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Papers by Benjamin Bruno
Revue Médicale Suisse, 2019
Le myélome multiple (MM) est le troisième cancer hématologique le plus fréquent. Le MM est une pr... more Le myélome multiple (MM) est le troisième cancer hématologique le plus fréquent. Le MM est une prolifération de plasmocytes. Son incidence passe de moins de 1 pour 100 000 à 40 ans, à 40 pour 100 000 à 80 ans. Aujourd’hui, il existe de nombreuses lignes de traitement pour le MM, qui vont de simples soins d’accompagnement à l’autogreffe. La décision quant à la meilleure thérapie peut s’avérer délicate au sein de la population gériatrique. En effet, cette population est hétérogène et il est risqué de baser la décision thérapeutique sur une limite d’âge. L’évaluation gériatrique est donc fondamentale, car elle permet de catégoriser le patient afin d’aider le clinicien à choisir la meilleure stratégie thérapeutique et d’évaluer les besoins spécifiques du patient
Revue Médicale Suisse, 2019
German Journal of Microbiology, 2021
Nowadays, rabbits and guinea pigs are frequently adopted as companion animals, representing a veh... more Nowadays, rabbits and guinea pigs are frequently adopted as companion animals, representing a vehicle for the dissemination of potentially pathogenic and allergenic fungi to their tutors. This study aimed to characterize the cutaneous mycobiota of these species and evaluate the association between mycological cultures results and several variables related to these animals’ husbandry. Hair and scales samples (n=102) were collected from 32 rabbits and 19 guinea pigs: 51 by pulling hairs surrounding lesions and collecting scales (if lesions present) or along the body of the animal (if absent); the other 51 samples were collected using Mackenzie’s technique. Samples were inoculated in Sabouraud Chloramphenicol Agar and Dermatophyte Test Media and observed daily during the incubation period. Isolated fungal species were identified based on their macro and microscopic morphology. A questionnaire was provided to the animal tutors to collect information on animal husbandry. The most frequen...
Andrology, 2022
Male hypogonadism (testosterone level < 300 ng/dl) is a clinical syndrome that results from fa... more Male hypogonadism (testosterone level < 300 ng/dl) is a clinical syndrome that results from failure of the testis to produce physiological levels of testosterone. Most marketed testosterone replacement therapy products often require multiple dose adjustment clinic visits to achieve the desired, eugonadal testosterone levels.
Journal of the Endocrine Society, 2021
Male hypogonadism is characterized by symptoms and deficiency (<300 ng/dL) in levels of in tot... more Male hypogonadism is characterized by symptoms and deficiency (<300 ng/dL) in levels of in total testosterone (TT), a critical hormone for sexual, cognitive, and body function and development. TLANDO, a testosterone undecanoate (TU) comprising lymphatically delivered oral testosterone replacement therapy (TRT) option not requiring dose titration, treatment has demonstrated effective restoration in hypogonadal men of TT levels to the eugonadal range in multiple clinical studies. TLANDO therapy resulted in decreased sex hormone binding globulin with increased free testosterone (FT). TLANDO’s unique delivery system enables consistent restoration of TT regardless of meal fat content. Moreover, TLANDO has shown potential to improve liver health through resolution of fatty liver disease in hypogonadal men and is not known to have any adverse liver effects. However, it is unclear if fixed dose TLANDO therapy without dose adjustment improves symptoms of psychosexual functions. The object...
Blood, 2020
Introduction Allogeneic hematopoietic stem cell transplantation (HSCT) is a well-established ther... more Introduction Allogeneic hematopoietic stem cell transplantation (HSCT) is a well-established therapeutic modality for a variety of hematological malignancies and congenital disorders. One of the major complications of the procedure is graft-versus-host-disease (GVHD) initiated by T cells co-administered with the graft. Removal of donor T cells from the graft is a widely employed and effective strategy to prevent GVHD, although its impact on post-transplant immune reconstitution might significantly affect anti-tumor and anti-infectious responses. Several approaches of T cell depletion (TCD) exist, including in vivo depletion using anti-thymocyte globulin (ATG) and/or post-transplant cyclophosphamide (PTCy) as well as in vitro manipulation of the graft. In this work, we analyzed the impact of different T cell depletion strategies on immune reconstitution after allogeneic HSCT. Methods We retrospectively analysed data from 168 patients transplanted between 2015 and 2019 at Geneva Unive...
