Synchronous or metachronous breast and colorectal cancers in younger-than-average-age patients: a case series.

BACKGROUND: The incidence of breast and colorectal cancer (CRC) in younger-than-average-age patients is rising and poorly understood. This is the largest study on patients with both cancers who are less than 60 years old and aims to characterize demographic, clinicopathologic, and genetic features and describe therapeutic dilemmas and management strategies. MATERIALS AND METHODS: This is a retrospective medical records review of patients at the University of California San Francisco with both primary breast and CRC before age 60. RESULTS: Fifty-one patients were identified; 41 had detailed medical records. Median age of diagnosis with breast cancer was 43 (range 27-59) and CRC was 50 (28-59). Most were Caucasian (38, 74.5%) and never smokers (23, 56.1%); about half were current alcohol consumers (20, 48.8%) and about one-third had sedentary jobs (14, 34.1%). Average BMI was 25.8 (range: 14-49), and 30% were overweight or obese. Breast was the first cancer diagnosed in 36 patients (70.6%) and 44 (86.3%) had a metachronous CRC diagnosis. Breast cancer was early stage (0-2) in 32 (78.0%) patients whereas CRC was split between early stage (1-2) in 14 (34.1%) and later stage (3-4) in 19 (46.2%). Ten patients (24.3%) had a known germline mutation, although 23 (56.1%) had a family history of cancer in a first-degree relative. CONCLUSION: Younger patients with both breast and CRC are a unique cohort, often without known risk factors. Alcohol consumption and sedentary jobs were the most common risk factors, and about one-quarter had a known genetic predisposition. Comanagement of both cancers requires individualized, multidisciplinary care.

Evaluating Survival After Hospitalization Due to Immune-Related Adverse Events From Checkpoint Inhibitors.

BACKGROUND: As immune checkpoint inhibitors (CPI) are increasingly approved for cancer treatment, hospitalizations related to severe immune-related adverse events (irAE) will increase. Here, we identify patients hospitalized due to irAEs and describe survival outcomes across irAE, CPI, and cancer type. METHODS: We identified patients hospitalized at our institution from January 2012 to December 2020 due to irAEs. Survival was analyzed using Kaplan-Meier survival curves with log-rank tests. RESULTS: Of 3137 patients treated with CPIs, 114 (3.6%) were hospitalized for irAEs, resulting in 124 hospitalizations. Gastrointestinal (GI)/hepatic, endocrine, and pulmonary irAEs were the most common causes of irAE-related hospitalization. After CPI initiation, the average time to hospitalization was 141 days. Median survival from hospital admission was 980 days. Patients hospitalized due to GI/hepatic and endocrine irAEs had longer median survival than patients with pulmonary irAEs (795 and 949 days vs. 83 days [P < .001]). Patients with melanoma and renal cell carcinoma had longer median survival than patients with lung cancer (2792 days and not reached vs. 159 days [P < .001]). There was longer median survival in the combination group compared to the PD-(L)1 group (1471 vs. 529 days [P = .04]). CONCLUSIONS: As CPI use increases, irAE-related hospitalizations will as well. These findings suggest that among patients hospitalized for irAEs, survival differs by irAE and cancer type, with worse survival for patients with irAE pneumonitis or lung cancer. This real-world data contributes to research pertaining to hospitalization due to severe irAEs, which may inform patient counseling and treatment decision-making.

Differential treatment outcomes in BRCA1/2-, CDK12-, and ATM-mutated metastatic castration-resistant prostate cancer.

