Survival Benefit for Individuals With Constitutional Mismatch Repair Deficiency Undergoing Surveillance

PURPOSE: Constitutional mismatch repair deficiency syndrome (CMMRD) is a lethal cancer predisposition syndrome characterized by early-onset synchronous and metachronous multiorgan tumors. We designed a surveillance protocol for early tumor detection in these individuals. PATIENTS AND METHODS: Data were collected from patients with confirmed CMMRD who were registered in the International Replication Repair Deficiency Consortium. Tumor spectrum, efficacy of the surveillance protocol, and malignant transformation of low-grade lesions were examined for the entire cohort. Survival outcomes were analyzed for patients followed prospectively from the time of surveillance implementation. RESULTS: A total of 193 malignant tumors in 110 patients were identified. Median age of first cancer diagnosis was 9.2 years (range: 1.7-39.5 years). For patients undergoing surveillance, all GI and other solid tumors, and 75% of brain cancers were detected asymptomatically. By contrast, only 16% of hematologic malignancies were detected asymptomatically (P \u3c .001). Eighty-nine patients were followed prospectively and used for survival analysis. Five-year overall survival (OS) was 90% (95% CI, 78.6 to 100) and 50% (95% CI, 39.2 to 63.7) when cancer was detected asymptomatically and symptomatically, respectively (P = .001). Patient outcome measured by adherence to the surveillance protocol revealed 4-year OS of 79% (95% CI, 54.8 to 90.9) for patients undergoing full surveillance, 55% (95% CI, 28.5 to 74.5) for partial surveillance, and 15% (95% CI, 5.2 to 28.8) for those not under surveillance (P \u3c .0001). Of the 64 low-grade tumors detected, the cumulative likelihood of transformation from low-to high-grade was 81% for GI cancers within 8 years and 100% for gliomas in 6 years. CONCLUSION: Surveillance and early cancer detection are associated with improved OS for individuals with CMMRD

Multidifferential study of identified charged hadron distributions in ZZ-tagged jets in proton-proton collisions at s=\sqrt{s}=13 TeV

Jet fragmentation functions are measured for the first time in proton-proton collisions for charged pions, kaons, and protons within jets recoiling against a $Z$ boson. The charged-hadron distributions are studied longitudinally and transversely to the jet direction for jets with transverse momentum 20 $< p_{\textrm{T}} < 100$ GeV and in the pseudorapidity range $2.5 < \eta < 4$. The data sample was collected with the LHCb experiment at a center-of-mass energy of 13 TeV, corresponding to an integrated luminosity of 1.64 fb$^{-1}$. Triple differential distributions as a function of the hadron longitudinal momentum fraction, hadron transverse momentum, and jet transverse momentum are also measured for the first time. This helps constrain transverse-momentum-dependent fragmentation functions. Differences in the shapes and magnitudes of the measured distributions for the different hadron species provide insights into the hadronization process for jets predominantly initiated by light quarks.Comment: All figures and tables, along with machine-readable versions and any supplementary material and additional information, are available at https://cern.ch/lhcbproject/Publications/p/LHCb-PAPER-2022-013.html (LHCb public pages

Study of the B−→Λc+Λˉc−K−B^{-} \to \Lambda_{c}^{+} \bar{\Lambda}_{c}^{-} K^{-} decay

