Karan Kanhai - Academia.edu (original) (raw)

Papers by Karan Kanhai

Blood advances, Jul 10, 2024

Journal of Clinical Oncology, Jun 1, 2022

Background: Siltuximab is the only FDA-and EMA-approved therapy for idiopathic multicentric Castl... more Background: Siltuximab is the only FDA-and EMA-approved therapy for idiopathic multicentric Castleman disease. Its long-term efficacy and safety were established in a 6-year extension study featuring patients who responded to treatment or had stable disease in a phase 1 or phase 2 trial. However, dosage could be adjusted at physician discretion; of 60 patients, 33 remained on the on-label dosing of 11 mg/kg administered every 3 weeks. To assess the safety and efficacy of on-label dosing, we performed a post hoc analysis in patients who maintained this dosing. Methods: A mixed-effects model was used to analyze longitudinal measurements for tumor response, C-reactive protein (CRP), hemoglobin (Hb), erythrocyte sedimentation rate (ESR), fibrinogen, albumin, and platelet counts at multiple time points. Adverse events (AEs) were also assessed. Greenhouse-Geisser correction was used to ensure that the assumption of sphericity was met for the mixed-effects model. Tukey post hoc correction was applied to determine significant differences between specific time points. Results: Of the 33 patients on 3-week dosing, one transitioned to receiving siltuximab every 6 weeks for 25 cycles but restarted 3-weekly dosing due to suspected progressive disease (PD). Disease control was observed in 31 of the 33 patients (93.9%) at their last on-study assessment (complete response [CR] in 9 [27.3%]). Quantitative analyses were performed on the 32 patients who maintained 3-weekly dosing until their last on-study assessment. Siltuximab led to sustained mean levels of CRP, Hb, ESR, fibrinogen, albumin, and platelet counts for the duration of the study. In the 19 patients with residual IL-6 activity at screening (CRP levels > 4 mg/L) there was an overall reduction in CRP from baseline at multiple time points. This group showed a trend towards improved total Hb levels, which increased by 9.43% (adjusted p = 0.048) at cycle 31, and some demonstrated an improvement in ESR, fibrinogen, and albumin levels. All patients reported AEs, mostly grade 1 or 2, with no deaths. At point of enrolment into the extension study, the three most common AEs were hypertension (36.4%), fatigue (42.4%), and pain (51.5%). Conclusions: Our findings show that long-term on-label dosage of siltuximab sustains an improved inflammatory profile and disease control. Research Sponsor: EUSA Pharma.

Critical Care Medicine, Apr 1, 2000

Springer eBooks, 1999

The study aimed to identify the risk factors for respiratory failure after surgery. Postoperative... more The study aimed to identify the risk factors for respiratory failure after surgery. Postoperative respiratory failure (PRF) was defined as prolonged intubation after surgery or reintubation after unsuccessful extubation. We conducted a retrospective analysis of the following risk factors: age, obesity as reflected by body mass index (BMI), gender, patient admitted to hospital (in-patient status) vs. outpatient surgery, smoking, hypertension, chronic obstructive pulmonary disease (COPD), diabetes, abnormal liver function, anaemia, respiratory infection, physical condition as reflected by ASA class, case type (elective or emergency), anaesthesia type, and surgical duration. The incidence of PRF was found to be 2.4%. Independent risk factors were older age, inpatient status, hypertension, COPD, elective procedure, surgical duration >2 hours, and ASA class !3. The study concludes that PRF results in significant postoperative complications. Minimising these risks is essential in improving PRF and subsequently surgical outcomes.

British Journal of Haematology, May 4, 2022

The Journal of Urology, Feb 1, 2017

We will provide journalists and editors with full-text copies of the articles in question prior t... more We will provide journalists and editors with full-text copies of the articles in question prior to the embargo date so that stories can be adequately researched and written. The standard embargo time is 12:01 AM ET on that date. Questions regarding embargo should be directed to