Revue medicale suisse, 2019
The prevalence of cancer is increasing, with an estimated number of new cases of 21.6 million wor... more The prevalence of cancer is increasing, with an estimated number of new cases of 21.6 million worldwide by 2030. Progress in cancer therapies has turned it into a chronic disease. Physical exercise is essential both for the general population and for oncology patients. Practicing exercise reduces the risk of developing certain cancer types and, in oncologic patients, it can reduce symptoms secondary to the disease and to treatment as well as decrease the risk of relapsing. Encouraging adapted physical exercise to every oncologic patient is therefore essential (or crucial). It is recommended to practice regular physical activity equivalent to 150 minutes of moderate intensity or 75 minutes of high intensity activity per week.
Journal of Urology, 2020
INTRODUCTION AND OBJECTIVE: Chronic use of testosterone replacement therapy (TRT) might impact ca... more INTRODUCTION AND OBJECTIVE: Chronic use of testosterone replacement therapy (TRT) might impact cardiovascular (CV) risk. Clinical trials for recently approved TRTs have shown impacts on blood pressure (BP) that led to an increase anti-hypertensive dose or new starts: e.g., Xyosted (10% of patients in a 1-year study) and Jatenzo (7.2% in a 4-month study). Here we present the effect of oral testosterone undecanoate (TLANDO, a novel prodrug of bioidentical testosterone) on BP and CV risk including Framingham Risk Score (FRS), and dipping patterns. The objective was to assess the impact of TLADO treatment on BP and CV risk in hypogonadal men. METHODS: Assessment of BP was conducted in a 16-week, multicenter, open-label, single arm ambulatory blood pressure monitoring (ABPM) study in hypogonadal men (N[138). A fixed dose of 225 mg TLANDO was given BID orally for 16 weeks. 24-hr mean changes from baseline (CBL) of BP were measured and analyzed. Subgroup analysis of systolic blood pressure (SBP) CBL was performed in subjects categorized as low, moderate, or high CV FRS risk at baseline (BL). Dipping was also measured. Dipping was categorized as reverse dipper (<0%), non-dipper (0-10%), dipper (10-20%), and extreme dipper (!20%). RESULTS: Demographics were 53.8 AE10.2 yrs, BMI 33.1 AE5.8 kg/m 2 , 79% white ethinicity. Co-morbidities were obesity (30%), type 2 diabetes (24%) and hypertension (48%). 126 subjects completed the study and 118 subjects had valid 24-hr evaluable ABPM data at both baseline and EOS. Overall, T was well tolerated with no death, no drug related SAEs, and no major adverse cardiovascular events (MACE). 1.4% of subjects either had an increase in anti-hypertensive medication dose or started a new medication with T treatment. 24-hr mean (95% CI) SBP CBL was 3.8 AE2.1 mmHg. 25 subjects had SBP>140 mmHg at BL and their 24-hr mean SBP CBL was-3.4 mmHg. Among them, 8 (32%) subjects were normalized post-treatment. Based on FRS categories at BL, 40 (33.9%), 74 (62.7%), and 4 (3.4%) subjects were at low, moderate and high risk, respectively. 24-hr mean SBP CBL for low, moderate, and high-risk subjects was 2.6, 4.8, and-1.8 mmHg, respectively. Post TLANDO treatment, shifts from less dippers at BL to greater dippers at EOS were slightly higher (or comparable with the opposite shifts) implying lower all-cause mortality. CONCLUSIONS: Marginal increases in BP, the dipping shifts, and the FRS with TLANDO treatment does not appear to have a meaningful impact on CV risk.
Revue medicale suisse, 2019
Multiple myeloma (MM) is the third most common hematological cancer. MM is a proliferation of pla... more Multiple myeloma (MM) is the third most common hematological cancer. MM is a proliferation of plasma cells Its incidence increases from 1 per 100 000 at 40 years to 40 per 100 000 at 80 years. Today, there are many treatment strategies for MM that go from simple care to self-transplantation. Choosing the most appropriate treatment can be challenging in geriatric patients. This population is heterogeneous and therapeutic decisions shouldn't be based on an age limit. Therefore, geriatric assessment is essential to help the clinician choose the best therapeutic strategy and assess the patient's specific needs.
