Hereditary factors play a key role in the risk of developing several cancers. Identification of a germline predisposition can have important implications for treatment decisions, risk-reducing ...interventions, cancer screening, and germline testing.
To examine the prevalence of pathogenic germline variants (PGVs) in patients with cancer using a universal testing approach compared with targeted testing based on clinical guidelines and the uptake of cascade family variant testing (FVT).
This prospective, multicenter cohort study assessed germline genetic alterations among patients with solid tumor cancer receiving care at Mayo Clinic cancer centers and a community practice between April 1, 2018, and March 31, 2020. Patients were not selected based on cancer type, disease stage, family history of cancer, ethnicity, or age.
Germline sequencing using a greater than 80-gene next-generation sequencing platform.
Proportion of PGVs detected with a universal strategy compared with a guideline-directed approach and uptake of cascade FVT in families.
A total of 2984 patients (mean SD age, 61.4 12.2 years; 1582 53.0% male) were studied. Pathogenic germline variants were found in 397 patients (13.3%), including 282 moderate- and high-penetrance cancer susceptibility genes. Variants of uncertain significance were found in 1415 patients (47.4%). A total of 192 patients (6.4%) had incremental clinically actionable findings that would not have been detected by phenotype or family history-based testing criteria. Of those with a high-penetrance PGV, 42 patients (28.2%) had modifications in their treatment based on the finding. Only younger age of diagnosis was associated with presence of PGV. Only 70 patients (17.6%) with PGVs had family members undergoing no-cost cascade FVT.
This prospective, multicenter cohort study found that universal multigene panel testing among patients with solid tumor cancer was associated with an increased detection of heritable variants over the predicted yield of targeted testing based on guidelines. Nearly 30% of patients with high-penetrance variants had modifications in their treatment. Uptake of cascade FVT was low despite being offered at no cost.
Background: Central nervous system (CNS) lymphoma manifests as a highly aggressive non-Hodgkins lymphoma, either confined to the central nervous system or secondary to spread of systemic diffuse ...large B cell lymphoma. Rising incidence of CNS lymphoma has been observed, especially in elderly populations. Presentation depends on the burden and location of disease, with a varying spectrum of symptoms ranging from headaches and cognitive changes to focal neurological deficits and seizures. Neuropsychiatric presentation of CNS lymphoma has been seen and anecdotally reported but appears to be under-represented in the literature. In this retrospective review of patients with CNS lymphoma at MCA we report a cohort of patients who presented with primarily neuropsychiatric symptoms
Methods: After receiving IRB approval, we retrospectively identified 135 patients with ICD 9 and 10 codes consistent with CNS lymphoma, seen at Mayo Clinic Arizona, between 1998-2018. Symptoms identified prior to presentation with the CNS component of the lymphoma were recorded with attention to those with depression, anxiety, agitation, psychosis, disinhibition, and apathy. Patients with long term premorbid psychiatric disease or symptoms that developed later in the course as a result the stressors of disease and treatment were excluded.
Results: A total of 19 out of 136 patients (14%) were noted to have primarily neuropsychiatric symptoms prior to diagnosis of CNS lymphoma. Symptom onset to diagnosis of PCNSL ranged from 3 weeks to 11 months. The average age was 65, and 47% of subjects were male. Depression, apathy, agitation and features of parkinsonism were the most common neuropsychiatric symptoms identified, with psychosis and disinhibition being the least frequent. The majority of these patients had frontal lobe lesions (42%), although several also had multifocal disease at time of diagnosis. Improvement of neuropsychiatric disease was not explicitly discussed or noted in the treatment and post-treatment notes. In fact, we found it notable that follow up notes generally did not comment on these psychiatric symptoms at all, and there was no clear management plan separate from treating the disease process.
Parkinsonian features were observed in 5 patients (26%), with onset range from 2 weeks to 29 months prior to PCNSL diagnosis. The associated lesions were mostly deep basal ganglia or corpus callosum except in one case of left parietal lobe tumor. Notably, all patients had resolution of their parkinsonism with treatment of the lymphoma.
Conclusions: Neuropsychiatric symptoms are a rare but noteworthy presentation of CNS lymphoma, distinct from cognitive changes that have been previously described with this condition. There is an increasing awareness of neurological illness presenting as pure psychiatric disturbance, prompting exclusion of organic disease, particularly in elderly patients who present with new psychiatric complaints.
No relevant conflicts of interest to declare.
Purpose
Automated scalp cooling (ASC) is available to patients undergoing chemotherapy for breast cancer to decrease chemotherapy-induced alopecia. This study sought to elucidate patient and ...chemotherapy nursing perspectives on the ASC experience.