European Journal of Surgery, Dec 2, 2003

Blood Advances, Aug 17, 2022

Idiopathic multicentric Castleman disease (iMCD) is a rare heterogeneous disorder involving multi... more Idiopathic multicentric Castleman disease (iMCD) is a rare heterogeneous disorder involving multicentric lymphadenopathy, systemic inflammation, and cytokine-driven organ dysfunction. Despite the approval of siltuximab, a monoclonal antibody against interleukin-6, for the treatment of iMCD, it is not known how long patients should receive siltuximab before determining whether the treatment is beneficial and should be continued. We performed post hoc analyses of the phase 2 randomized double-blind placebo-controlled trial of siltuximab for the treatment of patients with iMCD to determine the sequence of normalization of laboratory, clinical, and lymph node responses in patients who responded to siltuximab. Seventy-nine patients were enrolled in the trial (siltuximab, n 5 53; placebo plus best supportive care, n 5 26). Progression-free survival (PFS) was significantly improved in siltuximab-treated patients compared with those receiving placebo (P 5 .0001). The median PFS was 14.5 months (95% confidence interval, 13.6 months to upper bound not reached) for patients receiving placebo but was not reached for patients receiving siltuximab. In siltuximab-treated patients who achieved durable tumor (radiologic) and symptomatic responses (18 [34%] of 53), the median time to normalization of abnormal laboratory tests and clinical end points occurred in the following sequence: thrombocytosis, symptomatic response, elevated C-reactive protein, hypoalbuminemia, anemia, lymph node response, hyperfibrinogenemia, and elevated immunoglobulin G. Siltuximab treatment prolongs PFS, rapidly improves symptomatology, and provides meaningful clinical benefit despite some laboratory tests and enlarged lymph nodes taking months to normalize in treatment responders. These data support the continued frontline use of siltuximab for iMCD, as recommended by international guidelines. This trial was registered at www.clinicaltrials.gov as #NCT01024036.

Blood, Nov 5, 2021

Idiopathic multicentric Castleman disease (iMCD) is a rare, life-threatening hematologic disorder... more Idiopathic multicentric Castleman disease (iMCD) is a rare, life-threatening hematologic disorder involving multi-organ dysfunction driven by inflammatory cytokines, often including interleukin-6 (IL-6). The five-year overall survival rate varies considerably between cohorts, ranging from 50 to 77%. It is not well understood why administration of therapies such as the anti-IL-6 monoclonal antibody siltuximab induces complete and durable remission in some patients, whereas others succumb to their disease despite therapy. The aim of this study was to identify laboratory parameters associated with mortality in iMCD. To this end, iMCD patients enrolled in the ACCELERATE registry with fatal and non-fatal outcomes were compared. To determine differences in the laboratory profiles at time of diagnosis between the non-fatal (control) (n = 66) and fatal (mortality) (n = 6) iMCD groups, we performed two-tailed t-tests with Welch correction. P < 0.05 was considered significant. Due to the exploratory nature of this study and limited sample size, we did not perform correction for multiple comparisons among the 25 parameters assessed. In the fatal iMCD group, all patients were white, aged 15-66, and 33.3% were male. Four patients had a hypervascular histopathological subtype; one subtype was not stated, and one was mixed. The non-fatal iMCD group was mixed race and included 57.6% male patients; 38 patients had a hypervascular subtype, 19 had a mixed subtype, five patients had a plasmacytic subtype, three were not stated and one had a hyaline vascular subtype. The mean time from final diagnosis to death was 586.2 days (range: 16-2952 days). Around the time of diagnosis, immunoglobulin M (IgM) (Figure 1A), international normalized ratio (INR) (Figure 1B), and platelet count (PC) (Figure 1C) were significantly decreased in the fatal group compared with the non-fatal group (Figure 1D), with three mortality patients below the lower limit of normal (LLN) for IgM, and four mortality patients below the LLN for PC. Unlike the other two parameters, the INR levels were closer to normal in the fatal group than the non-fatal group. While C-reactive protein (CRP) levels were higher and hemoglobin (Hb) levels were lower in the mortality group, they did not surpass the significance threshold. These data provide new insights into differences between patients who have fatal and non-fatal outcomes. These preliminary findings from a small cohort of deceased patients demonstrate that patients with iMCD who have fatal outcomes may differ from those who do not. For instance, patients in the fatal group may be in a state of greater immune dysregulation (indicated by a lower IgM) and at increased risk of bleeding events (lower PC), compared with patients who go on to survive. The lower PC in the fatal group is likely reflective of patients with the recently-defined thrombocytopenia, anasarca, fever/elevated CRP, reticulin fibrosis/renal dysfunction, organomegaly (TAFRO) clinical subtype of iMCD having lower platelets and a more aggressive course. Thus, early evaluation of platelet count may be an early and actionable indicator of someone's likelihood of death. Additional research is needed into the role of PC and markers of inflammation and anemia in predicting mortality as well as the timing of decline of these markers. If validated in a larger cohort, certain laboratory values may be of use to identify patients at increased risk of death. Figure 1 Figure 1. Disclosures Kanhai: EUSA Pharma: Current Employment. Bagg: Scopio Labs: Research Funding. Lim: EUSA Pharma: Honoraria. Srkalovic: EUSA Pharma: Speakers Bureau; Takeda: Speakers Bureau; Foundation Medicine: Speakers Bureau; Janssen Pharmaceuticals: Speakers Bureau. Uldrick: Celgene: Research Funding; Merck: Other: Receives study drug; Roche: Research Funding; Regeneron: Current Employment. Fajgenbaum: EUSA Pharma: Research Funding; Pfizer: Other: Study drug for clinical trial of sirolimus; N/A: Other: Holds pending provisional patents for 'Methods of treating idiopathic multicentric Castleman disease with JAK1/2 inhibition' and 'Discovery and validation of a novel subgroup and therapeutic target in idiopathic multicentric Castleman disease'.