BACKGROUND: DNA damage repair mutations (DDRm) are common in patients with metastatic castration-resistant prostate cancer (mCRPC). The optimal standard therapy for this population is not well described. METHODS: A multi-institutional, retrospective study of patients with mCRPC and DDRm was conducted. Patient data, including systemic therapies and responses, were collected. The decline in prostate-specific antigen ≥ 50% from baseline (PSA50) and overall survival (OS) from the treatment start were compared by mutation and treatment type. A multivariable Cox proportional hazards model for OS was created that controlled for DDRm, first-line treatment received for mCRPC, and clinical factors. RESULTS: The most common DDRm observed among 149 men with mCRPC were BRCA1/2 (44%), CDK12 (32%), and ATM (15%). The majority received first-line abiraterone (40%) or enzalutamide (30%). The PSA50 rate with first-line abiraterone was lower for CDK12 (52%) than BRCA1/2 (89%; P = .02). After first-line abiraterone or enzalutamide, the median OS was longest with second-line carboplatin-chemotherapy (38 months) in comparison with abiraterone or enzalutamide (33 months), docetaxel (17 months), or cabazitaxel (11 months; P = .02). PSA50 responses to carboplatin-based chemotherapy were higher for BRCA1/2 (79%) than ATM (14%; P = .02) or CDK12 (38%; P = .08). In a multivariable analysis, neither the specific DDRm type nor the first-line treatment was associated with improved OS. CONCLUSIONS: Responses to standard therapies were generally superior in patients with BRCA1/2 mutations and inferior in patients with ATM or CDK12 mutations. The DDRm type did not independently predict OS. After progression on first-line abiraterone or enzalutamide, carboplatin-based chemotherapy was associated with the longest OS. These findings may inform treatment discussions and clinical trial design and require prospective validation.

Survey of American and Canadian general surgeons' perceptions of margin status and practice patterns for breast conserving surgery.

Although breast conservation surgery (BCS) is commonly performed, several aspects of the procedure remain controversial. We undertook a cross-sectional survey to compare Canadian (CDN) and American (AM) general surgeons' reported BCS practice patterns to better understand the cross-border differences in early-stage breast cancer surgery care. A modified Dillman Method survey was mailed to 1,447 AM and 1,443 CDN surgeons. Factors evaluated included preoperative assessment, margin definition, surgical techniques, and re-excision practices. The response rate was 26% and 51% for AM and CDN surgeons, respectively. There was variation in use of preoperative core biopsies. American surgeons required wider margins for invasive cancer and ductal carcinoma in situ, and more often recommend re-excision for invasive cancer with 1 and 2 mm margins (p < 0.05). There was also variability in surgical techniques used for intraoperative margin assessment. Wide variation in BCS practice was observed, with some of this variability related to surgeon country.

TERT promoter mutations and other prognostic factors in patients with advanced urothelial carcinoma treated with an immune checkpoint inhibitor.

BACKGROUND: Immune checkpoint inhibitors (ICI) can achieve durable responses in a subset of patients with locally advanced or metastatic urothelial carcinoma (aUC). The use of tumor genomic profiling in clinical practice may help suggest biomarkers to identify patients most likely to benefit from ICI. METHODS: We undertook a retrospective analysis of patients treated with an ICI for aUC at a large academic medical center. Patient clinical and histopathological variables were collected. Responses to treatment were assessed for all patients with at least one post-baseline scan or clear evidence of clinical progression following treatment start. Genomic profiling information was also collected for patients when available. Associations between patient clinical/genomic characteristics and objective response were assessed by logistic regression; associations between the characteristics and progression-free survival (PFS) and overall survival (OS) were examined by Cox regression. Multivariable analyses were performed to identify independent prognostic factors. RESULTS: We identified 119 aUC patients treated with an ICI from December 2014 to January 2020. Genomic profiling was available for 78 patients. Overall response rate to ICI was 29%, and median OS (mOS) was 13.4 months. Favorable performance status at the start of therapy was associated with improved OS (HR 0.46, p=0.025) after accounting for other covariates. Similarly, the presence of a TERT promoter mutation was an independent predictor of improved PFS (HR 0.38, p=0.012) and OS (HR 0.32, p=0.037) among patients who had genomic profiling available. Patients with both a favorable performance status and a TERT promoter mutation had a particularly good prognosis with mOS of 21.1 months as compared with 7.5 months in all other patients (p=0.03). CONCLUSIONS: The presence of a TERT promoter mutation was an independent predictor of improved OS in a cohort of aUC patients treated with an ICI who had genomic data available. Most of the clinical and laboratory variables previously shown to be prognostic in aUC patients treated with chemotherapy did not have prognostic value among patients treated with an ICI. Genomic profiling may provide important prognostic information and affect clinical decision making in this patient population. Validation of these findings in prospective patient cohorts is needed.

Constrained chromatin accessibility in PU.1-mutated agammaglobulinemia patients.

