A multi-center study on safety and efficacy of immune checkpoint inhibitors in cancer patients with kidney transplant.

Immune checkpoint inhibitors (ICIs) are widely used for various malignancies. However, their safety and efficacy in patients with a kidney transplant have not been defined. To delineate this, we conducted a multicenter retrospective study of 69 patients with a kidney transplant receiving ICIs between January 2010 and May 2020. For safety, we assessed the incidence, timing, and risk factors of acute graft rejection. For efficacy, objective response rate and overall survival were assessed in cutaneous squamous cell carcinoma and melanoma, the most common cancers in our cohort, and compared with stage-matched 23 patients with squamous cell carcinoma and 14 with melanoma with a kidney transplant not receiving ICIs. Following ICI treatment, 29 out of 69 (42%) patients developed acute rejection, 19 of whom lost their allograft, compared with an acute rejection rate of 5.4% in the non-ICI cohort. Median time from ICI initiation to rejection was 24 days. Factors associated with a lower risk of rejection were mTOR inhibitor use (odds ratio 0.26; 95% confidence interval, 0.09-0.72) and triple-agent immunosuppression (0.67, 0.48-0.92). The objective response ratio was 36.4% and 40% in the squamous cell carcinoma and melanoma subgroups, respectively. In the squamous cell carcinoma subgroup, overall survival was significantly longer in patients treated with ICIs (median overall survival 19.8 months vs. 10.6 months), whereas in the melanoma subgroup, overall survival did not differ between groups. Thus, ICIs were associated with a high risk of rejection in patients with kidney transplants but may lead to improved cancer outcomes. Prospective studies are needed to determine optimal immunosuppression strategies to improve patient outcomes.

Update in hematology and oncology.

This Update in Hematology and Oncology features 16 articles published in 2009 that the authors judged to be of high clinical relevance. Hematology topics include the use of dabigatran, anticoagulation in patients with deep venous thrombosis, estimation of warfarin dose, use of oral vitamin K to counter overanticoagulation, and adverse effects of erythropoiesis-stimulating agents. Oncology topics include screening for prostate and breast cancer, hormone replacement therapy and risk for breast cancer, cancer genomics and targeted therapies, short- and long-term cardiac effects of cancer treatment, and palliative care for patients with cancer.

Malignant Cutaneous Adnexal Tumors and Role of SLNB.

BACKGROUND: Malignant cutaneous adnexal tumors (MCATs) are rare and their natural history is poorly understood. Available literature indicates aggressive behavior with a significant risk of metastasis. STUDY DESIGN: Retrospective review of our institutional surgical oncology databases was performed for patients diagnosed with MCATs (2001-2020). We hypothesized that most patients have a low risk of lymph node involvement, recurrence, and death. Kaplan-Meier statistical analysis was used to assess risk of recurrence and 5-year survival. RESULTS: We identified 41 patients diagnosed with MCATs (median age 59 years, 68% were men). Most patients had long-standing cutaneous lesions (median 24 months) and no palpable adenopathy. Most patients had stage I or II disease (98%). Primary tumors were treated with wide local excision (n = 28 [68%]), Mohs surgery (n = 5 [12%]), or amputation (n = 8 [19%]). Of 25 patients who underwent SLNB (61%), 1 had lymphatic metastasis. These include apocrine carcinoma (1 of 3), digital papillary adenocarcinoma (0 of 8), porocarcinoma (0 of 4), and additional MCAT sub-types (0 of 10). Three patients (7%) had disease recurrence at a median interval of 3.6 years (interquartile range 1.5 to 4.4 years). Five patients (12%) died at a median interval of 7 years (interquartile range 6.7 to 9.2 years), but only 1 patient was known to have succumbed to MCAT. Overall 5-year survival rate was 96% (95% CI, 75% to 99%). CONCLUSIONS: Despite the historical impression that MCATs have a high metastatic potential, most patients have low recurrence rates and excellent 5-year survival rates. Lymphatic disease identified after SLNB in early-stage tumors is rare and the value of this staging procedure in MCAT remains unclear.