Blood, Nov 5, 2021

Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on ... more Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre-including this research content-immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active.

Journal of Clinical Oncology, Jun 1, 2022

Background: Idiopathic multicentric Castleman disease (iMCD) is a hematologic disorder characteri... more Background: Idiopathic multicentric Castleman disease (iMCD) is a hematologic disorder characterized by systemic inflammation, polyclonal lymphoproliferation, and multi-organ dysfunction due to hypercytokinemia often including interleukin-6 (IL-6). iMCD patients have had historically poor outcomes, particularly prior to the advent of anti-IL-6 therapy. We recently found that~90% of iMCD patients did not have any claims for anti-IL-6 therapy. One potential reason for inadequate treatment is limited understanding of associated morbidities that can be controlled with therapy. We aimed to assess emergent morbidities in iMCD patients using a large administrative claims database. Methods: An iMCD cohort was identified using an administrative health claims dataset that enrolled 30.7 million US patients between January 1, 2017 and December 2, 2020. This is an updated analysis from a previously published health claims study (Mukherjee et al, 2022). iMCD patients were identified based on CDspecific ICD-10 diagnosis code (D47•Z2), negative HHV-8 and HIV status, and diagnostic or laboratory claims for ≥2 minor criteria. Post-diagnosis hospitalizations, emergency room (ER) visits, and emergent morbidities in iMCD patients were identified in claims data and compared to non-iMCD cohort matched (1:50) by age group (0-17, 18-44, 45-54, 55-64, > 65 years), sex, insurance type, database history, and region. The iMCD cohort was further stratified by age (0-44 years, 45-60 years, > 60 years) or treatment (iMCD-directed therapy, steroid only, and no treatment) for subgroup analyses of morbidity rates. Results: We identified 271 individuals likely to have iMCD (iMCD patients) (mean age: 50•8 years; 59•4% female), including 191 patients previously reported (ASH, 2021). We found significantly higher odds of organ dysfunction (n = 116, OR = 6•5, 95% CI = 4•9, 8•5) and thrombotic events (n = 79, OR = 4•8, 95% CI = 3•4, 6•7) in iMCD patients compared to a matched non-iMCD cohort. We observed increasing proportions of morbidities with advancing age in iMCD and matched non-iMCD cohorts. Similar morbidity trends were observed in all three iMCD treatment cohorts. A high proportion of iMCD patients required an ER visit (47.8% and 42.6% in the year before and after initial diagnosis), dropping to 13.5% in the second year after diagnosis. A similar pattern was observed in inpatient stays, with a marked increase in patients hospitalized for > 5 days increasing from 6•2% two years prior to diagnosis to 34•3% and 15•6% in the two subsequent years. Conclusions: We report high odds of organ dysfunction and thrombotic events in iMCD patients from this population analysis of patient-claims data. In this iMCD cohort with previously reported low use of iMCD-directed therapies, a high proportion of patients required ER visits and inpatient hospitalizations. Research Sponsor: EUSA Pharma.

This review article aims to give an overview of the current literature on postoperative pulmonary... more This review article aims to give an overview of the current literature on postoperative pulmonary complications (PPC). Individual risk factors for the development of PPC are discussed. Limitations of previous studies are identified and goals for future research are suggested.