The decay $B^{-} \to \Lambda_{c}^{+} \bar{\Lambda}_{c}^{-} K^{-}$ is studied in proton-proton collisions at a center-of-mass energy of $\sqrt{s}=13$ TeV using data corresponding to an integrated luminosity of 5 $\mathrm{fb}^{-1}$ collected by the LHCb experiment. In the $\Lambda_{c}^+ K^{-}$ system, the $\Xi_{c}(2930)^{0}$ state observed at the BaBar and Belle experiments is resolved into two narrower states, $\Xi_{c}(2923)^{0}$ and $\Xi_{c}(2939)^{0}$, whose masses and widths are measured to be $$m(\Xi_{c}(2923)^{0}) = 2924.5 \pm 0.4 \pm 1.1 \,\mathrm{MeV}, \\ m(\Xi_{c}(2939)^{0}) = 2938.5 \pm 0.9 \pm 2.3 \,\mathrm{MeV}, \\ \Gamma(\Xi_{c}(2923)^{0}) = \phantom{000}4.8 \pm 0.9 \pm 1.5 \,\mathrm{MeV},\\ \Gamma(\Xi_{c}(2939)^{0}) = \phantom{00}11.0 \pm 1.9 \pm 7.5 \,\mathrm{MeV},$$ where the first uncertainties are statistical and the second systematic. The results are consistent with a previous LHCb measurement using a prompt $\Lambda_{c}^{+} K^{-}$ sample. Evidence of a new $\Xi_{c}(2880)^{0}$ state is found with a local significance of $3.8\,\sigma$, whose mass and width are measured to be $2881.8 \pm 3.1 \pm 8.5\,\mathrm{MeV}$ and $12.4 \pm 5.3 \pm 5.8 \,\mathrm{MeV}$, respectively. In addition, evidence of a new decay mode $\Xi_{c}(2790)^{0} \to \Lambda_{c}^{+} K^{-}$ is found with a significance of $3.7\,\sigma$. The relative branching fraction of $B^{-} \to \Lambda_{c}^{+} \bar{\Lambda}_{c}^{-} K^{-}$ with respect to the $B^{-} \to D^{+} D^{-} K^{-}$ decay is measured to be $2.36 \pm 0.11 \pm 0.22 \pm 0.25$, where the first uncertainty is statistical, the second systematic and the third originates from the branching fractions of charm hadron decays.Comment: All figures and tables, along with any supplementary material and additional information, are available at https://cern.ch/lhcbproject/Publications/p/LHCb-PAPER-2022-028.html (LHCb public pages

Measurement of the ratios of branching fractions R(D∗)\mathcal{R}(D^{*}) and R(D0)\mathcal{R}(D^{0})

The ratios of branching fractions $\mathcal{R}(D^{*})\equiv\mathcal{B}(\bar{B}\to D^{*}\tau^{-}\bar{\nu}_{\tau})/\mathcal{B}(\bar{B}\to D^{*}\mu^{-}\bar{\nu}_{\mu})$ and $\mathcal{R}(D^{0})\equiv\mathcal{B}(B^{-}\to D^{0}\tau^{-}\bar{\nu}_{\tau})/\mathcal{B}(B^{-}\to D^{0}\mu^{-}\bar{\nu}_{\mu})$ are measured, assuming isospin symmetry, using a sample of proton-proton collision data corresponding to 3.0 fb${ }^{-1}$ of integrated luminosity recorded by the LHCb experiment during 2011 and 2012. The tau lepton is identified in the decay mode $\tau^{-}\to\mu^{-}\nu_{\tau}\bar{\nu}_{\mu}$. The measured values are $\mathcal{R}(D^{*})=0.281\pm0.018\pm0.024$ and $\mathcal{R}(D^{0})=0.441\pm0.060\pm0.066$, where the first uncertainty is statistical and the second is systematic. The correlation between these measurements is $\rho=-0.43$. Results are consistent with the current average of these quantities and are at a combined 1.9 standard deviations from the predictions based on lepton flavor universality in the Standard Model.Comment: All figures and tables, along with any supplementary material and additional information, are available at https://cern.ch/lhcbproject/Publications/p/LHCb-PAPER-2022-039.html (LHCb public pages