Blood, 2020
Background: The AML EBMT Cytogenetic Risk score is a new prognostic model recently published (Can... more Background: The AML EBMT Cytogenetic Risk score is a new prognostic model recently published (Canaani et al. Leukemia. 2019 Aug;33(8):1944-1952; Nagler el al. Am J Hematol. 2020 Jun 12) combining cytogenetics and FLT3ITD status for AML patients in complete remission (CR) at transplant time. The AML EBMT Cytogenetic Risk score is prognostic for leukemia-free survival (LFS), overall survival (OS), GVHD-free/relapse-free survival (GRFS) and cumulative incidence of relapse (CIR). In our centre, we frequently offer in-vitro partial T-cell depleted graft (pTDEP) for patient in CR to decrease morbidity and mortality associated with graft-versus-host disease (GvHD). Currently, The AML EBMT Cytogenetic Risk score has not been evaluated in this population. Aims: We investigate the impact of the AML EBMT Cytogenetic Risk score for 3 years OS, LFS, GRFS, CIR and NRM in a cohort with patients allografted with pTDEP graft. Methods: All consecutive ≥18 years patients who received a first allograft...
Journal of the Endocrine Society, 2020
Most testosterone (T) replacement therapy (TRT) products have relied on dose titration to achieve... more Most testosterone (T) replacement therapy (TRT) products have relied on dose titration to achieve eugonadal levels. However, dose titration in clinical practice can be time-consuming, expensive, and subject to errors. TLANDO (LPCN 1021) is a novel oral testosterone undecanoate (TU) product absorbed via the intestinal lymphatic pathway. A previous clinical study (NCT02081300) suggested that titration with TLANDO has little to no impact to improve PK profiles. The objective of this study was to assess whether fixed dose of TLANDO can restore testosterone to eugonadal levels. A 24 day, open-label, single-arm, multicenter study with TLANDO in hypogonadal men (NCT03242590) was conducted. Subjects (N=95) received 225 mg testosterone undecanoate orally twice a day (i.e., 30 minutes after morning and evening meals) for 24 days. On Day 24, blood samples were collected over a 24 hour period. The primary endpoint was the percentage of TLANDO-treated subjects who achieved a 24-hour average seru...
Virchows Archiv, 2018
The assessment of nodal metastases in gynecological surgical specimen is an important staging par... more The assessment of nodal metastases in gynecological surgical specimen is an important staging parameter, directing further therapeutic procedures. Since the number of lymph nodes (LNs) removed is seen as an indicator of surgical and pathological quality, the demand for higher lymph node (LN) counts is raising. The goal of this prospective study was the comparison between lymph node counts of macroscopically detectable LNs and the LN yield by complete embedding and proceeding of all submitted LN-containing tissue in the pathology laboratory. One hundred six cases of cervical, uterine, or ovarian cancer, treated in three different hospitals within 3 years, were analyzed. All tissue submitted to the pathology from the surgically performed LN dissections was completely dissected and embedded in the institute of pathology. Subsequently, the amount of LN of all macroscopically detectable nodes was compared to the final histologically reached numbers of LN. Furthermore the histologically visible area of the LNs and their metastases was analyzed to assess the relation of LN numbers to the whole examined LN area. Complete embedding raises the average number of LN counted by 3 to 7 but did only minimally increase the LN area for microscopical examination by about 5% due to the small area of the additional LNs in the remaining fat tissue. The staging was in no case altered by complete embedding, even when additional nodal metastases were detected in the remaining fat tissue, since this was only seen in cases which had already metastatic nodes. Complete embedding of LN-containing tissue did not provide relevant additional staging information and seems therefore unnecessarily laborious, careful pathological work-up assumed.
