Did border closures slow SARS-CoV-2?

Despite the economic, social, and humanitarian costs of border closures, more than 1000 new international border closures were introduced in response to the 2020-2021 pandemic by nearly every country in the world. The objective of this study was to examine whether these border closures reduced the spread of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Prior to 2020, the impacts of border closures on disease spread were largely unknown, and their use as a pandemic policy was advised against by international organizations. We tested whether they were helpful in reducing spread by using matching techniques on our hand-coded COVID Border Accountability Project (COBAP) Team database of international closures, converted to a time-series cross-sectional data format. We controlled for national-level internal movement restrictions (domestic lockdowns) using the Oxford COVID-19 Government Response Tracker (OxCGRT) time-series data. We found no evidence in favor of international border closures, whereas we found a strong association between national-level lockdowns and a reduced spread of SARS-CoV-2 cases. More research must be done to evaluate the byproduct effects of closures versus lockdowns as well as the efficacy of other preventative measures introduced at international borders.

COVID Border Accountability Project, a hand-coded global database of border closures introduced during 2020.

Quantifying the timing and content of policy changes affecting international travel and immigration is key to ongoing research on the spread of SARS-CoV-2 and the socioeconomic impacts of border closures. The COVID Border Accountability Project (COBAP) provides a hand-coded dataset of >1000 policies systematized to reflect a complete timeline of country-level restrictions on movement across international borders during 2020. Trained research assistants used pre-set definitions to source, categorize and verify for each new border policy: start and end dates, whether the closure is "complete" or "partial", which exceptions are made, which countries are banned, and which air/land/sea borders were closed. COBAP verified the database through internal and external audits from public health experts. For purposes of further verification and future data mining efforts of pandemic research, the full text of each policy was archived. The structure of the COBAP dataset is designed for use by social and biomedical scientists. For broad accessibility to policymakers and the public, our website depicts the data in an interactive, user-friendly, time-based map.

Characterizing and prognosticating chronic lymphocytic leukemia in the elderly: prospective evaluation on 455 patients treated in the United States.

BACKGROUND: Median age at diagnosis of patients with chronic lymphocytic leukemia (CLL) is > 70 years. However, the majority of clinical trials do not reflect the demographics of CLL patients treated in the community. We examined treatment patterns, outcomes, and disease-related mortality in patients ≥ 75 years with CLL (E-CLL) in a real-world setting. METHODS: The Connect® CLL registry is a multicenter, prospective observational cohort study, which enrolled 1494 adult patients between 2010-2014, at 199 US sites. Patients with CLL were enrolled within 2 months of initiating first line of therapy (LOT1) or a subsequent LOT (LOT ≥ 2). Kaplan-Meier methods were used to evaluate overall survival. CLL- and infection-related mortality were assessed using cumulative incidence functions (CIF) and cause-specific hazards. Logistic regression was used to develop a classification model. RESULTS: A total of 455 E-CLL patients were enrolled; 259 were enrolled in LOT1 and 196 in LOT ≥ 2. E-CLL patients were more likely to receive rituximab monotherapy (19.3 vs. 8.6%; p < 0.0001) and chemotherapy-alone regimens (p < 0.0001) than younger patients. Overall and complete responses were lower in E-CLL patients than younger patients when given similar regimens. With a median follow-up of 3 years, CLL-related deaths were higher in E-CLL patients than younger patients in LOT1 (12.6 vs. 5.1% p = 0.0005) and LOT ≥ 2 (31.3 vs. 21.5%; p = 0.0277). Infection-related deaths were also higher in E-CLL patients than younger patients in LOT1 (7.4 vs. 2.7%; p = 0.0033) and in LOT ≥ 2 (16.2 vs. 11.2%; p = 0.0786). A prognostic score for E-CLL patients was developed: time from diagnosis to treatment < 3 months, enrollment therapy other than bendamustine/rituximab, and anemia, identified patients at higher risk of inferior survival. Furthermore, higher-risk patients experienced an increased risk of CLL- or infection-related death (30.6 vs 10.3%; p = 0.0006). CONCLUSION: CLL- and infection-related mortality are higher in CLL patients aged ≥ 75 years than younger patients, underscoring the urgent need for alternative treatment strategies for these understudied patients. TRIAL REGISTRATION: The Connect CLL registry was registered at clinicaltrials.gov: NCT01081015 on March 4, 2010.