The Lancet Haematology, Mar 1, 2020

Background Siltuximab is recommended by international consensus as a first-line treatment for idi... more Background Siltuximab is recommended by international consensus as a first-line treatment for idiopathic multicentric Castleman disease on the basis of durable efficacy and safety data. This study was done to assess the long-term safety and activity of siltuximab over up to 6 years of treatment. Methods This study is a prespecified open-label extension analysis of a phase 1 trial (NCT00412321) and a phase 2 trial (NCT01024036), done at 26 hospitals worldwide. Patients in both studies were at least 18 years old with histologically confirmed, symptomatic Castleman disease. This extension study enrolled 60 patients who completed the previous trials without disease progression on siltuximab. Patients received siltuximab infusions of 11 mg/kg every 3 weeks (which could be extended to 6 weeks) for up to 6 years. Descriptive statistics were used to summarise the data. No formal hypothesis testing was performed. The primary endpoint was the safety of siltuximab, assessed at each dosing cycle. The study was registered with ClinicalTrials.gov, number NCT01400503 and with EudraCT, number 2010-022837-27.

medRxiv (Cold Spring Harbor Laboratory), Apr 3, 2020

COVID-19 is caused by the Severe Acute Respiratory Syndrome Coronavirus-2 (SAR-CoV-2), resulting ... more COVID-19 is caused by the Severe Acute Respiratory Syndrome Coronavirus-2 (SAR-CoV-2), resulting in symptoms, such as fever, cough, and shortness of breath. The SARS-CoV-2 virus has also been suggested to initiate a cytokine storm in patients with COVID-19 evidenced by elevated cytokines, such as interleukin-6 (IL-6) and Creactive protein (CRP). We report preliminary data from 21 patients with COVID-19 who developed pneumonia/acute respiratory distress syndrome (ARDS) and participated in a compassionate-use program at Papa Giovanni XXIII hospital in Bergamo, Italy. All 21 patients received intravenous siltuximab-a chimeric mAb that binds to and blocks the effect of IL-6-at a dose ranging between 700 to 1,200 mg (median 900 mg). The median age of patients treated was 64 years, and all patients were followed for a median of eight days. Serum CRP levels reduced in all 16 patients with available

Blood advances, Jul 10, 2024

Journal of Clinical Oncology, Jun 1, 2022

Background: Siltuximab is the only FDA-and EMA-approved therapy for idiopathic multicentric Castl... more Background: Siltuximab is the only FDA-and EMA-approved therapy for idiopathic multicentric Castleman disease. Its long-term efficacy and safety were established in a 6-year extension study featuring patients who responded to treatment or had stable disease in a phase 1 or phase 2 trial. However, dosage could be adjusted at physician discretion; of 60 patients, 33 remained on the on-label dosing of 11 mg/kg administered every 3 weeks. To assess the safety and efficacy of on-label dosing, we performed a post hoc analysis in patients who maintained this dosing. Methods: A mixed-effects model was used to analyze longitudinal measurements for tumor response, C-reactive protein (CRP), hemoglobin (Hb), erythrocyte sedimentation rate (ESR), fibrinogen, albumin, and platelet counts at multiple time points. Adverse events (AEs) were also assessed. Greenhouse-Geisser correction was used to ensure that the assumption of sphericity was met for the mixed-effects model. Tukey post hoc correction was applied to determine significant differences between specific time points. Results: Of the 33 patients on 3-week dosing, one transitioned to receiving siltuximab every 6 weeks for 25 cycles but restarted 3-weekly dosing due to suspected progressive disease (PD). Disease control was observed in 31 of the 33 patients (93.9%) at their last on-study assessment (complete response [CR] in 9 [27.3%]). Quantitative analyses were performed on the 32 patients who maintained 3-weekly dosing until their last on-study assessment. Siltuximab led to sustained mean levels of CRP, Hb, ESR, fibrinogen, albumin, and platelet counts for the duration of the study. In the 19 patients with residual IL-6 activity at screening (CRP levels > 4 mg/L) there was an overall reduction in CRP from baseline at multiple time points. This group showed a trend towards improved total Hb levels, which increased by 9.43% (adjusted p = 0.048) at cycle 31, and some demonstrated an improvement in ESR, fibrinogen, and albumin levels. All patients reported AEs, mostly grade 1 or 2, with no deaths. At point of enrolment into the extension study, the three most common AEs were hypertension (36.4%), fatigue (42.4%), and pain (51.5%). Conclusions: Our findings show that long-term on-label dosage of siltuximab sustains an improved inflammatory profile and disease control. Research Sponsor: EUSA Pharma.