Oncotarget, 2019
Introduction: Mammography is the gold standard for early breast cancer detection, but shows impor... more Introduction: Mammography is the gold standard for early breast cancer detection, but shows important limitations. Blood-based approaches on basis of cell-free DNA (cfDNA) provide minimally invasive screening tools to characterize epigenetic alterations of tumor suppressor genes and could serve as a liquid biopsy, complementing mammography. Methods: Potential biomarkers were identified from The Cancer Genome Atlas (TCGA), using HumanMethylation450-BeadChip data. Promoter methylation status was evaluated quantitatively by pyrosequencing in a serum test cohort (n = 103), a serum validation cohort (n = 368) and a plasma cohort (n = 125). Results: SPAG6, NKX2-6 and PER1 were identified as novel biomarker candidates. ITIH5 was included on basis of our previous work. In the serum test cohort, a panel of SPAG6 and ITIH5 showed 63% sensitivity for DCIS and 51% sensitivity for early invasive tumor (pT1, pN0) detection at 80% specificity. The serum validation cohort revealed 50% sensitivity for DCIS detection on basis of NKX2-6 and ITIH5. Furthermore, an inverse correlation between methylation frequency and cfDNA concentration was uncovered. Therefore, markers were tested in a plasma cohort, achieving a 64% sensitivity for breast cancer detection using SPAG6, PER1 and ITIH5. Conclusions: Although liquid biopsy remains challenging, a combination of SPAG6, NKX2-6, ITIH5 and PER1 (SNiPER) provides a promising tool for blood-based breast cancer detection.
The Journal of Physical Chemistry B, 2018
The oncogenic gene product Bcr-Abl is the principal cause of chronic myeloid leukemia (CML) and t... more The oncogenic gene product Bcr-Abl is the principal cause of chronic myeloid leukemia (CML) and though several therapies exist to curb the aberrant kinase activity of Bcr-Abl through targeting of the Abl kinase domain, these therapies are rendered ineffective by frequent mutations in the corresponding gene. It has been demonstrated that a designed protein known as CCmut3 is able to produce a dominant negative inactivating effect on Bcr-Abl kinase by preferentially oligomerizing with the N-terminal coiled-coil oligomerization domain of Bcr-Abl (Bcr-CC) to effectively reduce the oncogenic potential of Bcr-Abl. However, the sheer length of the CCmut3 peptide introduces a high degree of conformational variability and opportunity for targeting by intracellular proteolytic mechanisms. Here we have examined the effects on introducing one or two molecular staples, or cross-links, spanning i,i+7 backbone residues of the CCmut3 construct which have been suggested to reinforce α-helical conformation, enhance cellular internalization, and increase resistance to proteolytic degradation leading to enhanced pharmacokinetic properties. The importance of optimizing staple location along a highly-tuned biological construct such as CCmut3 has been widely emphasized and as such, we have employed in silico techniques to swiftly build, relax, and characterize a large number of candidates. This approach effectively allowed exploring each and every possible staple location along the peptide backbone so that every possible candidate is considered. While many of stapled candidate peptides displayed enhanced binding characteristics for Bcr-CC and improved conformational stability in the (Bcr-CC) bound form, simulations of the stapled peptides in the unbound form revealed widespread conformational variability among stapled candidates dependent on staple type and location, implicating the molecular replacement of helix-stabilizing residues with staple-containing residues in disrupting the native α-helical conformation of
Chemistry - A European Journal, 2017
The application of thiol-yne/thiol-ene reactions to synthesize mono-a nd bicyclic-stapled peptide... more The application of thiol-yne/thiol-ene reactions to synthesize mono-a nd bicyclic-stapled peptides and proteins is reported. First, at hiol-ene-based peptide-stapling method in aqueous conditions was developed. This method enabled the efficient stapling of recombinantly expressed coil-coiled proteins. The resulting stapled proteind emonstrated higher stabilityi ni ts secondarys tructure than the unstapled version. Furthermore, at hiol-yne coupling was performed by using an a,w-diynet or eact with two cysteiner esidues to synthesize as tapled peptide with two vinyl sulfide groups. The stapled peptide could furtherr eact with another biscysteinep eptide to yield ab icyclic stapled peptidew ith enhanced properties. For example, the cell permeability of as tapled peptidew as furtheri ncreased by appending an oligoarginine cell-penetratingp eptide. The robustness and versatility of thiol-yne/thiol-ener eactions that can be applied to both synthetic ande xpressedp eptides and proteins were demonstrated.
