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1.
J Hepatobiliary Pancreat Sci ; 31(5): 308-317, 2024 May.
Article in English | MEDLINE | ID: mdl-38282543

ABSTRACT

BACKGROUND: This meta-analysis investigated the effects of enhanced recovery after surgery (ERAS) protocols compared to conventional care on postoperative outcomes in patients aged 70 years or older undergoing pancreatoduodenectomy (PD). METHODS: Five databases were systematically searched. Comparative studies with available individual patient data (IPD) were included. The main outcomes were postoperative morbidity, length of stay, readmission and postoperative functional recovery elements. To assess an age-dependent effect, the group was divided in septuagenarians (70-79 years) and older patients (≥80 years). RESULTS: IPD were obtained from 15 of 31 eligible studies comprising 1109 patients. The overall complication and major complication rates were comparable in both groups (OR 0.92 [95% CI: 0.65-1.29], p = .596 and OR 1.22 [95% CI: 0.61-2.46], p = .508). Length of hospital stay tended to be shorter in the ERAS group compared to the conventional care group (-0.14 days [95% CI: -0.29 to 0.01], p = .071) while readmission rates were comparable and the total length of stay including days in hospital after readmission tended to be shorter in the ERAS group (-0.28 days [95% CI: -0.62 to 0.05], p = .069). In the subgroups, the length of stay was shorter in octogenarians treated with ERAS (-0.36 days [95% CI: -0.71 to -0.004], p = .048). The readmission rate increased slightly but not significantly while the total length of stay was not longer in the ERAS group. CONCLUSION: ERAS in the elderly is safe and its benefits are preserved in the care of even in patients older than 80 years. Standardized care protocol should be encouraged in all pancreatic centers.


Subject(s)
Enhanced Recovery After Surgery , Length of Stay , Pancreaticoduodenectomy , Postoperative Complications , Humans , Pancreaticoduodenectomy/adverse effects , Aged , Aged, 80 and over , Length of Stay/statistics & numerical data , Postoperative Complications/epidemiology , Age Factors , Recovery of Function , Female , Male , Patient Readmission/statistics & numerical data
2.
Ann Surg Oncol ; 31(1): 405-412, 2024 Jan.
Article in English | MEDLINE | ID: mdl-37865940

ABSTRACT

BACKGROUND: Most patients with resectable gastric cancer present with locally advanced disease and warrant neoadjuvant chemotherapy based on level 1 evidence. However, the incremental benefit of adding radiation to chemotherapy as a neoadjuvant treatment strategy for these patients is less clear. METHODS: While awaiting the results of two ongoing randomized clinical trials attempting to specifically address this question (TOPGEAR and CRITICS-II), this article presents the debate between two gastric cancer surgery experts supporting each side of the argument on the use or omission of neoadjuvant radiation in this setting. RESULTS: On the one hand, neoadjuvant radiation may be better tolerated compared with modern triplet chemotherapy and may be associated with higher rates of major pathologic response. Additionally, there is evidence to suggest that radiation may offer a survival benefit when the tumor is located at the gastroesophageal junction or there is concern for a margin-positive resection. However, in the setting of adequate surgery, no survival benefit has been demonstrated by adding radiation to modern chemotherapy, likely reflecting the fact that death from gastric cancer is a result of distant recurrence, which is not addressed by local treatment such as radiotherapy. CONCLUSION: While awaiting the results of the TOPGEAR and CRITICS-II trials, this discussion of current evidence can facilitate the refinement of an optimal neoadjuvant therapy strategy in patients with resectable gastric cancer.


Subject(s)
Adenocarcinoma , Stomach Neoplasms , Humans , Adenocarcinoma/pathology , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Chemoradiotherapy , Chemotherapy, Adjuvant , Neoadjuvant Therapy , Stomach Neoplasms/pathology , Randomized Controlled Trials as Topic
3.
J Clin Med ; 12(21)2023 Oct 27.
Article in English | MEDLINE | ID: mdl-37959264

ABSTRACT

The peritoneum is a common site of metastases for gastrointestinal tumors that predicts a poor outcome. In addition to decreased survival, peritoneal metastases (PMs) can significantly impact quality of life from the resulting ascites and bowel obstructions. The peritoneum has been a target for regional therapies due to the unique properties of the blood-peritoneum barrier. Cytoreductive surgery (CRS) and heated intraperitoneal chemotherapy (HIPEC) have become accepted treatments for limited-volume peritoneal disease in appendiceal, ovarian, and colorectal malignancies, but there are limitations. Pressurized intraperitoneal aerosolized chemotherapy (PIPAC) improves drug distribution and tissue penetration, allowing for a minimally invasive application for patients who are not CRS/HIPEC candidates based on high disease burden. PIPAC is an emerging treatment that may convert the patient to resectable disease, and may increase survival without major morbidity, as indicated by many small studies. In this review, we discuss the rationale and benefits of PIPAC, as well as sentinel papers describing its application for gastric, colorectal, appendiceal, and pancreatobiliary PMs. While no PIPAC device has yet met FDA approval, we discuss next steps needed to incorporate PIPAC into neoadjuvant/adjuvant treatment paradigms, as well as palliative settings. Data on active clinical trials using PIPAC are provided.