The pioneer transcription factor (TF) PU.1 controls hematopoietic cell fate by decompacting stem cell heterochromatin and allowing nonpioneer TFs to enter otherwise inaccessible genomic sites. PU.1 deficiency fatally arrests lymphopoiesis and myelopoiesis in mice, but human congenital PU.1 disorders have not previously been described. We studied six unrelated agammaglobulinemic patients, each harboring a heterozygous mutation (four de novo, two unphased) of SPI1, the gene encoding PU.1. Affected patients lacked circulating B cells and possessed few conventional dendritic cells. Introducing disease-similar SPI1 mutations into human hematopoietic stem and progenitor cells impaired early in vitro B cell and myeloid cell differentiation. Patient SPI1 mutations encoded destabilized PU.1 proteins unable to nuclear localize or bind target DNA. In PU.1-haploinsufficient pro-B cell lines, euchromatin was less accessible to nonpioneer TFs critical for B cell development, and gene expression patterns associated with the pro- to pre-B cell transition were undermined. Our findings molecularly describe a novel form of agammaglobulinemia and underscore PU.1's critical, dose-dependent role as a hematopoietic euchromatin gatekeeper.

Timed inhibition of CDC7 increases CRISPR-Cas9 mediated templated repair.

Repair of double strand DNA breaks (DSBs) can result in gene disruption or gene modification via homology directed repair (HDR) from donor DNA. Altering cellular responses to DSBs may rebalance editing outcomes towards HDR and away from other repair outcomes. Here, we utilize a pooled CRISPR screen to define host cell involvement in HDR between a Cas9 DSB and a plasmid double stranded donor DNA (dsDonor). We find that the Fanconi Anemia (FA) pathway is required for dsDonor HDR and that other genes act to repress HDR. Small molecule inhibition of one of these repressors, CDC7, by XL413 and other inhibitors increases the efficiency of HDR by up to 3.5 fold in many contexts, including primary T cells. XL413 stimulates HDR during a reversible slowing of S-phase that is unexplored for Cas9-induced HDR. We anticipate that XL413 and other such rationally developed inhibitors will be useful tools for gene modification.

Campath induction for kidney transplantation: report of 297 cases.

OBJECTIVE: To evaluate 297 adult renal transplantation patients who received Campath-1H-based induction protocol. METHODS: Single center Institutional Review Board approved retrospective chart review of 297 patients who received alemtuzumab induction between November 2003 and December 2005. Maintenance immunosuppression consisted of tacrolimus, mycophenolate mofetil, and rapidly tapered solumedrol with few exceptional cases. The mean patient follow-up was 362 days. All rejection episodes were biopsy confirmed. Posttransplant infection rates were recorded. RESULTS: There were 153 living donor and 144 deceased donor recipients. One-year survival rates for recipient and kidney allografts were 100% and 98% for living donors, 97.4% and 89.7% for non-extended criteria donors (ECD) deceased donors, and 85.7% and 89.3% for ECD deceased donors. The overall rejection rate was 7%. Overall infectious rate was 19.8%. We had no cases of posttransplant lymphoproliferative disease. Of the 289 recipients discharged off prednisone, 269 (93%) remain steroid free. CONCLUSION: Alemtuzumab and reduced dosages of tacrolimus and mycophenolate without long-term steroids can achieve low rates of rejection and excellent graft and patient survival without excessive risk of infection or malignancy. There is still a need for large randomized trials with long-term follow-up to determine its exact role in solid organ transplantation.

Budd-Chiari syndrome: illustrated review of current management.

Budd-Chiari syndrome (BCS) is characterized by hepatic venous outflow obstruction at any level from the small hepatic veins to the atriocaval junction. BCS is a complex disease with a wide spectrum of aetiologies and presentations. This article reviews the current literature with respect to presentation, management and prognosis of the disease. Medical, interventional and surgical management of BCS is discussed. Particular attention is paid to interventional and surgical aspects of management. The review is augmented by images, which provide a clinical corollary to the text.

Liver transplantation for sinusoidal obstructive syndrome (veno-occlusive disease): case report with review of the literature and the UNOS database.

