Summary
Little is known on factors predicting toxicity of anti-PD1 checkpoint inhibitors. Sarcopenic obesity is associated with increased acute toxicity of cytotoxic agents and targeted therapies. We ...explored whether body composition also influenced the occurrence of early acute limiting toxicity (ALT) of anti-PD1 in melanoma patients. This is a monocentric, retrospective study analyzing toxicity outcome in consecutive melanoma patients treated with nivolumab or pembrolizumab. Various parameters linked to the patient or the disease status have been analysed. Body mass index (BMI; kg/m
2
) and muscle mass using CT were measured prior to treatment initiation. Chi-squared test and Mann-Whitney’s tests were used for the comparison of categorical and continuous variables respectively. Among 68 melanoma patients treated with anti-PD1 (47 pembrolizumab, 21 nivolumab), 38 (56%) patients had a BMI ≥ 25 kg/m
2
and 11 (16%) a BMI ≥ 30, while 13 (19%) had both sarcopenia and a BMI ≥ 25 kg/m
2
. For the 11 (16%) patients who experienced early ALT, the mean BMI was higher (27.9 versus 24.7 kg/m
2
;
p
= 0.04). Among the 32 female patients, sarcopenic overweight patients had a 6.5-fold increased risk of ALT (50 versus 7.7%;
p
= 0.01). Sarcopenic overweight is associated with more early ALT of anti-PD1 in melanoma patients.
In this study of 21 patients with severe pemphigus whose disease was refractory to or dependent on systemic corticosteroids or who had contraindications to corticosteroids, 18 patients (86%) had a ...complete remission after a single cycle of rituximab treatment. Two patients had serious infections, one of which resulted in death. The efficacy of rituximab for pemphigus must be weighed against the risk of severe adverse events.
In this study of 21 patients with severe pemphigus, 18 patients (86%) had a complete remission after a single cycle of rituximab treatment. The efficacy of rituximab must be weighed against the risk of severe adverse events.
Pemphigus is a life-threatening autoimmune blistering disease affecting the skin and mucosa. It is mediated by pathogenic autoantibodies directed against desmoglein 1 and desmoglein 3, adhesion molecules of the epidermis that are responsible for the cohesion between keratinocytes in skin and mucosa, respectively.
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Patients with severe pemphigus require long-term treatment with corticosteroids and other immunosuppressive drugs, which can lead to serious adverse events.
4
,
5
Rituximab, a monoclonal antibody directed against the CD20 antigen of B lymphocytes, has been demonstrated to be effective in various autoimmune diseases
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–
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and in occasional cases of life-threatening pemphigus.
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Recently, the combination of . . .
Learning Objectives
After completing this course, the reader will be able to:
Describe the profile of severe toxicities in patients treated with sorafenib.
Summarize the pharmacokinetics of ...sorafenib‐induced toxicities.
Identify predictive factors for early and delayed toxicities in patients treated with sorafenib.
This article is available for continuing medical education credit at CME.TheOncologist.com
Background.
Sorafenib displays major interpatient pharmacokinetic variability. It is unknown whether the pharmacokinetics of sorafenib influence its toxicity.
Methods.
We analyzed the severity and kinetics of sorafenib‐induced toxicities in unselected consecutive patients with cancer, as well as their relationship with biological, clinical, and pharmacokinetic parameters. Toxicity was recorded bimonthly. Sorafenib plasma concentrations were assessed by liquid chromatography.
Results.
For 83 patients (median age, 62 years; range, 21–84 years), median sorafenib 12‐hour area under the curve (AUC0–12) was 52.8 mg · h/L (range: 11.8–199.6). A total of 51 patients (61%) experienced grade 3–4 toxicities, including hand‐foot skin reactions (23%), asthenia (18%), and diarrhea (11%). Sorafenib AUC0–12 preceding grade 3–4 toxicities was significantly higher than that observed in the remaining population (61.9 mg · h/L vs. 53 mg · h/L). In 25 patients treated with fixed doses of sorafenib for the first 4 months, median dose‐normalized AUC0–12 on day 120 was significantly lower than on day 15 (63 vs. 102 mg · h/L). The incidence of hypertension and hand‐foot skin reactions significantly decreased over time.