Revue Médicale Suisse, 2019
Le myélome multiple (MM) est le troisième cancer hématologique le plus fréquent. Le MM est une pr... more Le myélome multiple (MM) est le troisième cancer hématologique le plus fréquent. Le MM est une prolifération de plasmocytes. Son incidence passe de moins de 1 pour 100 000 à 40 ans, à 40 pour 100 000 à 80 ans. Aujourd’hui, il existe de nombreuses lignes de traitement pour le MM, qui vont de simples soins d’accompagnement à l’autogreffe. La décision quant à la meilleure thérapie peut s’avérer délicate au sein de la population gériatrique. En effet, cette population est hétérogène et il est risqué de baser la décision thérapeutique sur une limite d’âge. L’évaluation gériatrique est donc fondamentale, car elle permet de catégoriser le patient afin d’aider le clinicien à choisir la meilleure stratégie thérapeutique et d’évaluer les besoins spécifiques du patient
Revue Médicale Suisse, 2019
German Journal of Microbiology, 2021
Nowadays, rabbits and guinea pigs are frequently adopted as companion animals, representing a veh... more Nowadays, rabbits and guinea pigs are frequently adopted as companion animals, representing a vehicle for the dissemination of potentially pathogenic and allergenic fungi to their tutors. This study aimed to characterize the cutaneous mycobiota of these species and evaluate the association between mycological cultures results and several variables related to these animals’ husbandry. Hair and scales samples (n=102) were collected from 32 rabbits and 19 guinea pigs: 51 by pulling hairs surrounding lesions and collecting scales (if lesions present) or along the body of the animal (if absent); the other 51 samples were collected using Mackenzie’s technique. Samples were inoculated in Sabouraud Chloramphenicol Agar and Dermatophyte Test Media and observed daily during the incubation period. Isolated fungal species were identified based on their macro and microscopic morphology. A questionnaire was provided to the animal tutors to collect information on animal husbandry. The most frequen...
Andrology, 2022
Male hypogonadism (testosterone level < 300 ng/dl) is a clinical syndrome that results from fa... more Male hypogonadism (testosterone level < 300 ng/dl) is a clinical syndrome that results from failure of the testis to produce physiological levels of testosterone. Most marketed testosterone replacement therapy products often require multiple dose adjustment clinic visits to achieve the desired, eugonadal testosterone levels.
Journal of the Endocrine Society, 2021
Male hypogonadism is characterized by symptoms and deficiency (<300 ng/dL) in levels of in tot... more Male hypogonadism is characterized by symptoms and deficiency (<300 ng/dL) in levels of in total testosterone (TT), a critical hormone for sexual, cognitive, and body function and development. TLANDO, a testosterone undecanoate (TU) comprising lymphatically delivered oral testosterone replacement therapy (TRT) option not requiring dose titration, treatment has demonstrated effective restoration in hypogonadal men of TT levels to the eugonadal range in multiple clinical studies. TLANDO therapy resulted in decreased sex hormone binding globulin with increased free testosterone (FT). TLANDO’s unique delivery system enables consistent restoration of TT regardless of meal fat content. Moreover, TLANDO has shown potential to improve liver health through resolution of fatty liver disease in hypogonadal men and is not known to have any adverse liver effects. However, it is unclear if fixed dose TLANDO therapy without dose adjustment improves symptoms of psychosexual functions. The object...
Blood, 2020
Introduction Allogeneic hematopoietic stem cell transplantation (HSCT) is a well-established ther... more Introduction Allogeneic hematopoietic stem cell transplantation (HSCT) is a well-established therapeutic modality for a variety of hematological malignancies and congenital disorders. One of the major complications of the procedure is graft-versus-host-disease (GVHD) initiated by T cells co-administered with the graft. Removal of donor T cells from the graft is a widely employed and effective strategy to prevent GVHD, although its impact on post-transplant immune reconstitution might significantly affect anti-tumor and anti-infectious responses. Several approaches of T cell depletion (TCD) exist, including in vivo depletion using anti-thymocyte globulin (ATG) and/or post-transplant cyclophosphamide (PTCy) as well as in vitro manipulation of the graft. In this work, we analyzed the impact of different T cell depletion strategies on immune reconstitution after allogeneic HSCT. Methods We retrospectively analysed data from 168 patients transplanted between 2015 and 2019 at Geneva Unive...