Generalized Acquired Cutis Laxa Associated with Monoclonal Gammopathy of Dermatological Significance.

BACKGROUND: Cutis laxa is a rare dermatosis that is inherited or acquired and clinically features loose, wrinkled, and redundant skin with decreased elasticity. This heterogeneous connective tissue disorder may be localized or generalized, with or without internal manifestations. Generalized cutis laxa often has a cephalocaudal progression and is attributed to inflammatory cutaneous eruptions, medications, and infections. Cutis laxa is also associated with several other conditions including rheumatoid arthritis, systemic lupus erythematosus, and plasma-cell dyscrasias. Case Presentation. We report an unusual case of a 35-year-old male with progression of generalized acquired cutis laxa and vasculitis that occurred over a period of one year. No cutaneous inflammatory eruption preceded or accompanied his decreased skin elasticity, and a biopsy of the skin showed elastolysis. His cutaneous manifestation led to systemic evaluation and an eventual diagnosis of smoldering multiple myeloma accompanied by aortitis and anemia. His myeloma and vasculitis were successfully treated with cyclophosphamide, bortezomib, and dexamethasone and high-dose prednisone, respectively, with no improvement to his cutis laxa. CONCLUSIONS: The presence of monoclonal gammopathy is strongly associated with several dermatological entities such as acquired cutis laxa. We propose a new term for the dermatological manifestations caused by paraproteinemia: monoclonal gammopathy of dermatological significance, or MGODS, and stress the evaluation of an underlying gammopathy in the setting of certain dermatologic conditions, including scleromyxedema and amyloidosis. We present a case of a newly acquired cutis laxa secondary to plasma-cell dyscrasias that exemplifies MGODS, alongside a brief literature review, and underscore the clinical relevance of monoclonal gammopathies of dermatological significance.

Treatment disparities for disabled medicare beneficiaries with stage I non-small cell lung cancer.

UNLABELLED: Treatment disparities for disabled Medicare beneficiaries with stage I non-small cell lung cancer. OBJECTIVE: To compare initial treatment and survival of nonelderly adults with and without disabilities newly diagnosed with non-small cell lung cancer. DESIGN: Retrospective analyses; population-based cohorts. SETTING: Eleven Surveillance, Epidemiology, and End Results cancer registries. PARTICIPANTS: Persons with disability Medicare entitlement (n=1016) and nondisabled persons (n=8425) ages 21 to 64 years when diagnosed with stage I, pathologically confirmed, first primary non-small cell lung cancer between January 1, 1988, and December 31, 1999. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Initial cancer treatments (surgery, radiotherapy), survival (through December 31, 2001). Multivariable logistic regression and Cox proportional hazards regression estimated adjusted associations of disability status with treatments and survival. RESULTS: Persons with disabilities were much more likely to be male, non-Hispanic black, and not currently married. Although 82.2% of nondisabled persons had surgery, 68.5% of disabled persons received operations. Adjusted relative risks (RRs) of receiving surgery were especially low for persons with respiratory disabilities (adjusted RR=.76; 95% confidence interval [CI], .67-.85), nervous system conditions (adjusted RR=.86; 95% CI, .76-.98), and mental health and/or mental retardation disorders (adjusted RR=.92; 95% CI, .86-.99). Persons with disabilities had significantly higher cancer-specific mortality rates (hazard ratio [HR]=1.37; 95% CI, 1.24-1.51) than persons without disabilities. Observed differences in cancer mortality persisted after adjusting for demographic and tumor characteristics (adjusted relative HR=1.23; 95% CI, 1.10-1.39). Further adjustment for surgery use eliminated statistically significant differences in cancer mortality between persons with and without disabilities across disabling conditions. CONCLUSIONS: Persons with disabilities were much less likely than nondisabled Medicare beneficiaries to receive surgery; statistically significant cancer-specific mortality differences disappeared after accounting for these treatment differences. Future research must explore reasons for these findings and whether survival of disabled Medicare beneficiaries with early-stage, non-small cell lung cancer could improve if surgical treatment disparities were eliminated.