Methods
This is a survey-based study of chemotherapy nursing staff and patients with breast cancer regarding perceived efficacy, side effects, administration, support, and overall opinions of ASC. Chemotherapy nurses across a large, multi-regional tertiary healthcare system completed a one-time survey regarding their experiences in administering ASC. Breast cancer patients who utilized ASC were surveyed along with a control group who underwent alopecia-inducing chemotherapy without ASC use for comparison.
Results
The majority of nursing responses reported inadequate technical support, an increased burden of administering ASC compared to other clinical duties, and that they would not recommend ASC to a family member or friend. Patients who underwent ASC reported significantly less hair loss and were significantly less likely to shave their heads or wear a wig, but this did not translate into significant differences in body image or psychosocial wellbeing responses. Time investment was the most significant burden related to ASC.
Conclusion
Patients using ASC reported significantly less hair loss compared to those not using ASC during alopecia-inducing breast cancer chemotherapy, but this did not translate to improved body image. The majority of chemotherapy nurses reported they lacked adequate support in administering ASC and would not recommend it. Enhanced nursing support may provide a means for improving the ASC experience for both nursing staff and patients.
To evaluate the incidence of and characterize the presentation of neuropsychiatric symptoms and/or Parkinsonism as a presentation of central nervous system lymphoma (CNSL) in either its primary CNSL ...form or when it spreads to the brain in systemic diffuse large B-cell lymphoma (secondary CNSL).
With Institutional Review Board approval we identified patients who had been treated at Mayo Clinic from 1998 to 2018 and were recorded to have a combination of ICD 9/10 codes for CNSL and various psychiatric diagnoses.
A total of 20 of the 232 patients (9%) were noted to have neuropsychiatric symptoms preceding diagnosis. The average age at diagnosis was 62, with even split for sex. The majority (85%) of patients had primary CNSL. The average duration of symptoms before the diagnosis was 4.8 months. Confusion (80%), depression (40%), apathy (30%), anxiety (30%), and agitation (30%) were the most common symptoms identified. The majority (65%) of patients had subcortical lesions followed by the frontal lobe (50%). Parkinsonism was identified in 5 of the 20 patients with 4 demonstrating resolution of symptoms with treatment of the lymphoma.
Neuropsychiatric symptoms are a rare but notable symptom before the presentation of CNSL. There is an increasing awareness of neurological illness presenting as pure psychiatric disturbance, prompting the need to exclude organic and treatable diseases, particularly in elderly patients. Acknowledgment and diagnosis are important for an appropriate management as there is a significant impact on patient and caregiver quality of life.
Therapy-related myeloid neoplasms are a potentially life-threatening consequence of treatment for autoimmune disease (AID) and an emerging clinical phenomenon.
To query the association of cytotoxic, ...anti-inflammatory, and immunomodulating agents to treat patients with AID with the risk for developing myeloid neoplasm.
This retrospective case-control study and medical record review included 40 011 patients with an International Classification of Diseases, Ninth Revision, coded diagnosis of primary AID who were seen at 2 centers from January 1, 2004, to December 31, 2014; of these, 311 patients had a concomitant coded diagnosis of myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML). Eighty-six cases met strict inclusion criteria. A case-control match was performed at a 2:1 ratio.
Odds ratio (OR) assessment for AID-directed therapies.
Among the 86 patients who met inclusion criteria (49 men 57%; 37 women 43%; mean SD age, 72.3 15.6 years), 55 (64.0%) had MDS, 21 (24.4%) had de novo AML, and 10 (11.6%) had AML and a history of MDS. Rheumatoid arthritis (23 26.7%), psoriasis (18 20.9%), and systemic lupus erythematosus (12 14.0%) were the most common autoimmune profiles. Median time from onset of AID to diagnosis of myeloid neoplasm was 8 (interquartile range, 4-15) years. A total of 57 of 86 cases (66.3%) received a cytotoxic or an immunomodulating agent. In the comparison group of 172 controls (98 men 57.0%; 74 women 43.0%; mean SD age, 72.7 13.8 years), 105 (61.0%) received either agent (P = .50). Azathioprine sodium use was observed more frequently in cases (odds ratio OR, 7.05; 95% CI, 2.35- 21.13; P < .001). Notable but insignificant case cohort use among cytotoxic agents was found for exposure to cyclophosphamide (OR, 3.58; 95% CI, 0.91-14.11) followed by mitoxantrone hydrochloride (OR, 2.73; 95% CI, 0.23-33.0). Methotrexate sodium (OR, 0.60; 95% CI, 0.29-1.22), mercaptopurine (OR, 0.62; 95% CI, 0.15-2.53), and mycophenolate mofetil hydrochloride (OR, 0.66; 95% CI, 0.21-2.03) had favorable ORs that were not statistically significant. No significant association between a specific length of time of exposure to an agent and the drug's category was observed.
