carbonate- or organic-based paleothermometry and are complete and expanded enough to resolve changes on short time scales. We address the problem by analyzing the oxygen isotopic composition of fish debris, phosphatic microfossils that are relatively resistant to diagenetic alteration, from the Global Stratotype Section and Point for the Cretaceous/Paleogene boundary at El Kef, Tunisia. We report an ~1 per mil decrease in oxygen isotopic values (~5°C warming) beginning at the boundary and spanning ~300 centimeters of section (~100,000 years). The pattern found matches expectations for impact-initiated greenhouse warming.