Revue medicale suisse, 2019
The prevalence of cancer is increasing, with an estimated number of new cases of 21.6 million wor... more The prevalence of cancer is increasing, with an estimated number of new cases of 21.6 million worldwide by 2030. Progress in cancer therapies has turned it into a chronic disease. Physical exercise is essential both for the general population and for oncology patients. Practicing exercise reduces the risk of developing certain cancer types and, in oncologic patients, it can reduce symptoms secondary to the disease and to treatment as well as decrease the risk of relapsing. Encouraging adapted physical exercise to every oncologic patient is therefore essential (or crucial). It is recommended to practice regular physical activity equivalent to 150 minutes of moderate intensity or 75 minutes of high intensity activity per week.
Journal of Urology, 2020
INTRODUCTION AND OBJECTIVE: Chronic use of testosterone replacement therapy (TRT) might impact ca... more INTRODUCTION AND OBJECTIVE: Chronic use of testosterone replacement therapy (TRT) might impact cardiovascular (CV) risk. Clinical trials for recently approved TRTs have shown impacts on blood pressure (BP) that led to an increase anti-hypertensive dose or new starts: e.g., Xyosted (10% of patients in a 1-year study) and Jatenzo (7.2% in a 4-month study). Here we present the effect of oral testosterone undecanoate (TLANDO, a novel prodrug of bioidentical testosterone) on BP and CV risk including Framingham Risk Score (FRS), and dipping patterns. The objective was to assess the impact of TLADO treatment on BP and CV risk in hypogonadal men. METHODS: Assessment of BP was conducted in a 16-week, multicenter, open-label, single arm ambulatory blood pressure monitoring (ABPM) study in hypogonadal men (N[138). A fixed dose of 225 mg TLANDO was given BID orally for 16 weeks. 24-hr mean changes from baseline (CBL) of BP were measured and analyzed. Subgroup analysis of systolic blood pressure (SBP) CBL was performed in subjects categorized as low, moderate, or high CV FRS risk at baseline (BL). Dipping was also measured. Dipping was categorized as reverse dipper (<0%), non-dipper (0-10%), dipper (10-20%), and extreme dipper (!20%). RESULTS: Demographics were 53.8 AE10.2 yrs, BMI 33.1 AE5.8 kg/m 2 , 79% white ethinicity. Co-morbidities were obesity (30%), type 2 diabetes (24%) and hypertension (48%). 126 subjects completed the study and 118 subjects had valid 24-hr evaluable ABPM data at both baseline and EOS. Overall, T was well tolerated with no death, no drug related SAEs, and no major adverse cardiovascular events (MACE). 1.4% of subjects either had an increase in anti-hypertensive medication dose or started a new medication with T treatment. 24-hr mean (95% CI) SBP CBL was 3.8 AE2.1 mmHg. 25 subjects had SBP>140 mmHg at BL and their 24-hr mean SBP CBL was-3.4 mmHg. Among them, 8 (32%) subjects were normalized post-treatment. Based on FRS categories at BL, 40 (33.9%), 74 (62.7%), and 4 (3.4%) subjects were at low, moderate and high risk, respectively. 24-hr mean SBP CBL for low, moderate, and high-risk subjects was 2.6, 4.8, and-1.8 mmHg, respectively. Post TLANDO treatment, shifts from less dippers at BL to greater dippers at EOS were slightly higher (or comparable with the opposite shifts) implying lower all-cause mortality. CONCLUSIONS: Marginal increases in BP, the dipping shifts, and the FRS with TLANDO treatment does not appear to have a meaningful impact on CV risk.
Revue medicale suisse, 2019
Multiple myeloma (MM) is the third most common hematological cancer. MM is a proliferation of pla... more Multiple myeloma (MM) is the third most common hematological cancer. MM is a proliferation of plasma cells Its incidence increases from 1 per 100 000 at 40 years to 40 per 100 000 at 80 years. Today, there are many treatment strategies for MM that go from simple care to self-transplantation. Choosing the most appropriate treatment can be challenging in geriatric patients. This population is heterogeneous and therapeutic decisions shouldn't be based on an age limit. Therefore, geriatric assessment is essential to help the clinician choose the best therapeutic strategy and assess the patient's specific needs.