Critical Care Medicine, Apr 1, 2000

Springer eBooks, 1999

The study aimed to identify the risk factors for respiratory failure after surgery. Postoperative... more The study aimed to identify the risk factors for respiratory failure after surgery. Postoperative respiratory failure (PRF) was defined as prolonged intubation after surgery or reintubation after unsuccessful extubation. We conducted a retrospective analysis of the following risk factors: age, obesity as reflected by body mass index (BMI), gender, patient admitted to hospital (in-patient status) vs. outpatient surgery, smoking, hypertension, chronic obstructive pulmonary disease (COPD), diabetes, abnormal liver function, anaemia, respiratory infection, physical condition as reflected by ASA class, case type (elective or emergency), anaesthesia type, and surgical duration. The incidence of PRF was found to be 2.4%. Independent risk factors were older age, inpatient status, hypertension, COPD, elective procedure, surgical duration >2 hours, and ASA class !3. The study concludes that PRF results in significant postoperative complications. Minimising these risks is essential in improving PRF and subsequently surgical outcomes.

British Journal of Haematology, May 4, 2022

The Journal of Urology, Feb 1, 2017

We will provide journalists and editors with full-text copies of the articles in question prior t... more We will provide journalists and editors with full-text copies of the articles in question prior to the embargo date so that stories can be adequately researched and written. The standard embargo time is 12:01 AM ET on that date. Questions regarding embargo should be directed to

European Journal of Surgery, Dec 2, 2003

Blood Advances, Aug 17, 2022

Idiopathic multicentric Castleman disease (iMCD) is a rare heterogeneous disorder involving multi... more Idiopathic multicentric Castleman disease (iMCD) is a rare heterogeneous disorder involving multicentric lymphadenopathy, systemic inflammation, and cytokine-driven organ dysfunction. Despite the approval of siltuximab, a monoclonal antibody against interleukin-6, for the treatment of iMCD, it is not known how long patients should receive siltuximab before determining whether the treatment is beneficial and should be continued. We performed post hoc analyses of the phase 2 randomized double-blind placebo-controlled trial of siltuximab for the treatment of patients with iMCD to determine the sequence of normalization of laboratory, clinical, and lymph node responses in patients who responded to siltuximab. Seventy-nine patients were enrolled in the trial (siltuximab, n 5 53; placebo plus best supportive care, n 5 26). Progression-free survival (PFS) was significantly improved in siltuximab-treated patients compared with those receiving placebo (P 5 .0001). The median PFS was 14.5 months (95% confidence interval, 13.6 months to upper bound not reached) for patients receiving placebo but was not reached for patients receiving siltuximab. In siltuximab-treated patients who achieved durable tumor (radiologic) and symptomatic responses (18 [34%] of 53), the median time to normalization of abnormal laboratory tests and clinical end points occurred in the following sequence: thrombocytosis, symptomatic response, elevated C-reactive protein, hypoalbuminemia, anemia, lymph node response, hyperfibrinogenemia, and elevated immunoglobulin G. Siltuximab treatment prolongs PFS, rapidly improves symptomatology, and provides meaningful clinical benefit despite some laboratory tests and enlarged lymph nodes taking months to normalize in treatment responders. These data support the continued frontline use of siltuximab for iMCD, as recommended by international guidelines. This trial was registered at www.clinicaltrials.gov as #NCT01024036.