Real-world clinical experience in the Connect® chronic lymphocytic leukaemia registry: a prospective cohort study of 1494 patients across 199 US centres.

The clinical course of chronic lymphocytic leukaemia (CLL) is heterogeneous, and treatment options vary considerably. The Connect® CLL registry is a multicentre, prospective observational cohort study that provides a real-world perspective on the management of, and outcomes for, patients with CLL. Between 2010 and 2014, 1494 patients with CLL and that initiated therapy, were enrolled from 199 centres throughout the USA (179 community-, 17 academic-, and 3 government-based centres). Patients were grouped by line of therapy at enrolment (LOT). We describe the clinical and demographic characteristics of, and practice patterns for, patients with CLL enrolled in this treatment registry, providing patient-level observational data that represent real-world experiences in the USA. Fluorescence in situ hybridization (FISH) analyses were performed on 49·3% of patients at enrolment. The most common genetic abnormalities detected by FISH were del(13q) and trisomy 12 (45·7% and 20·8%, respectively). Differences in disease characteristics and comorbidities were observed between patients enrolled in LOT1 and combined LOT2/≥3 cohorts. Important trends observed include the infrequent use of genetic prognostic testing, and differences in patient characteristics for patients receiving chemoimmunotherapy combinations. These data represent experiences of patients with CLL in the USA, which may inform treatment decisions in everyday practice.

Immunotherapy in acute myeloid leukemia.

Despite the remarkable progress made in some leukemias such as CML and CLL, cytotoxic treatment for AML remains essentially unchanged over the last 4 decades. Several lines of evidence, including the graft versus leukemia effect associated with allogeneic hematopoietic stem cell transplantation (HSCT), suggest that immunotherapy is an active modality in AML. Given the lack of progress for chemotherapy in this disease, many novel immunologic treatment approaches have been explored. The goals of non-transplant-based immune approaches have largely consisted of the stimulation or restoration of endogenous immune responses or the targeting of specific tumor antigens by immune cells. These strategies have been associated with less toxicity than allogeneic HSCT but typically have inferior efficacy. Allogeneic HSCT exploits major and minor histocompatibility differences between the donor and recipient in order to recognize and eradicate malignancy. With the recognition that the immune system itself provides a basis for treating AML, immunotherapy continues to be an attractive modality to exploit in the treatment of this disease.

Liposomal vincristine for relapsed or refractory Ph-negative acute lymphoblastic leukemia: a review of literature.

Acute lymphoblastic leukemia (ALL) is a heterogeneous group of hematologic malignancies that arise from clonal proliferation of immature lymphoid cells in the bone marrow, peripheral blood and other organs. There are approximately 3000 new adult cases diagnosed every year in the United States with a 5-year overall survival ranging from 22% to 50%. Most adult patients with ALL who achieve a complete response will ultimately relapse and for this subset of patients the only hope of curative therapy is successful re-induction to achieve a complete response followed by allogeneic transplant. Conventional vincristine has been used in all phases of ALL therapy but its efficacy is limited by cumulative toxicity, typically neuropathic in nature. Historically, the dose of conventional vincristine has been capped at 2 mg to avoid severe neurotoxicity. Liposomal vincristine [as vincristine sulfate liposomal injection (VSLI)] constitutes encapsulating vincristine in a sphingomyelin/cholesterol envelope. This process is thought to enhance drug delivery to the target tissues, decrease neurotoxicity by reducing the percentage of free drug in the plasma and therefore results in increased efficacy with acceptable toxicity. Results from recent trials using VSLI in the setting of relapsed/refractory Ph-negative ALL have been encouraging. VSLI as salvage monotherapy has been successful in inducing complete responses in a minority of adults with relapsed/refractory ALL so that they can be bridged to stem-cell transplantation. Rigorous post-approval testing needs to be conducted to clarify its utility in the clinic.

Neanderthal and Denisova genetic affinities with contemporary humans: introgression versus common ancestral polymorphisms.