Conclusion.
Sorafenib AUC0–12 decreases over time, similarly to the incidence of hypertension and hand‐foot skin reactions. Monitoring of sorafenib plasma concentrations may help to prevent acute severe toxicities and detect patients with suboptimal exposure at disease progression.
This study analyzes the severity and timing of sorafenib‐induced toxicities in a cohort of unselected consecutive patients with cancer to determine whether the pharmacokinetics of sorafenib influence its toxicity.
Background
Major therapeutic advances including immunotherapy and targeted therapies have been changing the face of oncology and resulted in improved prognosis as well as in new toxic complications. ...The aim of this study is to appraise the trends in intensive care unit (ICU) admissions and outcomes of critically ill patients with solid malignancies. We performed a retrospective single-centre study over a 12-year period (2007–2018) including adult patients with solid malignancies requiring unplanned ICU admission. Admission patterns were classified as: (i) specific if directly related to the underlying cancer; (ii) non-specific; (iii) drug-related or procedural adverse events.
Results
1525 patients were analysed. Lung and gastro-intestinal tract accounted for the two main tumour sites. The proportion of patients with metastatic diseases increased from 48.6% in 2007–2008 to 60.2% in 2017–2018 (
p
= 0.004). Critical conditions were increasingly related to drug- or procedure-related adverse events, from 8.8% of ICU admissions in 2007–2008 to 16% in 2017–2018 (
p
= 0.01). The crude severity of critical illness at ICU admission did not change over time. The ICU survival rate was 77.4%, without any significant changes over the study period. Among the 1279 patients with complete follow-up, the 1-year survival rate was 33.2%. Independent determinants of ICU mortality were metastatic disease, cancer in progression under treatment, admission for specific complications and the extent of organ failures (invasive and non-invasive ventilation, inotropes/vasopressors, renal replacement therapy and SOFA score). One-year mortality in ICU-survivors was independently associated with lung cancer, metastatic disease, cancer in progression under treatment, admission for specific complications and decision to forgo life-sustaining therapies.
Conclusion
Advances in the management and the prognosis of solid malignancies substantially modified the ICU admission patterns of cancer patients. Despite underlying advanced and often metastatic malignancies, encouraging short-term and long-term outcomes should help changing the dismal perception of critically ill cancer patients.
Cutaneous involvement in Waldenström’s macroglobulinaemia (WM) has been poorly characterized. To describe this involvement, a retrospective study of 19 patients with WM and cutaneous involvement of ...tumour B cells was performed. Twelve patients (group 1) had lymphoplasmacytic, non-transformed cutaneous proliferation, while in 7 cases (group 2) cutaneous involvement corresponded to histological transformation. In group 1, skin involvement was inaugural in 6 cases. The lesions were infiltrated plaques (83%), papules (25%) and tumours (42%). Four patients had a similar clinical picture (purplish, bilateral and symmetrical infiltration on the face).
MYD88
L265P mutation was detected in the skin biopsy in all 6 cases tested. The 3-year specific survival rate was 88%. In group 2, cutaneous transformation occurred during the followup of the WM (71%). Lesions presented as ulcerated tumours (86%) of the trunk (57%) and lower limbs (57%). The 3-year specific survival rate was 22%. Skin involvement in WM has distinctive characteristics (e.g. clinical, histological, immunohistochemical,
MYD88
L265P mutation).