In a large population with primary AID, azathioprine exposure was associated with a 7-fold risk for myeloid neoplasm. The control and case cohorts had similar systemic exposures by agent category. No association was found for anti-tumor necrosis factor agents. Finally, no timeline was found for the association of drug exposure with the incidence in development of myeloid neoplasm.
Highlights • Cytogenetic evolution (CGE) is associated with significantly shortened post-transplant and post relapse survivals compared to patients without CGE (p=0.004 and p<0.001) in patients with ...myeloid neoplasms who relapsed after an allogeneic hematopoietic cell transplant (allo-HCT). • The CGE group is characterized by a higher frequency of cytogenetic abnormalities at primary diagnosis, more high-risk disease per IPSS criteria and a trend of higher frequency of MDS and MPN as opposed to AML. • No particular type of chemotherapy emerged as a predisposing factor to CGE.
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Background
Myeloid neoplasms (MN) occurring secondary to treatment of non-malignant disease, especially autoimmune diseases (AID), and the overlap between them, is an increasing clinically ...important observation. Confounding variables for myeloid transformation include the nature of autoimmune disease as an incessant, chronically activated inflammatory cascade that has been associated with an increased risk of myeloid malignancy, and disease modifying therapies, often with cytotoxic and immunosuppressive drugs. Thus, the addition of therapeutic agents for treatment of AID theoretically amplifies the opportunity for MN to develop in genetically susceptible individuals. To our knowledge, there is no large study evaluating a comprehensive primary AID population that developed MDS or AML with detailed assessment of therapeutic interventions for AID. The presented study queries the association of cytotoxic, anti-inflammatory, and immune-modulating agents to treat AID as risk factors for developing myelodysplastic syndromes (MDS) or acute myeloid leukemia (AML).
Methods
In a 10-year period from 2004-2014, a total of 40,011 patients with an ICD-9 coded diagnosis of AID were seen at Mayo Clinic Arizona and Florida campuses; 311 patients from this population had a concomitant coded diagnosis of MDS and/or AML. In an IRB approved, retrospective chart review, we confirmed 86 cases meeting strict inclusion criteria for AID and confirmed MDS or AML. We performed a case-control match from the same primary autoimmune population for age, gender, and autoimmune specific diagnosis at a 2:1 ratio querying for therapeutic interventions.
Results
Myeloid neoplasm specifics in our case cohort of 86 patients were 55 MDS, 21 de novo AML, and 10 AML with history of MDS. Average age was 72 years with a slight male predominance (57%). Rheumatoid arthritis (26.4%), psoriasis (20.7%), systemic lupus (13.8%), was the most common autoimmune profiles. Median onset of autoimmune disease to diagnosis of myeloid neoplasm was 6 years (range 1-54 years). Up to 26% controls documented no systemic agent for treatment of autoimmune disease and similarly 12.8% of the case cohort (p=0.142). Case and control populations treated with systemic therapies had similar exposures by category for immune-modulating agents (33.7% and 37.8% respectively) and cytotoxic therapies (47.7 and 44.8% respectively). A total of 57/86 cases (66.3%) received either a cytotoxic or immune-modulating agent. In comparison, 105/172 (61.1%) controls received either agent; p=0.495. Azathioprine was the only statistically significant agent exposure observed more frequently in the study cohort than controls with an OR of 7.05 (p= < 0.001). There was no increased incidence of MDS or AML in TNF-antagonist treated patients. No significant correlation for duration of agent exposure by drug category was observed.
Discussion
In a large primary AID population, azathioprine exposure was associated with a 7 fold risk of MDS or AML (p=< 0.001). Notable, but not statistically significant case cohort trends among cytotoxic agents was exposure to cyclophosphamide (OR 3.58) followed by mitoxantrone (OR 2.73). Methotrexate, mercaptopurine, and mycophenolate had favorable odd ratios, but these were not statistically significant. No association was found for TNF-inhibitory agents. Finally, there was no association of drug exposure time to the incidence in development of MDS or AML.
Dueck:Bayer: Honoraria. Mesa:Gilead: Research Funding; Novartis: Consultancy; Celgene: Research Funding; Incyte Corporation: Research Funding; Galena: Consultancy; Ariad: Consultancy; CTI: Research Funding; Promedior: Research Funding. Al-Kali:Onconova Therapeutics, Inc.: Research Funding; Celgene: Research Funding. Foran:Millennium Pharmaceuticals, Inc.: Research Funding; novartis: Honoraria; karyopharm: Honoraria; medscape: Honoraria; pfizer: Honoraria; boehringer ingelheim: Research Funding; agios: Research Funding; Cellerant: Research Funding.