Analyses of the genetic relationships among modern humans, Neanderthals and Denisovans have suggested that 1-4% of the non-Sub-Saharan African gene pool may be Neanderthal derived, while 6-8% of the Melanesian gene pool may be the product of admixture between the Denisovans and the direct ancestors of Melanesians. In the present study, we analyzed single nucleotide polymorphism (SNP) diversity among a worldwide collection of contemporary human populations with respect to the genetic constitution of these two archaic hominins and Pan troglodytes (chimpanzee). We partitioned SNPs into subsets, including those that are derived in both archaic lineages, those that are ancestral in both archaic lineages and those that are only derived in one archaic lineage. By doing this, we have conducted separate examinations of subsets of mutations with higher probabilities of divergent phylogenetic origins. While previous investigations have excluded SNPs from common ancestors in principal component analyses, we included common ancestral SNPs in our analyses to visualize the relative placement of the Neanderthal and Denisova among human populations. To assess the genetic similarities among the various hominin lineages, we performed genetic structure analyses to provide a comparison of genetic patterns found within contemporary human genomes that may have archaic or common ancestral roots. Our results indicate that 3.6% of the Neanderthal genome is shared with roughly 65.4% of the average European gene pool, which clinally diminishes with distance from Europe. Our results suggest that Neanderthal genetic associations with contemporary non-Sub-Saharan African populations, as well as the genetic affinities observed between Denisovans and Melanesians most likely result from the retention of ancient mutations in these populations.

Treatment of adults with acute lymphoblastic leukemia: do the specifics of the regimen matter?: Results from a prospective randomized trial.

BACKGROUND: Induction therapy for adults with acute lymphoblastic leukemia (ALL) is similar across essentially all regimens, comprised of vincristine, corticosteroids, and anthracyclines intensified with cyclophosphamide, asparaginase, or both. Given the lack of randomized data, to date, no regimen has emerged as standard. The authors previously evaluated cytarabine 3 g/m(2) daily for 5 days with mitoxantrone 80 mg/m(2) (the ALL-2 regimen) as a novel induction regimen. Compared with historic controls, the ALL-2 regimen was superior in terms of incidence of complete remission, failure with resistant disease, and activity in patients with Philadelphia chromosome (Ph)-positive ALL. METHODS: The authors conducted a multicenter, prospective, randomized trial of the ALL-2 regimen compared with a standard 4-drug induction (the L-20 regimen). Patients also received consolidation, maintenance therapy, and central nervous system prophylaxis. The trial accrued patients from August 1996 to October 2004. RESULTS: The median follow-up for survivors was 7 years, and the median patient age was 43 years. Responses were evaluated in 164 patients. The treatment arms were balanced in terms of pretreatment characteristics. The frequency of complete remission for the ALL-2 regimen versus the L-20 regimen was 83% versus 71% (P = .06). More patients on the L-20 arm failed with resistant disease (21% vs 8%; P = .02). Induction deaths were comparable at 9% (ALL-2) versus 7% (L-20). The median survival was similar; and, at 5 years, the survival rate was 33% alive on the ALL-2 arm versus 27% on the L-20. CONCLUSIONS: Despite superior results of induction therapy with the ALL-2 regimen, this treatment did not improve long-term outcomes. When coupled to the reported experience of other studies in adults with ALL, the results of this randomized trial raise the possibility that ultimate outcomes in adult ALL may be independent of the specific regimen chosen. Cancer 2013. © 2012 American Cancer Society.

Sequential therapy with fludarabine, high-dose cyclophosphamide, and rituximab in previously untreated patients with chronic lymphocytic leukemia produces high-quality responses: molecular remissions predict for durable complete responses.

PURPOSE: Modern combination strategies are active in chronic lymphocytic leukemia (CLL) but can have significant myelosuppression and immunosuppression that may require dose attenuation for safety. We explored a sequential treatment strategy to allow safe delivery of active agents at full doses. Previously, we studied sequential therapy with fludarabine followed by cyclophosphamide (F-->C). In that study, cyclophosphamide consolidation improved the frequency of complete response (CR) four-fold. Subsequently, rituximab was added to this regimen (F-->C-->R). PATIENTS AND METHODS: Thirty-six previously untreated CLL patients received therapy with fludarabine 25 mg/m(2) on days 1 through 5 every 4 weeks for six cycles, followed by consolidation with cyclophosphamide 3,000 mg/m(2) administered every 3 weeks for three cycles, followed by consolidation with weekly rituximab 375 mg/m(2) for four cycles. Evaluation for minimal residual disease included flow cytometry and a highly sensitive clonotypic polymerase chain reaction (PCR). The median age was 59 years (range, 37 to 71 years), 61% of patients had high-risk disease, and 58% had unmutated IgV(H) genes. RESULTS: There were 32 responses (89%), including 22 CRs (61%). Consolidation with cyclophosphamide improved responses in 13 patients (36%); nine patients (25%) further improved their response with rituximab. Twenty patients (56%) achieved flow cytometric CRs, and 12 patients (33%) achieved a molecular CR (PCR negative). Patients achieving molecular CRs had an excellent prognosis with a plateau in the response duration curve, and 90% remain in clinical CR at 5 years. For the entire group, 5-year survival rate is 71% compared with a rate of 48% with our prior F-->C regimen (P = .10). CONCLUSION: Sequential therapy with F-->C-->R yields improvement in quality of response, with many patients achieving a PCR-negative state.