Cross-species Modeling of Replication Repair Deficient Cancers

Replication repair deficiency (RRD) is a leading cause of cancer hypermutation. RRD cancers are found across tissue types, often resistant to chemo-radiation therapy, and therefore universally lethal. Among children, germline deficiencies in either replication repair mechanism—DNA polymerase proofreading or the mismatch repair (MMR) system—result in early-onset cancers which were considered incurable. Despite recent success of immune checkpoint inhibition (ICI) in treating RRD cancers, most tumors remain refractory or unresponsive. Novel treatments and robust models to study RRD cancers are lacking.Using a multi-omics approach, we found that RRD hypermutant cancers are enriched for RAS/MAPK mutations, exhibited increased RAS/MAPK pathway activity, and responded to MEK inhibition. Treatment of patients with RRD gliomas revealed durable responses to MEK inhibition, suggesting these tumors are addicted to oncogenic pathways resulting in favorable response to targeted therapies. To better study hypermutant cancers in vivo, we established mouse models harboring cancer-associated POLE mutations P286R and S459F, which caused rapid yet distinct time to cancer initiation, enabled stratification of POLE mutations into 3 groups based on clinical phenotype and mutagenicity, and mirrored human cancer ultrahypermutation and mutational signatures. These animals primarily developed lymphomas which could not be prevented, and were likely exacerbated by ICI, as observed in humans. We then used the Pole models to study combined RRD (MMRD+Pole mutations), which commonly occur in childhood hypermutant cancers. We developed novel brain and gastrointestinal-specific RRD mouse models. Both models resulted in highly penetrant, rapid onset cancers that genomically mimicked human RRD cancers. We observed that increased RRD likely contributes to mutational loads not sustainable for normal cell function as manifested by maldevelopment and malfunction of colon and brain from MMRD+Pole mutant homozygous mice. Moreover, serial passaging of RRD brain tumors revealed differences in mutation accumulation between intracranially and subcutaneously transplanted tumors in immunocompromised and immunocompetent animals, likely due to differences in immune surveillance within and outside the brain. Collectively, our observations provide insights into the carcinogenesis of POLE-driven tumors, information for genetic counselling, surveillance, and immunotherapy for patients. Finally, this work provides insight on immune editing, and platforms to further study RRD cancers in vivo.Ph.D

Quality of life in institutionalized elderly people with moderate-severe dementia: Contributions from music therapy

Different studies show the benefits of music therapy on the Quality of Life of people with dementia, especially on the maintenance of preserved skills, expression, and socialization. The objectives of this presentation are: (1) To present empirical data on the effects of music therapy programs on the quality of life of elderly people with moderate-severe dementia, who live in nursing homes; and (2) To identify and analyze the changes in affect that may take place during music therapy sessions. The design used was quasi-experimental pretest/posttest. The sample included 10 people with moderate-severe dementia. The scale GENCAT on quality of life (Verdugo, 2008) was administered at two different times: At sessions 1 and 12; and sessions 1, 6, and 12 were recorded for “post-hoc” analysis. Data were analyzed with Windows software (version 17) and SCRIBE 4.1, depending on the objectives. Results show no changes in the overall quality of life, but positive changes in the emotional well-being and personal development subscales. Also video observations show positive changes in affect after the music therapy program

Quality of life in institutionalized elderly people with moderate-severe dementia. Contributions from music therapy