Blood, Nov 5, 2021

Idiopathic multicentric Castleman disease (iMCD) is a rare, life-threatening hematologic disorder... more Idiopathic multicentric Castleman disease (iMCD) is a rare, life-threatening hematologic disorder involving multi-organ dysfunction driven by inflammatory cytokines, often including interleukin-6 (IL-6). The five-year overall survival rate varies considerably between cohorts, ranging from 50 to 77%. It is not well understood why administration of therapies such as the anti-IL-6 monoclonal antibody siltuximab induces complete and durable remission in some patients, whereas others succumb to their disease despite therapy. The aim of this study was to identify laboratory parameters associated with mortality in iMCD. To this end, iMCD patients enrolled in the ACCELERATE registry with fatal and non-fatal outcomes were compared. To determine differences in the laboratory profiles at time of diagnosis between the non-fatal (control) (n = 66) and fatal (mortality) (n = 6) iMCD groups, we performed two-tailed t-tests with Welch correction. P < 0.05 was considered significant. Due to the exploratory nature of this study and limited sample size, we did not perform correction for multiple comparisons among the 25 parameters assessed. In the fatal iMCD group, all patients were white, aged 15-66, and 33.3% were male. Four patients had a hypervascular histopathological subtype; one subtype was not stated, and one was mixed. The non-fatal iMCD group was mixed race and included 57.6% male patients; 38 patients had a hypervascular subtype, 19 had a mixed subtype, five patients had a plasmacytic subtype, three were not stated and one had a hyaline vascular subtype. The mean time from final diagnosis to death was 586.2 days (range: 16-2952 days). Around the time of diagnosis, immunoglobulin M (IgM) (Figure 1A), international normalized ratio (INR) (Figure 1B), and platelet count (PC) (Figure 1C) were significantly decreased in the fatal group compared with the non-fatal group (Figure 1D), with three mortality patients below the lower limit of normal (LLN) for IgM, and four mortality patients below the LLN for PC. Unlike the other two parameters, the INR levels were closer to normal in the fatal group than the non-fatal group. While C-reactive protein (CRP) levels were higher and hemoglobin (Hb) levels were lower in the mortality group, they did not surpass the significance threshold. These data provide new insights into differences between patients who have fatal and non-fatal outcomes. These preliminary findings from a small cohort of deceased patients demonstrate that patients with iMCD who have fatal outcomes may differ from those who do not. For instance, patients in the fatal group may be in a state of greater immune dysregulation (indicated by a lower IgM) and at increased risk of bleeding events (lower PC), compared with patients who go on to survive. The lower PC in the fatal group is likely reflective of patients with the recently-defined thrombocytopenia, anasarca, fever/elevated CRP, reticulin fibrosis/renal dysfunction, organomegaly (TAFRO) clinical subtype of iMCD having lower platelets and a more aggressive course. Thus, early evaluation of platelet count may be an early and actionable indicator of someone's likelihood of death. Additional research is needed into the role of PC and markers of inflammation and anemia in predicting mortality as well as the timing of decline of these markers. If validated in a larger cohort, certain laboratory values may be of use to identify patients at increased risk of death. Figure 1 Figure 1. Disclosures Kanhai: EUSA Pharma: Current Employment. Bagg: Scopio Labs: Research Funding. Lim: EUSA Pharma: Honoraria. Srkalovic: EUSA Pharma: Speakers Bureau; Takeda: Speakers Bureau; Foundation Medicine: Speakers Bureau; Janssen Pharmaceuticals: Speakers Bureau. Uldrick: Celgene: Research Funding; Merck: Other: Receives study drug; Roche: Research Funding; Regeneron: Current Employment. Fajgenbaum: EUSA Pharma: Research Funding; Pfizer: Other: Study drug for clinical trial of sirolimus; N/A: Other: Holds pending provisional patents for 'Methods of treating idiopathic multicentric Castleman disease with JAK1/2 inhibition' and 'Discovery and validation of a novel subgroup and therapeutic target in idiopathic multicentric Castleman disease'.

Blood, Nov 5, 2021

Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on ... more Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre-including this research content-immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active.