Patients treated with dabrafenib/trametinib (DAB/TRA) exhibit a large interindividual variability in clinical outcomes. The aims of this study were to characterize the pharmacokinetics of DAB, ...hydroxy-dabrafenib (OHD), and TRA in BRAF-mutated patients and to investigate the exposure-response relationship for toxicity and efficacy in metastatic melanoma (MM) patients. Univariate Fisher and Wilcoxon models including drug systemic exposure (area under the plasma concentration curve, AUC) were used to identify prognostic factors for the onset of dose-limiting toxicities (DLT), and Cox models for overall (OS) and progression-free survival (PFS). Seventy-three BRAF-mutated patients were included in pharmacokinetic (n = 424, NONMEM) and 52 in pharmacokinetic/pharmacodynamic analyses. Age and sex were identified as determinants of DAB and OHD clearances (
< 0.01). MM patients experiencing DLT were overexposed to DAB compared to patients without DLT (AUC: 9624 vs. 7485 ng∙h/mL, respectively,
< 0.01). Eastern Cooperative Oncology Group Performance Status (ECOG PS) ≥ 2 and plasma ratio AUC
/AUC
≥ 1 were independently associated with shorter OS (HR: 6.58 (1.29-33.56);
= 0.023 and 10.61 (2.34-48.15),
= 0.022, respectively). A number of metastatic sites ≥3 and cerebral metastases were associated with shorter PFS (HR = 3.25 (1.11-9.50);
= 0.032 and HR = 1.23 (1.35-10.39),
= 0.011; respectively). TRA plasma exposure was neither associated with toxicity nor efficacy. Our results suggest that early drug monitoring could be helpful to prevent the onset of DLT in MM patients, especially in fragile patients such as the elderly. Regarding efficacy, the clinical benefit to monitor plasma ratio AUC
/AUC
deserves more investigation in a larger cohort of MM patients.
CDK11(p58) is a mitotic protein kinase, which has been shown to be required for different mitotic events such as centrosome maturation, chromatid cohesion and cytokinesis.
In addition to these ...previously described roles, our study shows that CDK11(p58) inhibition induces a failure in the centriole duplication process in different human cell lines. We propose that this effect is mediated by the defective centrosomal recruitment of proteins at the onset of mitosis. Indeed, Plk4 protein kinase and the centrosomal protein Cep192, which are key components of the centriole duplication machinery, showed reduced levels at centrosomes of mitotic CDK11-depleted cells. CDK11(p58), which accumulates only in the vicinity of mitotic centrosomes, directly interacts with the centriole-associated protein kinase Plk4 that regulates centriole number in cells. In addition, we show that centriole from CDK11 defective cells are not able to be over duplicated following Plk4 overexpression.
We thus propose that CDK11 is required for centriole duplication by two non-mutually-exclusive mechanisms. On one hand, the observed duplication defect could be caused indirectly by a failure of the centrosome to fully maturate during mitosis. On the other hand, CDK11(p58) could also directly regulate key centriole components such as Plk4 during mitosis to trigger essential mitotic centriole modifications, required for centriole duplication during subsequent interphase.
Background:
To examine the feasibility and acceptability of integrating a tele-mentoring component into the identification of oral lesions at the dental clinics of a Federally Qualified Health Center ...network.
Design and Methods:
General Practice Residency faculty and residents completed research ethics courses and trained dentists to use intra-oral cameras at chairside to photograph oral lesions of patients at routine dental visits. These images were then uploaded into the patient electronic health records (EHRs) with attendant descriptions and an oral surgeon was notified, who reviewed the charts, placed his observations in the EHR, and communicated his findings via secure e-mail to the involved residents, who in turn contacted their patients regarding follow-up actions. Feasibility was assessed via checklists completed by provider participants and semi-structured interviews. Acceptability was assessed via brief exit interviews completed by patient participants.
Results:
All 12 of the dentist participants reported that they had successfully provided the tele-mentoring intervention, and that the process (from EHR data entry to interaction with the oral surgeon over findings to patient referral) was clear and straightforward. Of 39 patient participants, most strongly agreed or agreed that the use of an intra-oral camera by their dentists helped them to better understand oral cancer screening (94.9%) and that dentists answered their questions about oral cancer and were able to provide them with resources (94.8%).
Conclusions:
Findings support further implementation research into adapting tele-mentoring using intra-oral cameras for training dental residents to detect and identify oral lesions and educating patients about oral cancer across settings.
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