Diferentes estudios muestran los beneficios de la musicoterapia en la calidad de vida de las personas con demencia, especialmente en el mantenimiento de las habilidades conservadas, la expresión y la socialización. Los objetivos de esta exposición son: (1) Presentar datos empíricos sobre los efectos de los programas de musicoterapia en la calidad de vida de las personas mayores con demencia moderada-grave, que viven en residencias de ancianos; y (2) Identificar y analizar los cambios en el afecto que pueden tener lugar durante las sesiones de musicoterapia. El diseño utilizado fue cuasi-experimental pretest/posttest. La muestra incluyó a 10 personas con demencia moderada-grave. La escala GENCAT sobre calidad de vida (Verdugo, 2008) se aplicó en dos momentos diferentes: en las sesiones 1 y 12; y se registraron las sesiones 1, 6 y 12 para su análisis "post-hoc". Los datos fueron analizados con software Windows (versión 17) y SCRIBE 4.1, dependiendo de los objetivos. Los resultados no muestran cambios en la calidad de vida general, sino cambios positivos en las subescalas de bienestar emocional y desarrollo personal. También las observaciones de video muestran cambios positivos en el afecto después del programa de musicoterapia.Different studies show the benefits of music therapy on the Quality of Life of people with dementia, especially on the maintenance of preserved skills, expression, and socialization. The objectives of this presentation are: (1) To present empirical data on the effects of music therapy programs on the quality of life of elderly people with moderate-severe dementia, who live in nursing homes; and (2) To identify and analyze the changes in affect that may take place during music therapy sessions. The design used was quasi-experimental pretest/posttest. The sample included 10 people with moderate- severe dementia. The scale GENCAT on quality of life (Verdugo, 2008) was administered at two different times: At sessions 1 and 12; and sessions 1, 6, and 12 were recorded for “post-hoc” analysis. Data were analyzed with Windows software (version 17) and SCRIBE 4.1, depending on the objectives. Results show no changes in the overall quality of life, but positive changes in the emotional well-being and personal development subscales. Also video observations show positive changes in affect after the music therapy program.peerReviewe

Aportacions de la musicoteràpia a les persones amb demència

La incidència de les demències en la societat actual va en augment. A causa de la seva llarga durada i de les conseqüències físiques, psicològiques i socials que representa s’ha evidenciat la necessitat de buscar diferents tipus d’intervencions, tant farmacològiques com biopsicosocials, que pal·liïn els seus efectes negatius, ajudin el malalt a preservar, el màxim temps possible, les seves funcions, i contribueixin a una millora de la qualitat de vida de la persona amb demència i dels seus cuidadors i familiars. En aquest article es farà una aproximació breu a les demències i als tractaments biopsicosocials, per entrar amb més detall en la intervenció musicoterapèutica. Es donarà a conèixer què és la musicoteràpia, quins són els beneficis que aquesta teràpia aporta al malalt i a la seva qualitat de vida segons les recerques científiques actuals més rellevants, per acabar mostrant com és el treball del musicoterapeuta en les diferents fases de les demències

Survival benefit for individuals with constitutional mismatch repair deficiency undergoing surveillance

Purpose: Constitutional mismatch repair deficiency syndrome (CMMRD) is a lethal cancer predisposition syndrome characterized by early-onset synchronous and metachronous multiorgan tumors. We designed a surveillance protocol for early tumor detection in these individuals.Patients and methods: Data were collected from patients with confirmed CMMRD who were registered in the International Replication Repair Deficiency Consortium. Tumor spectrum, efficacy of the surveillance protocol, and malignant transformation of low-grade lesions were examined for the entire cohort. Survival outcomes were analyzed for patients followed prospectively from the time of surveillance implementation.Results: A total of 193 malignant tumors in 110 patients were identified. Median age of first cancer diagnosis was 9.2 years (range: 1.7-39.5 years). For patients undergoing surveillance, all GI and other solid tumors, and 75% of brain cancers were detected asymptomatically. By contrast, only 16% of hematologic malignancies were detected asymptomatically (P \u3c .001). Eighty-nine patients were followed prospectively and used for survival analysis. Five-year overall survival (OS) was 90% (95% CI, 78.6 to 100) and 50% (95% CI, 39.2 to 63.7) when cancer was detected asymptomatically and symptomatically, respectively (P = .001). Patient outcome measured by adherence to the surveillance protocol revealed 4-year OS of 79% (95% CI, 54.8 to 90.9) for patients undergoing full surveillance, 55% (95% CI, 28.5 to 74.5) for partial surveillance, and 15% (95% CI, 5.2 to 28.8) for those not under surveillance (P \u3c .0001). Of the 64 low-grade tumors detected, the cumulative likelihood of transformation from low-to high-grade was 81% for GI cancers within 8 years and 100% for gliomas in 6 years.Conclusion: Surveillance and early cancer detection are associated with improved OS for individuals with CMMRD