Journal of Clinical Oncology, Jun 1, 2022

Background: Idiopathic multicentric Castleman disease (iMCD) is a hematologic disorder characteri... more Background: Idiopathic multicentric Castleman disease (iMCD) is a hematologic disorder characterized by systemic inflammation, polyclonal lymphoproliferation, and multi-organ dysfunction due to hypercytokinemia often including interleukin-6 (IL-6). iMCD patients have had historically poor outcomes, particularly prior to the advent of anti-IL-6 therapy. We recently found that~90% of iMCD patients did not have any claims for anti-IL-6 therapy. One potential reason for inadequate treatment is limited understanding of associated morbidities that can be controlled with therapy. We aimed to assess emergent morbidities in iMCD patients using a large administrative claims database. Methods: An iMCD cohort was identified using an administrative health claims dataset that enrolled 30.7 million US patients between January 1, 2017 and December 2, 2020. This is an updated analysis from a previously published health claims study (Mukherjee et al, 2022). iMCD patients were identified based on CDspecific ICD-10 diagnosis code (D47•Z2), negative HHV-8 and HIV status, and diagnostic or laboratory claims for ≥2 minor criteria. Post-diagnosis hospitalizations, emergency room (ER) visits, and emergent morbidities in iMCD patients were identified in claims data and compared to non-iMCD cohort matched (1:50) by age group (0-17, 18-44, 45-54, 55-64, > 65 years), sex, insurance type, database history, and region. The iMCD cohort was further stratified by age (0-44 years, 45-60 years, > 60 years) or treatment (iMCD-directed therapy, steroid only, and no treatment) for subgroup analyses of morbidity rates. Results: We identified 271 individuals likely to have iMCD (iMCD patients) (mean age: 50•8 years; 59•4% female), including 191 patients previously reported (ASH, 2021). We found significantly higher odds of organ dysfunction (n = 116, OR = 6•5, 95% CI = 4•9, 8•5) and thrombotic events (n = 79, OR = 4•8, 95% CI = 3•4, 6•7) in iMCD patients compared to a matched non-iMCD cohort. We observed increasing proportions of morbidities with advancing age in iMCD and matched non-iMCD cohorts. Similar morbidity trends were observed in all three iMCD treatment cohorts. A high proportion of iMCD patients required an ER visit (47.8% and 42.6% in the year before and after initial diagnosis), dropping to 13.5% in the second year after diagnosis. A similar pattern was observed in inpatient stays, with a marked increase in patients hospitalized for > 5 days increasing from 6•2% two years prior to diagnosis to 34•3% and 15•6% in the two subsequent years. Conclusions: We report high odds of organ dysfunction and thrombotic events in iMCD patients from this population analysis of patient-claims data. In this iMCD cohort with previously reported low use of iMCD-directed therapies, a high proportion of patients required ER visits and inpatient hospitalizations. Research Sponsor: EUSA Pharma.

This review article aims to give an overview of the current literature on postoperative pulmonary... more This review article aims to give an overview of the current literature on postoperative pulmonary complications (PPC). Individual risk factors for the development of PPC are discussed. Limitations of previous studies are identified and goals for future research are suggested.

The Lancet Haematology, Mar 1, 2020

Background Siltuximab is recommended by international consensus as a first-line treatment for idi... more Background Siltuximab is recommended by international consensus as a first-line treatment for idiopathic multicentric Castleman disease on the basis of durable efficacy and safety data. This study was done to assess the long-term safety and activity of siltuximab over up to 6 years of treatment. Methods This study is a prespecified open-label extension analysis of a phase 1 trial (NCT00412321) and a phase 2 trial (NCT01024036), done at 26 hospitals worldwide. Patients in both studies were at least 18 years old with histologically confirmed, symptomatic Castleman disease. This extension study enrolled 60 patients who completed the previous trials without disease progression on siltuximab. Patients received siltuximab infusions of 11 mg/kg every 3 weeks (which could be extended to 6 weeks) for up to 6 years. Descriptive statistics were used to summarise the data. No formal hypothesis testing was performed. The primary endpoint was the safety of siltuximab, assessed at each dosing cycle. The study was registered with ClinicalTrials.gov, number NCT01400503 and with EudraCT, number 2010-022837-27.

medRxiv (Cold Spring Harbor Laboratory), Apr 3, 2020

COVID-19 is caused by the Severe Acute Respiratory Syndrome Coronavirus-2 (SAR-CoV-2), resulting ... more COVID-19 is caused by the Severe Acute Respiratory Syndrome Coronavirus-2 (SAR-CoV-2), resulting in symptoms, such as fever, cough, and shortness of breath. The SARS-CoV-2 virus has also been suggested to initiate a cytokine storm in patients with COVID-19 evidenced by elevated cytokines, such as interleukin-6 (IL-6) and Creactive protein (CRP). We report preliminary data from 21 patients with COVID-19 who developed pneumonia/acute respiratory distress syndrome (ARDS) and participated in a compassionate-use program at Papa Giovanni XXIII hospital in Bergamo, Italy. All 21 patients received intravenous siltuximab-a chimeric mAb that binds to and blocks the effect of IL-6-at a dose ranging between 700 to 1,200 mg (median 900 mg). The median age of patients treated was 64 years, and all patients were followed for a median of eight days. Serum CRP levels reduced in all 16 patients with available