Kaposi's varicelliform eruption in a patient with metastatic melanoma and primary cutaneous anaplastic large cell lymphoma treated with talimogene laherparepvec and nivolumab.

BACKGROUND: Immune-directed therapies have become front-line therapy for melanoma and are transforming the management of advanced disease. In refractory cases, multi-modal immunoncology (IO) approaches are being utilized, including combining immune checkpoint blockade (ICB) with oncolytic herpes viruses. Talimogene laherparepvec (T-VEC) is the first genetically modified oncolytic viral therapy (OVT) approved for the treatment of recurrent and unresectable melanoma. The use of IO in patients with concomitant malignancies and/or compromised immune systems is limited due to systematic exclusion from clinical trials. For example, a single case report of a solid organ transplant patient successfully treated with T-VEC for metastatic melanoma has been reported. Furthermore, the use of ICB in T-cell malignancies is limited and paradoxical worsening has been described. To our knowledge, this is the first report of dual ICB/T-VEC being administered to a patient with concurrent primary cutaneous anaplastic large cell lymphoma (pcALCL) and melanoma. CASE PRESENTATION: Here we present the case of a patient with concomitant primary cutaneous ALCL and metastatic melanoma, progressing on anti-programmed death (PD)-1 therapy, who developed Kaposi's varicelliform eruption after receiving the first dose of Talimogene laherparepvec. CONCLUSION: This case highlights the complexities of care of patients with coexistent cancers, demonstrates rapid progression of primary cutaneous ALCL on nivolumab and introduces a novel adverse effect of Talimogene laherparepvec.

Cancer stage at diagnosis and survival among persons with Social Security Disability Insurance on Medicare.

OBJECTIVE: To examine stage at diagnosis and survival for disabled Medicare beneficiaries diagnosed with cancer under age 65 and compare their experiences with those of other persons diagnosed under age 65. DATA SOURCES: Surveillance, Epidemiology, and End Results (SEER) Program data and SEER-Medicare linked data for 1988-1999. SEER-11 Program includes 11 population-based tumor registries collecting information on all incident cancers in catchment areas. Tumor registry and Medicare data are linked for persons enrolled in Medicare. STUDY DESIGN: 307,595 incident cases of non-small cell lung (51,963), colorectal (52,092), breast (142,281), and prostate (61,259) cancer diagnosed in persons under age 65 from 1988 to 1999. Persons who qualified for Social Security Disability Insurance and had Medicare (SSDI/Medicare) were identified from Medicare enrollment files. Ordinal polychotomous logistic regression and Cox proportional hazards regression were used to estimate adjusted associations between disability status and later-stage diagnoses and mortality (all-cause and cancer-specific). PRINCIPAL FINDINGS: Persons with SSDI/Medicare had lower rates of Stages III/IV diagnoses than others for lung (63.3 versus 69.5 percent) and prostate (25.5 versus 30.8 percent) cancers, but not for breast or colorectal cancers. After adjustment, they remained less likely to be diagnosed at later stages for lung and prostate cancers. Nevertheless, persons with SSDI/Medicare experienced higher all-cause mortality for each cancer. Cancer-specific mortality was higher among persons with SSDI/Medicare for breast and colorectal cancer patients. CONCLUSIONS: Disabled Medicare beneficiaries are diagnosed with cancer at similar or earlier stages than others. However, they experience higher rates of cancer-related mortality when diagnosed at the same stage of breast and colorectal cancer.

Disparities in breast cancer treatment and survival for women with disabilities.