Pentostatin in chronic lymphocytic leukemia.

BACKGROUND: Chronic lymphocytic leukemia (CLL) is a disease that typically afflicts older individuals with a median age of diagnosis in the eighth decade of life for which treatments available now are not curative. Although purine analogue based combinations produce complete responses (CRs) in many patients, the use of these combinations has been limited by toxicity including myelosuppression and an increased risk of infectious complications. OBJECTIVE: To identify the role of pentostatin, a specific inhibitor of adenosine deaminase (ADA), in the treatment of CLL. We compare pentostatin to other purine analogues, most notably fludarabine, with regard to safety and efficacy. Finally, we review the use of pentostatin in other diseases. METHODS: The scope of this review encompasses the history of treatment for CLL as well as the genesis of modern combination chemoimmunotherapy and the advantages of pentostatin within such a treatment program. RESULTS: Combination therapy with pentostatin seems to provide response frequencies comparable to fludarabine based combinations but with less toxicity and with greater ease of administration.

Presentation of the PATH Alliance registry for prospective data collection and analysis of the epidemiology, therapy, and outcomes of invasive fungal infections.

Randomized clinical trials for patients with invasive fungal infections (IFIs) are often limited or precluded, necessitating alternate sources of information. The Prospective Antifungal Therapy Alliance (PATH Alliance) is a registry that collects data on patients with IFIs at medical centers in North America. Patients with a diagnosis of proven or probable IFI are enrolled and followed prospectively for 12 weeks. Using a Web-based electronic data capture and reporting system, the registry collects anonymous data to address end points in epidemiology, diagnosis, treatment, and outcome of IFIs. As of October 2006, 1892 IFIs were observed in 1710 patients enrolled at 22 sites. The most commonly encountered IFIs were caused by Candida spp. (73.0%), presenting predominantly as candidemia, followed by Aspergillus spp. (14.8%). A small number of IFIs with uncommon and emerging moulds were observed. Culture remains the main diagnostic tool for most IFIs (91.8%). Antifungal agent choice depended on the fungal species isolated, with fluconazole being the most frequently administered agent (58.2%). The overall crude 12-week mortality, excluding the patients lost to follow-up, was 43.9%. PATH Alliance is a network of medical institutions gathering significant information about IFIs in North America. Significant trends and treatment practices concerning yeasts and moulds were observed. As enrollment continues, additional data will be analyzed and published, which will provide valuable information concerning the epidemiology, therapy, and outcomes of IFIs.

Purine analogue-based chemotherapy regimens for second-line therapy in patients with chronic lymphocytic leukemia.

A dramatic change has occurred in the management of chronic lymphocytic leukemia (CLL) over the past 20 years. The use of newer therapies, including the purine analogues, has resulted in higher frequencies of response. Combination therapy with purine analogues, alkylators, and/or monoclonal antibodies represents a promising new approach to the treatment of patients with CLL. The most commonly studied regimens have utilized fludarabine, but severe myelosuppression and immunosuppression of these combinations require close attention to dosing and schedule. Of the purine analogues that show activity in CLL, pentostatin appears to be the least myelosuppressive. These combination strategies are associated with high-quality responses in the majority of patients and may one day lead to improved survival or possibly even a cure for patients with CLL.

Efficacy and safety results with the LifeSite hemodialysis access system versus the Tesio-Cath hemodialysis catheter at 12 months.