BACKGROUND: Severe sinusoidal obstructive syndrome (SOS) is a life-threatening complication of stem cell transplantation. We report the case of a young man transplanted for SOS. METHOD: A single chart review with query of the United Network of Organ Sharing database and review of the medical literature. CASE: A 23-yr-old male diagnosed with chronic myeloid leukemia underwent a matched unrelated stem cell transplant. The conditioning regimen included high-dose cyclophosphamide and busulfan. Within one month, he developed painful hepatomegaly, jaundice, ascites, and weight gain, and was diagnosed with biopsy-proven SOS. Despite therapy with defibrotide, he continued to deteriorate with the development of progressive renal failure and encephalopathy. The patient underwent orthotopic liver transplantation. After surgery, he developed cytomegalovirus infection and six wk later presented with a bile leak, hepatic artery thrombosis, and a liver abscess. A repeat bone marrow biopsy showed no evidence of recurrent disease. Although the patient was listed for re-transplantation, he succumbed prior to an organ becoming available. CONCLUSION: Severe SOS in the setting of bone marrow transplantation portends a poor prognosis. Careful patient selection, timing, and perhaps less immunosuppression should be considered when performing a liver transplantation in the setting of severe SOS.

Zebrafish Caudal Haematopoietic Embryonic Stromal Tissue (CHEST) Cells Support Haematopoiesis.

Haematopoiesis is an essential process in early vertebrate development that occurs in different distinct spatial locations in the embryo that shift over time. These different sites have distinct functions: in some anatomical locations specific hematopoietic stem and progenitor cells (HSPCs) are generated de novo. In others, HSPCs expand. HSPCs differentiate and renew in other locations, ensuring homeostatic maintenance. These niches primarily control haematopoiesis through a combination of cell-to-cell signalling and cytokine secretion that elicit unique biological effects in progenitors. To understand the molecular signals generated by these niches, we report the generation of caudal hematopoietic embryonic stromal tissue (CHEST) cells from 72-hours post fertilization (hpf) caudal hematopoietic tissue (CHT), the site of embryonic HSPC expansion in fish. CHEST cells are a primary cell line with perivascular endothelial properties that expand hematopoietic cells in vitro. Morphological and transcript analysis of these cultures indicates lymphoid, myeloid, and erythroid differentiation, indicating that CHEST cells are a useful tool for identifying molecular signals critical for HSPC proliferation and differentiation in the zebrafish. These findings permit comparison with other temporally and spatially distinct haematopoietic-supportive zebrafish niches, as well as with mammalian haematopoietic-supportive cells to further the understanding of the evolution of the vertebrate hematopoietic system.

Developmental Vitamin D Availability Impacts Hematopoietic Stem Cell Production.

Vitamin D insufficiency is a worldwide epidemic affecting billions of individuals, including pregnant women and children. Despite its high incidence, the impact of active vitamin D3 (1,25(OH)D3) on embryonic development beyond osteo-regulation remains largely undefined. Here, we demonstrate that 1,25(OH)D3 availability modulates zebrafish hematopoietic stem and progenitor cell (HSPC) production. Loss of Cyp27b1-mediated biosynthesis or vitamin D receptor (VDR) function by gene knockdown resulted in significantly reduced runx1 expression and Flk1+cMyb+ HSPC numbers. Selective modulation in vivo and in vitro in zebrafish indicated that vitamin D3 acts directly on HSPCs, independent of calcium regulation, to increase proliferation. Notably, ex vivo treatment of human HSPCs with 1,25(OH)D3 also enhanced hematopoietic colony numbers, illustrating conservation across species. Finally, gene expression and epistasis analysis indicated that CXCL8(IL-8) was a functional target of vitamin D3-mediated HSPC regulation. Together, these findings highlight the relevance of developmental 1,25(OH)D3 availability for definitive hematopoiesis and suggest potential therapeutic utility in HSPC expansion.

Successful transplantation of donor organs from a hemlock poisoning victim.

BACKGROUND: The poison hemlock plant (Conium maculatum) has been a known poison since early in human history, most notably as the agent used for the execution/suicide of Socrates in ancient Greece. No experience has been reported regarding the suitability of a hemlock victim's organs for transplantation. METHODS AND RESULTS: This report documents successful transplantation of the liver, kidney, and pancreas from a 14-year-old girl who died of anoxic encephalopathy from asphyxia after the accidental ingestion of fresh hemlock while on a nature hike. Predonation laboratory values were not remarkable, and liver and kidney biopsy results were normal. All organs in the three recipients had immediate function, and no recipient had any clinical evidence of transmitted toxin. All recipients are well, with functioning transplants at greater than 6 months after transplantation. CONCLUSIONS: Poison hemlock intoxication does not seem to be a contraindication to organ donation.