BACKGROUND: Breast-conserving surgery combined with axillary lymph node dissection and radiotherapy or mastectomy are definitive treatments for women with early-stage breast cancer. Little is known about breast cancer treatment for women with disabilities. OBJECTIVE: To compare initial treatment for early-stage breast cancer between women with and without disabilities and to examine the association of treatment differences and survival. DESIGN: Retrospective cohort study. SETTING: 11 Surveillance, Epidemiology, and End Results (SEER) Program tumor registries. PARTICIPANTS: 100,311 women who received a diagnosis of stage I to IIIA breast cancer at 21 to 64 years of age from 1988 to 1999. Women who qualified for Social Security Disability Insurance (SSDI) and Medicare at breast cancer diagnosis were considered disabled. MEASUREMENTS: Receipt of breast-conserving surgery versus mastectomy. For women who had breast-conserving surgery (n = 49 166), the authors examined receipt of radiotherapy and axillary lymph node dissection. Survival was measured from diagnosis until death or until 31 December 2001. RESULTS: Women with SSDI and Medicare coverage had lower rates of breast-conserving surgery than other women (43.2% vs. 49.2%; adjusted relative risk, 0.80 [95% CI, 0.76 to 0.84]). Among women who had breast-conserving surgery, women with SSDI and Medicare coverage were less likely than other women to receive radiotherapy (adjusted relative risk, 0.83 [CI, 0.77 to 0.90]) and axillary lymph node dissection (adjusted relative risk, 0.81 [CI, 0.74 to 0.90]). Women with SSDI and Medicare coverage had lower survival rates than those of other women in all-cause mortality (adjusted hazard ratio, 2.02 [CI, 1.88 to 2.16]) and breast cancer-specific mortality (adjusted hazard ratio, 1.31 [CI, 1.18 to 1.45]). Results were similar after adjustment for treatment differences. LIMITATIONS: Findings are limited to women who qualified for SSDI and Medicare. No data on adjuvant chemotherapy and hormonal therapy were available, and details about the underlying disability were lacking. CONCLUSIONS: Women with disabilities had higher breast cancer mortality rates and were less likely to undergo standard therapy after breast-conserving surgery than other women. Differences in treatment did not explain the differences in breast cancer mortality rates.

Drug-associated disease: hematologic dysfunction.

Hematologic dysfunction, including thrombocytopenia, anemia, neutropenia, thromboses, and coagulopathy, occur commonly during critical illnesses. A major challenge is to identify drug-induced causes of hematologic dysfunction. Given the wide variety of drug-induced hematologic effects, clinicians always should consider any concomitant drugs in the differential diagnosis of acquired hematologic dysfunction. The most severe effects include drug-induced aplastic anemia, heparin-induced thrombocytopenia, and drug-induced thrombotic microangiopathy. Certain drugs are associated with multiple hematologic effects. For example, cisplatin can cause hemolytic uremia syndrome and erythropoietin deficiency, and quinine can precipitate immune-mediated thrombocytopenia, immune-mediated thrombocytopenia, and thrombotic microangiopathy.

Critical issues in hematology: anemia, thrombocytopenia, coagulopathy, and blood product transfusions in critically ill patients.