PURPOSE: To compare the performance and safety of a fully subcutaneous vascular access device, the LifeSite hemodialysis access system, versus a tunneled hemodialysis catheter, the Tesio-Cath, at 1 year after implantation. MATERIALS AND METHODS: Sixty-eight patients who required hemodialysis received implantation of the LifeSite device or a Tesio-Cath device as a part of this multicenter study. Thirty-four patients were treated in each group. The endpoints observed included blood flow rates and associated venous pressures, overall and device-related adverse events, the need for thrombolytic infusions, device-related infections (DRIs) and associated hospitalizations, and technical device survival. RESULTS: During the 12-month observation period, significantly higher venous pressures were required in patients with the Tesio-Cath to achieve blood flow rates comparable with those achieved with the LifeSite device. Patients in the LifeSite group experienced a significantly lower rate of non-device-related adverse events (P < .001), device-related adverse events (P < .016), need for thrombolytic infusions (P < .002), and DRIs (P < .013) compared with patients in the Tesio-Cath group. There was a trend toward a lower number of hospital days per month for DRIs in the LifeSite group, with the rate for the Tesio-Cath group being twice that in the LifeSite group. The use of the LifeSite device was also associated with a significantly higher probability of device survival for 12 months after censoring for planned removals (P < .031). CONCLUSIONS: The results of the present study demonstrate superior device performance and technical device survival, reduced complications, and the need for fewer interventions with the LifeSite hemodialysis access system compared with a standard hemodialysis catheter during a 1-year time period after implantation.

Pentostatin, cyclophosphamide, and rituximab is an active, well-tolerated regimen for patients with previously treated chronic lymphocytic leukemia.

PURPOSE: Purine analogs and alkylators are important agents for treating chronic lymphocytic leukemia (CLL). Early studies combining fludarabine and chlorambucil were abandoned owing to increased toxicity from overlapping myelosuppression and immunosuppression. Of the purine analogs active in CLL, pentostatin appears to be the least myelosuppressive. We previously reported that pentostatin and cyclophosphamide (PC) is active and well-tolerated in patients with relapsed or refractory CLL. Subsequently, we added rituximab, and now report on this three-drug combination. PATIENTS AND METHODS: We treated 46 patients with either previously treated CLL (32 patients) or other low-grade B-cell neoplasms (14 patients). Patients received pentostatin 4 mg/m2, cyclophosphamide 600 mg/m2, and rituximab 375 mg/m2 (PCR). All drugs were administered on the same day (rituximab omitted from cycle 1), and patients received six cycles at 3-week intervals. Filgrastim, sulfamethoxazole/trimethoprim, and acyclovir were administered prophylactically. RESULTS: The median age was 62 years (range, 30 to 80 years). The median number of prior regimens was two (range, one to seven). For CLL patients, there were 24 responses (75%), including eight complete responses (25%). In fludarabine-refractory patients, 75% responded. Toxicity was acceptable, with grade 3/4 infections (including fever of unknown origin) in 28%. The regimen was well tolerated, with 72% of patients receiving the planned treatment at full dose. CONCLUSION: PCR is safe and effective in previously treated patients with CLL. In comparison with our prior two-drug regimen, we find that rituximab did not seem to add significantly to the toxicity, but did appear to confer a survival advantage. Based on these results, we are currently studying PCR as initial therapy for patients with CLL.

Inflammatory myofibroblastic tumors of the kidney: a clinicopathologic and immunohistochemical study of 12 cases.

Inflammatory myofibroblastic tumor is a rare entity composed of spindle cells admixed with variable amounts of extracellular collagen, lymphocytes, and plasma cells. In the genitourinary tract, inflammatory myofibroblastic tumor most commonly occurs in the bladder. Isolated case studies of inflammatory myofibroblastic tumor of the kidney, renal pelvis, and ureter have been previously reported. Our series includes 12 cases of inflammatory myofibroblastic tumor occurring in the renal pelvis (six cases), renal parenchyma (four cases), and immediate perirenal soft tissue (two cases). Clinical presentation included flank pain (two patients), painless gross hematuria (one patient), and ureteropelvic junction stenosis with hydronephrosis (one patient). The remaining eight patients were asymptomatic. All patients underwent nephrectomy. The tumors were characterized by firm white tissue or had a myxoid "gelatinous" appearance. Three histologic patterns were identified in the tumors, including a myxoid vascular pattern, a compact spindle cell pattern, and a hypocellular fibrous pattern. Immunohistochemical and electron microscopic studies supported a myofibroblastic proliferation. All cases were negative for anaplastic lymphoma kinase. Follow-up was available in eight cases and ranged from 1 to 17 years with no evidence of recurrence. Based on this series, renal inflammatory myofibroblastic tumor is a proliferative lesion of myofibroblasts of uncertain pathogenesis with no identified potential for recurrence or metastases.