Conversion of stable renal allograft recipients to a bioequivalent cyclosporine formulation.

BACKGROUND: Gengraf capsule, an AB-rated generic cyclosporine for Neoral, has been shown to be bioequivalent in previous studies. The purpose of this pharmacokinetic study performed in stable renal transplant recipients was to evaluate interchangeability of Gengraf and Neoral. METHODS: Using an open-label, three-period design, 50 renal transplant recipients taking stable doses of Neoral completed a multicenter study. Subjects continued their Neoral regimen during period I (days 1-14). Subjects then switched from Neoral on a milligram-for-milligram basis to Gengraf during period II (days 15-28), followed by conversion to the same milligram-for-milligram dosing regimen of Neoral during period III (days 29-35). Twelve-hour pharmacokinetic evaluations (maximum observed blood concentration [C(max) ], concentration before dosing [C(trough) ], time to maximum observed concentration [T(max) ], and area under the blood concentration-vs.-time curve [AUC]) occurred on days 1, 14, 15, 28, and 29. Additional predose samples (C (trough)) were evaluated on days 7, 21, and 35. Laboratory and safety parameters were also evaluated. RESULTS: The pharmacokinetics of Gengraf (C(max), T(max), C(trough), and AUC) were indistinguishable from the Neoral values in stable renal allograft recipients. The bioequivalent capsules were interchangeable with respect to C(max), C(trough), and AUC at steady state and also on conversion from one capsule formulation to the other. The 90% confidence intervals (CI) for the Gengraf versus Neoral comparison at steady state (day 28 vs. day 14) were 0.95 to 1.03 for AUC and 0.92 to 1.04 for C(max). Trough concentrations remained consistent throughout the study, with no need for dosage adjustment in any of the subjects. Gengraf is well tolerated, with an excellent safety profile, comparable to the safety profile of Neoral. CONCLUSIONS The pharmacokinetics of Gengraf are equivalent and indistinguishable from those of Neoral. Gengraf is well tolerated and interchangeable with Neoral in stable renal transplant recipients.

Practice patterns and perceptions of margin status for breast conserving surgery for breast carcinoma: National Survey of Canadian General Surgeons.

BACKGROUND: We surveyed Canadian General Surgeons to examine decision-making in early stage breast cancer. METHODS: A modified Dillman Method was used for this mail survey of 1443 surgeons. Practice patterns and factors that influence management choices for: preoperative assessment, definition of margin status, surgical techniques and recommendations for re-excision were assessed. RESULTS: The response rate was 51% with 41% treating breast cancer. Most (80%) were community surgeons, with equal distribution of low/medium/high volume and years of practice categories. Approximately 25% of surgeons "sometimes or frequently" performed diagnostic excisional biopsies while 90% report "frequently" or "always" performing preoperative core biopsies. There was marked variation in defining negative and close margins, in the use of intra-operative margin assessment techniques and recommendations for re-excision. CONCLUSIONS: Responses revealed significant variation in attitudes and practices. These findings likely reflect an absence of consensus in the literature and potential gaps between best evidence and practice.

Kidney paired donation: a single center approach to increase living donor transplantation.

Methodist Specialty and Transplant Hospital has performed a total of 125 KPD transplants from the onset of the program in Dec. 2007. With the addition of the KPD program, live donor transplants have increased annually by 35% demonstrating the ability to substantially increase access to transplantation utilizing this modality. Furthermore, KPD combined with selective desensitization has provided a means for individualized assessment and management of the highly sensitized patient.

A virtual crossmatch protocol significantly increases access of highly sensitized patients to deceased donor kidney transplantation.