Blood, 2020
Background: The AML EBMT Cytogenetic Risk score is a new prognostic model recently published (Can... more Background: The AML EBMT Cytogenetic Risk score is a new prognostic model recently published (Canaani et al. Leukemia. 2019 Aug;33(8):1944-1952; Nagler el al. Am J Hematol. 2020 Jun 12) combining cytogenetics and FLT3ITD status for AML patients in complete remission (CR) at transplant time. The AML EBMT Cytogenetic Risk score is prognostic for leukemia-free survival (LFS), overall survival (OS), GVHD-free/relapse-free survival (GRFS) and cumulative incidence of relapse (CIR). In our centre, we frequently offer in-vitro partial T-cell depleted graft (pTDEP) for patient in CR to decrease morbidity and mortality associated with graft-versus-host disease (GvHD). Currently, The AML EBMT Cytogenetic Risk score has not been evaluated in this population. Aims: We investigate the impact of the AML EBMT Cytogenetic Risk score for 3 years OS, LFS, GRFS, CIR and NRM in a cohort with patients allografted with pTDEP graft. Methods: All consecutive ≥18 years patients who received a first allograft...
Journal of the Endocrine Society, 2020
Most testosterone (T) replacement therapy (TRT) products have relied on dose titration to achieve... more Most testosterone (T) replacement therapy (TRT) products have relied on dose titration to achieve eugonadal levels. However, dose titration in clinical practice can be time-consuming, expensive, and subject to errors. TLANDO (LPCN 1021) is a novel oral testosterone undecanoate (TU) product absorbed via the intestinal lymphatic pathway. A previous clinical study (NCT02081300) suggested that titration with TLANDO has little to no impact to improve PK profiles. The objective of this study was to assess whether fixed dose of TLANDO can restore testosterone to eugonadal levels. A 24 day, open-label, single-arm, multicenter study with TLANDO in hypogonadal men (NCT03242590) was conducted. Subjects (N=95) received 225 mg testosterone undecanoate orally twice a day (i.e., 30 minutes after morning and evening meals) for 24 days. On Day 24, blood samples were collected over a 24 hour period. The primary endpoint was the percentage of TLANDO-treated subjects who achieved a 24-hour average seru...
Virchows Archiv, 2018
The assessment of nodal metastases in gynecological surgical specimen is an important staging par... more The assessment of nodal metastases in gynecological surgical specimen is an important staging parameter, directing further therapeutic procedures. Since the number of lymph nodes (LNs) removed is seen as an indicator of surgical and pathological quality, the demand for higher lymph node (LN) counts is raising. The goal of this prospective study was the comparison between lymph node counts of macroscopically detectable LNs and the LN yield by complete embedding and proceeding of all submitted LN-containing tissue in the pathology laboratory. One hundred six cases of cervical, uterine, or ovarian cancer, treated in three different hospitals within 3 years, were analyzed. All tissue submitted to the pathology from the surgically performed LN dissections was completely dissected and embedded in the institute of pathology. Subsequently, the amount of LN of all macroscopically detectable nodes was compared to the final histologically reached numbers of LN. Furthermore the histologically visible area of the LNs and their metastases was analyzed to assess the relation of LN numbers to the whole examined LN area. Complete embedding raises the average number of LN counted by 3 to 7 but did only minimally increase the LN area for microscopical examination by about 5% due to the small area of the additional LNs in the remaining fat tissue. The staging was in no case altered by complete embedding, even when additional nodal metastases were detected in the remaining fat tissue, since this was only seen in cases which had already metastatic nodes. Complete embedding of LN-containing tissue did not provide relevant additional staging information and seems therefore unnecessarily laborious, careful pathological work-up assumed.