Background
Cytotoxic agents are a well-established risk factor for therapy related myeloid neoplasms (t-MN). The incidence of t-MN in patients (pts) with autoimmune diseases (AID) treated with ...cytotoxic and immuno-modulatory agents are not well described in the literature. Most case series assess an MDS/AML population and co-occurrence with an AID. To our knowledge, there exists no large case-control studies evaluating a primary AID population that developed therapy-related MDS or AML, and the relationship to detailed therapeutic intervention for AID. Our study queries the association of cytotoxic and immune-modulating agents to treat AID as risk factor for developing MDS or AML.
Methods
Between 2004-2014, 23,671 pts with an ICD-9 coded AID were seen at Mayo Clinic Arizona; 148 pts from this population had a concomitant coded diagnosis of MDS/AML. In an IRB approved, retrospective chart review we confirmed 61 cases meeting strict inclusion criteria. We performed a case-control match from the same primary AID population for age, gender, and autoimmune specific diagnosis at a 2:1 ratio. AML/MDS cases were compared to controls by use of chi-square test for frequency data. Odds ratios with 95% confidence interval were constructed using conditional logistic regression. Case incidence was compared to SEER data for the general population
Results
Of 61 cases 33 were MDS, 20 de-novo AML, and 8 MDS transformed to AML. Psoriasis 16 (26.2%) and rheumatoid arthritis 14 (23.0%) were the most common autoimmune diagnoses, followed by systemic lupus 11 (18%), Crohn's disease 7 (11.5%), and ulcerative colitis 5 (8.2%). 39 out of 61 cases (63.9%) received either a cytotoxic or immune modulating agent for AID, compared to 64/122 (52.5%) in the control group; p=0.140. 7/61 cases (11.5%) received both a cytotoxic and immune modulating agent as compared to 16/122 (13.1%) in controls; p=0.753.
Overall, the case population received more agents than controls. No cytotoxic or immune-modulating treatment was documented in 16% of cases and 36% controls. Exposures to cytotoxic and immune-modulating agents were similar in both case and control cohorts. Exposure time was not statistically significant. Azathioprine was the only statistically significant agent exposure observed more often in the case cohort than control. Per SEER data, over a 10-year period in a general age-matched population that is comparable to our AID population cohort, we would expect 54 MDS and 35 AML cases.
Table 1Exposures and TimelineCases (n=61)Controls (n=122)P value *Number of Systemic Agents, Total None 1 2 3 4+- 10 (16.4%) 26 (42.6%) 12 (19.7%) 7 (11.5%) 6 (9.8%)- 44 (36.1%) 32 (26.2%) 31 (25.4%) 9 (7.4%) 6 (4.9%)0.020Exposure to Cytotoxic agent < 1 year 2-5 years 6-10 years 11 years or more Unknown(n=26) 7 (26.9%) 6 (23.1%) 5 (19.2%) 3 (11.5%) 5 (19.2%)(n=43) 5 (11.6%) 8 (18.6%) 6 (13.9%) 12 (27.9%) 12 (27.9%)0.276Exposure to Immune modulating agent < 1 year 2-5 years 6-10 years 11 years or more Unknown(n=20) 6 (30%) 6 (30%) 3 (15%) 1 (5%) 4 (20%)(n=37) 6 (16.2%) 10 (27.0%) 5 (13.5%) 3 (8.1%) 13 (35.1%)0.661
Table 2Treatments and Odds RatioOdds Ratio95% CI for ORP value *Cytotoxic OVERALLAzathioprine Cyclophosphamide Methotrexate Mitoxantrone 6-MP Mycophenolate1.39 4.16 1.28 0.74 2.73 1.00 1.210.72, 2.67 1.29, 13.44 0.24, 6.89 0.29, 1.88 0.23, 33.0 0.23, 4.35 0.28, 5.210.322 0.017 0.773 0.528 0.429 0.999 0.803Immune modulating agent OVERALLAnti-TNF Leflunomide Plaquenil1.19 0.73 2.00 2.730.52, 2.73 0.24, 2.24 0.40, 9.91 0.80, 8.330.672 0.585 0.396 0.077
Discussion
Treatment of AID does not seem to increase the incidence of MDS or AML. Furthermore, the incidence of myeloid neoplasm occurring in association with treatment of AID is not higher than expected in the general SEER population. However, the case cohort was exposed to more agents overall and more likely to have exposure to azathioprine than controls. Limitations of our study are associated with its retrospective nature, possible associated underrepresentation of t-MN, and autoimmune population profile. Nevertheless, this is the largest case study with detailed drug exposures with timelines for pts with AID, contributing to a better understanding regarding possible risk of developing MDS/AML in pts treated for AID. Confirmation of the same study at Mayo Clinic Rochester and Florida are ongoing.
Al-Kali:Novartis: Research Funding.
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