Systematic evaluations of anemia, thrombocytopenia, and coagulopathy are essential to identifying and managing their causes successfully. In all cases, clinicians should evaluate RBC measurements alongside WBC and platelet counts and WBC differentials. Multiple competing factors may coexist; certain factors affect RBCs independent of those that affect WBCs or platelets. Ideally, clinicians should examine the peripheral blood smear for morphologic features of RBCs, WBCs, and platelets that provide important clues to the cause of the patient's hematologic disorder. Thrombocytopenia arises from decreased platelet production, increased platelet destruction, or dilutional or distributional causes. Drug-induced thrombocytopenias present diagnostic challenges, because many medicines can cause thrombocytopenia and critically ill patients often receive multiple medications. If they suspect type II HIT, clinicians must promptly discontinue all heparin sources, including LMWHs, without awaiting laboratory confirmation, to avoid thrombotic sequelae. Because warfarin anticoagulation induces acquired protein C deficiency, thereby exacerbating the prothrombotic state of type II HIT, warfarin should be withheld until platelet counts increase to more than 100,000/microL and type II HIT is clearly resolving. The presence of a consumptive coagulopathy in the setting of thrombocytopenia supports a diagnosis of DIC, not TTP-HUS, and is demonstrated by decreasing serum fibrinogen levels, and increasing TTs, PTs, aPTTs, and fibrin degradation products. Increasing D-dimer, levels are the most specific DIC parameter and reflect fibrinolysis of cross-linked fibrin. Elevated PTs or a PTTs can result from the absence of factors or the presence of inhibitors. Clinicians should suspect factor inhibitors when the prolonged PT or aPTT does not correct or only partially corrects following an immediate assay of a 1:1 mix of patient and normal plasma. In addition to factor inhibitors, antiphospholipid antibodies (e.g., lupus anticoagulant) can produce a prolonged aPTT that does not correct with normal plasma but is overcome by adding excess phospholipid or platelets. Paradoxically, a tendency to thrombosis, not bleeding, accompanies lupus anticoagulants and the antiphospholipid antibody syndrome. Transfusion of red blood cells, platelets, or plasma products is sometimes warranted, but clinicians must carefully weigh potential benefits against known risks. In critically ill patients, administering RBCs can enhance oxygen delivery to tissues. Among euvolemic patients who do not have ischemic heart disease, guidelines recommend a transfusion threshold of HGB levels in the range of 6.0 to 8.0 g/dL; patients who have HGB that is at least 10.0 g/dL are unlikely to benefit from blood transfusion. The use of rHuEPO to increase erythropoiesis offers an alternative to RBC transfusion, assuming normal, responsive progenitor cells and adequate iron, folate, and cobalamin stores. Future research should examine whether clinical outcomes from rHuEPO use in critically ill patients are important and cost-effective. Because platelets play an instrumental role in primary hemostasis, platelet transfusions are often important in managing patients who are bleeding or at risk of bleeding with thrombocytopenia or impaired platelet function. Platelet transfusions carry risks, and decisions to transfuse platelets must consider clinical circumstances. Most important, platelet transfusions are generally contraindicated if the underlying disorder is TTP or type II HIT, because platelet transfusion in these settings may fuel thrombosis and worsen clinical signs and symptoms. Plasma products can correct hemostasis when bleeding arises from malfunction, consumption, or underproduction of plasma coagulation proteins. Choice of plasma product for transfusion depends on clinical circumstances. FFP is the most commonly used plasma product to correct clotting factor deficiencies, particularly coagulopathies that are attributable to multiple clotting factor deficiency states as in liver disease, DIC, or warfarin anticoagulation. PCC or rFVIIa that is administered in small volumes may provide advantages over FFP when coagulopathies require quick reversal without risk of volume overload. Factor concentrates can replace specific factor deficiencies. Recombinant FVIIa bypasses inhibitors to factors VIII and IX and vWF. Use of rFVIIa in managing hemostatic abnormalities from severe liver dysfunction; extensive surgery, trauma, or bleeding; excessive warfarin anticoagulation; and certain platelet disorders requires further study to determine optimal and cost-effective dosing regimens. Recombinant activated protein C reduces mortality from severe sepsis that is associated with organ dysfunction in adults who are at high risk for death (APACHE scores of at least 25). In severe sepsis, levels of protein C decrease, as do fibrinogen and platelet levels. Because of its anticoagulant effect, however, drotrecogin alfa may induce bleeding. Guidelines for drotrecogin alfa use must take into account bleeding risks.

Physician inter-annotator agreement in the Quality Oncology Practice Initiative manual abstraction task.