Oncotarget, 2019
Introduction: Mammography is the gold standard for early breast cancer detection, but shows impor... more Introduction: Mammography is the gold standard for early breast cancer detection, but shows important limitations. Blood-based approaches on basis of cell-free DNA (cfDNA) provide minimally invasive screening tools to characterize epigenetic alterations of tumor suppressor genes and could serve as a liquid biopsy, complementing mammography. Methods: Potential biomarkers were identified from The Cancer Genome Atlas (TCGA), using HumanMethylation450-BeadChip data. Promoter methylation status was evaluated quantitatively by pyrosequencing in a serum test cohort (n = 103), a serum validation cohort (n = 368) and a plasma cohort (n = 125). Results: SPAG6, NKX2-6 and PER1 were identified as novel biomarker candidates. ITIH5 was included on basis of our previous work. In the serum test cohort, a panel of SPAG6 and ITIH5 showed 63% sensitivity for DCIS and 51% sensitivity for early invasive tumor (pT1, pN0) detection at 80% specificity. The serum validation cohort revealed 50% sensitivity for DCIS detection on basis of NKX2-6 and ITIH5. Furthermore, an inverse correlation between methylation frequency and cfDNA concentration was uncovered. Therefore, markers were tested in a plasma cohort, achieving a 64% sensitivity for breast cancer detection using SPAG6, PER1 and ITIH5. Conclusions: Although liquid biopsy remains challenging, a combination of SPAG6, NKX2-6, ITIH5 and PER1 (SNiPER) provides a promising tool for blood-based breast cancer detection.
The Journal of Physical Chemistry B, 2018
The oncogenic gene product Bcr-Abl is the principal cause of chronic myeloid leukemia (CML) and t... more The oncogenic gene product Bcr-Abl is the principal cause of chronic myeloid leukemia (CML) and though several therapies exist to curb the aberrant kinase activity of Bcr-Abl through targeting of the Abl kinase domain, these therapies are rendered ineffective by frequent mutations in the corresponding gene. It has been demonstrated that a designed protein known as CCmut3 is able to produce a dominant negative inactivating effect on Bcr-Abl kinase by preferentially oligomerizing with the N-terminal coiled-coil oligomerization domain of Bcr-Abl (Bcr-CC) to effectively reduce the oncogenic potential of Bcr-Abl. However, the sheer length of the CCmut3 peptide introduces a high degree of conformational variability and opportunity for targeting by intracellular proteolytic mechanisms. Here we have examined the effects on introducing one or two molecular staples, or cross-links, spanning i,i+7 backbone residues of the CCmut3 construct which have been suggested to reinforce α-helical conformation, enhance cellular internalization, and increase resistance to proteolytic degradation leading to enhanced pharmacokinetic properties. The importance of optimizing staple location along a highly-tuned biological construct such as CCmut3 has been widely emphasized and as such, we have employed in silico techniques to swiftly build, relax, and characterize a large number of candidates. This approach effectively allowed exploring each and every possible staple location along the peptide backbone so that every possible candidate is considered. While many of stapled candidate peptides displayed enhanced binding characteristics for Bcr-CC and improved conformational stability in the (Bcr-CC) bound form, simulations of the stapled peptides in the unbound form revealed widespread conformational variability among stapled candidates dependent on staple type and location, implicating the molecular replacement of helix-stabilizing residues with staple-containing residues in disrupting the native α-helical conformation of
Chemistry - A European Journal, 2017
The application of thiol-yne/thiol-ene reactions to synthesize mono-a nd bicyclic-stapled peptide... more The application of thiol-yne/thiol-ene reactions to synthesize mono-a nd bicyclic-stapled peptides and proteins is reported. First, at hiol-ene-based peptide-stapling method in aqueous conditions was developed. This method enabled the efficient stapling of recombinantly expressed coil-coiled proteins. The resulting stapled proteind emonstrated higher stabilityi ni ts secondarys tructure than the unstapled version. Furthermore, at hiol-yne coupling was performed by using an a,w-diynet or eact with two cysteiner esidues to synthesize as tapled peptide with two vinyl sulfide groups. The stapled peptide could furtherr eact with another biscysteinep eptide to yield ab icyclic stapled peptidew ith enhanced properties. For example, the cell permeability of as tapled peptidew as furtheri ncreased by appending an oligoarginine cell-penetratingp eptide. The robustness and versatility of thiol-yne/thiol-ener eactions that can be applied to both synthetic ande xpressedp eptides and proteins were demonstrated.