BACKGROUND: Patients with preexisting antihuman leukocyte antigen (HLA) antibodies (sensitized patients) are more likely to have a positive crossmatch with possible donors and have a lower likelihood of receiving a renal transplant with longer wait times. A virtual crossmatch protocol using solid-phase technology to determine the specificity of anti-HLA antibodies may improve the probability of identifying a crossmatch-negative compatible donor and increase access of sensitized patients to kidney transplantation. METHODS: A virtual crossmatch protocol was implemented on October 1, 2006 with solid-phase HLA antibody characterization for all sensitized patients on the waiting list. Transplant rates for the period from October 2006 to June 2008 were compared with Scientific Registry of Transplant Recipients (SRTR) data from 2006 to determine national transplant rates for sensitized patients. RESULTS: SRTR data for 2006 showed that nationally 590 of 10,659 transplants (5.5%) were in-patients with panel reactive antibody (PRA) more than or equal to 80%. During 2006 to 2008, after initiation of the virtual crossmatch protocol, we performed 122 deceased donor kidney transplants, of which 15 (12.3%) sensitized patients (PRA>or=80%) received transplants (P=0.004 compared with SRTR national data), with 9 (7.4%) patients having a PRA more than 90%. The virtual crossmatch protocol was predictive of a negative-final crossmatch and eliminated the use of preliminary cross-matching with attendant cost savings of more than $100,000. CONCLUSION: Initiation of a virtual crossmatch protocol using solid-phase histocompatibility techniques significantly increased access of sensitized patients to kidney transplantation and was more cost effective. Usage of a virtual crossmatch may facilitate greater sharing of kidneys to improve access to transplantation for sensitized recipients.

Renal function with cyclosporine C2 monitoring, enteric-coated mycophenolate sodium and basiliximab: a 12-month randomized trial in renal transplant recipients.

BACKGROUND: Cyclosporine exposure, as estimated by the area under the curve (AUC), predicts outcomes in renal transplantation. Cyclosporine concentration at two h post-dose (C(2)) has been shown to be the most reliable, single-point surrogate marker for AUC. The objective of this study was to measure renal function beyond month 2 post-transplant using two different C(2) maintenance targets in combination with enteric-coated mycophenolate sodium (EC-MPS), corticosteroids, and basiliximab induction. METHODS: In this open-label, multicenter trial, renal transplant recipients entered one of two randomized groups at day 61 post-transplant: group A (higher-C(2) range) or group B (lower-C(2) range). RESULTS: Patients (164) were recruited, and 141 patients were entered the randomized groups (group A, n = 66; group B, n = 75). At 12 months, the mean calculated creatinine clearance was significantly greater in group B than in group A (79.2 vs. 71.0 mL/min, p < 0.05). Biopsy-proven acute rejection occurred in 14.7% patients in group B and in 24.2% patients in group A (n.s.). During the 12-month trial, 17.7% patients discontinued EC-MPS because of adverse events. Group B (44.0%) had fewer serious adverse events when compared with group A (62.1%; p = 0.04). Overall patient and graft survival were 99.4% and 95.7% respectively. Among 99 high-risk patients (i.e., African-American race, previous transplant, PRA >35% or >4 HLA mismatches), mean creatinine clearance at 12 months was 65.6 mL/min and biopsy-proven rejection occurred in 20.2% patients. CONCLUSIONS: Low cyclosporine C(2) levels are associated with improved renal function compared with higher C(2) levels when used in conjunction with EC-MPS, steroids and basiliximab induction. EC-MPS with low cyclosporine C(2) levels, corticosteroids and basiliximab provides excellent renal function with good efficacy even in high-risk patients.

Comparison of two design optimality criteria applied to a nonlinear model.

In chemical kinetic or pharmacokinetic studies, many mathematical models are nonlinear with respect to the model parameters. This may cause serious problems for parameter estimation. A D-optimum design, which is very popular and effective for linear models, is not so good for nonlinear models with strong parameter curvature. In this article, we compare two optimality criteria applied to a nonlinear model. Both of them minimize the volume of the confidence ellipsoid of the parameters: D-optimality uses a linear approximation of the volume, and Q-optimality uses a quadratic approximation. We compute the relative design efficiencies and use a parameter-effect curvature measure to compute the number of observations that reduces the "curvature effect" to a specified level and improves the parameter estimation. The calculated designs differ significantly, and the Q-optimum design shows increasingly better statistical properties as the curvature increases. We present our results both graphically and as tables of numerical values.