PURPOSE: The Quality Oncology Practice Initiative (QOPI) relies on the accuracy of manual abstraction of clinical data from paper-based and electronic medical records (EMRs). Although there is no "gold standard" to measure manual abstraction accuracy, measurement of inter-annotator agreement (IAA) is a commonly agreed-on surrogate. We quantified the IAA of QOPI abstractions on a cohort of cancer patients treated at Beth Israel Deaconess Medical Center. METHODS: The EMR charts of 49 patients (20 colorectal cancer; 18 breast cancer; 11 non-Hodgkin lymphoma) were abstracted by separate physician abstractors in the fall 2010 and fall 2011 QOPI abstraction rounds. Cohen's kappa (κ) was calculated for encoded data; raw levels of agreement and magnitude of discrepancies were calculated for numeric and dated data. RESULTS: One hundred two data elements with 2,035 paired entries were analyzed. Overall IAA for the 1,496 coded entries was κ = 0.75; median IAA for n = 85 individual coded elements was κ = 0.84 (interquartile range, 0.30 to 1.00). Overall IAA for the 421 dated entries was 73%; median IAA for n = 17 individual dated elements was 67% (interquartile range, 61% to 86%). CONCLUSION: This study establishes a baseline level of IAA for a complex medical abstraction task with clear relevance for the oncology community. Given that the observed κ is considered only fair IAA, and that the rate of date discrepancy is high, caution is necessary in interpreting the results of QOPI and other manual abstractions of clinical oncology data. The accuracy of automated data extraction efforts, possibly including a future evolution of QOPI, will also need to be carefully evaluated.

Early stage breast cancer treatments for younger Medicare beneficiaries with different disabilities.

OBJECTIVE: To explore how underlying disability affects treatments and outcomes of disabled women with breast cancer. DATA SOURCES: Surveillance, Epidemiology, and End Results program data, linked with Medicare files and Social Security Administration disability group. STUDY DESIGN: Ninety thousand two hundred and forty-three incident cases of early-stage breast cancer under age 65; adjusted relative risks and hazards ratios examined treatments and survival, respectively, for women in four disability groups compared with nondisabled women. PRINCIPAL FINDINGS: Demographic characteristics, treatments, and survival varied among four disability groups. Compared with nondisabled women, those with mental disorders and neurological conditions had significantly lower adjusted rates of breast conserving surgery and radiation therapy. Survival outcomes also varied by disability type. CONCLUSIONS: Compared with nondisabled women, certain subgroups of women with disabilities are especially likely to experience disparities in care for breast cancer.

Managed care and cancer outcomes for Medicare beneficiaries with disabilities.

OBJECTIVE: To determine if the type of insurance arrangement, specifically health maintenance organization (HMO) vs fee-for-service (FFS), affects cancer outcomes for Medicare beneficiaries with disabilities. STUDY DESIGN: Retrospective cohort. METHODS: We used the Surveillance, Epidemiology, and End Results-Medicare linked dataset to identify beneficiaries older and younger than 65 years entitled to Medicare benefits because of disability (Social Security Disability Insurance) who subsequently were diagnosed as having breast cancer (n = 6839) or non-small cell lung cancer (n = 10,229) from 1988 through 1999. We categorized persons according to Medicare insurance arrangement (continuous FFS, continuous HMO, or mixed FFS/HMO) during the periods 12 months before diagnosis and 6 months after diagnosis. Using a retrospective cohort design, we examined stage at diagnosis, cancer-directed treatments, and survival. RESULTS: Women with continuous HMO insurance had earlier-stage breast cancer diagnosis (adjusted relative risk, 0.77; 95% confidence interval, 0.65-0.91) and were more likely to receive radiation therapy following breast-conserving surgery (adjusted relative risk, 1.11; 95% confidence interval, 1.03-1.19). Women having continuous HMO insurance had better breast cancer survival, primarily resulting from earlier-stage diagnosis. Among persons with non-small cell lung cancer, those having mixed FFS/HMO insurance were more likely to receive definitive surgery for early-stage disease (adjusted odds ratio, 1.23; 95% confidence interval, 1.02-1.49) and to have better overall survival but not significantly better lung cancer survival. CONCLUSION: When diagnosed as having breast cancer or non-small cell lung cancer, some Medicare beneficiaries with disabilities fare better with managed care compared with FFS insurance plans.