4.
J Clin Med ; 12(20)2023 Oct 10.
Article in English | MEDLINE | ID: mdl-37892582

ABSTRACT

Hyperthermic intraperitoneal chemotherapy (HIPEC) is a locoregional therapy that may be combined with cytoreductive surgery (CRS) to treat patients with colorectal cancer and peritoneal metastases (PM). In recent years, three randomized controlled trials (RCTs) have investigated the role of prophylactic or adjuvant HIPEC in preventing the development of PM in patients with high-risk colorectal cancer: PROPHYLOCHIP and COLOPEC evaluated adjuvant HIPEC, and HIPECT4 studied concurrent HIPEC and CRS. Although PROPHYLOCHIP and COLOPEC were negative trials, a great deal may be learned from their methodology, outcome measures, and patient selection criteria. HIPECT4 is the first RCT to show a clinical benefit of HIPEC in high-risk T4 colorectal cancer, demonstrating improved locoregional disease control with the addition of HIPEC to CRS with no increase in the rate of complications. This review critically examines the strengths and limitations of each major trial and discusses their potential impact on the practice of HIPEC. Several additional ongoing clinical trials also seek to investigate the role of HIPEC in preventing PM in advanced colorectal cancer.

5.
Cancer Gene Ther ; 30(9): 1227-1233, 2023 09.
Article in English | MEDLINE | ID: mdl-37296315

ABSTRACT

Although it can promote effector T-cell function, the summative effect of interleukin-10 (IL-10) in the tumor microenvironment (TME) appears to be suppressive; therefore, blocking this critical regulatory cytokine has therapeutic potential to enhance antitumor immune function. As macrophages efficiently localize to the TME, we hypothesized that they could be used as a delivery vehicle for drugs designed to block this pathway. To test our hypothesis, we created and evaluated genetically engineered macrophages (GEMs) that produce an IL-10-blocking antibody (αIL-10). Healthy donor human peripheral blood mononuclear cells were differentiated and transduced with a novel lentivirus (LV) encoding BT-063, a humanized αIL-10 antibody. The efficacy of αIL-10 GEMs was assessed in human gastrointestinal tumor slice culture models developed from resected specimens of pancreatic ductal adenocarcinoma primary tumors and colorectal cancer liver metastases. LV transduction led to sustained production of BT-063 by αIL-10 GEMs for at least 21 days. Transduction did not alter GEM phenotype as evaluated by flow cytometry, but αIL-10 GEMs produced measurable quantities of BT-063 in the TME that was associated with an ~5-fold higher rate of tumor cell apoptosis than control.


Subject(s)
Gastrointestinal Neoplasms , Pancreatic Neoplasms , Humans , Apoptosis/genetics , Gastrointestinal Neoplasms/genetics , Gastrointestinal Neoplasms/therapy , Interleukin-10/antagonists & inhibitors , Interleukin-10/immunology , Leukocytes, Mononuclear , Macrophages/pathology , Pancreatic Neoplasms/therapy , Pancreatic Neoplasms/drug therapy , Tumor Microenvironment/genetics
6.
EJNMMI Res ; 13(1): 35, 2023 Apr 27.
Article in English | MEDLINE | ID: mdl-37103671

ABSTRACT

BACKGROUND: Early intrahepatic recurrence is common after surgical resection of hepatocellular carcinoma (HCC) and leads to increased morbidity and mortality. Insensitive and nonspecific diagnostic imaging contributes to EIR and results in missed treatment opportunities. In addition, novel modalities are needed to identify targets amenable for targeted molecular therapy. In this study, we evaluated a zirconium-89 radiolabeled glypican-3 (GPC3) targeting antibody conjugate (89Zr-αGPC3) for use in positron emission tomography (PET) for detection of small, GPC3+ HCC in an orthotopic murine model. Athymic nu/J mice received hepG2, a GPC3+ human HCC cell line, into the hepatic subcapsular space. Tumor-bearing mice were imaged by PET/computerized tomography (CT) 4 days after tail vein injection of 89Zr-αGPC3. Livers were then excised for the tumors to be identified, measured, bisected, and then serially sectioned at 500 µm increments. Sensitivity and specificity of PET/CT for 89Zr-αGPC3-avid tumors were assessed using tumor confirmation on histologic sections as the gold standard. RESULTS: In tumor-bearing mice, 89Zr-αGPC3 avidly accumulated in the tumor within four hours of injection with ongoing accumulation over time. There was minimal off-target deposition and rapid bloodstream clearance. Thirty-eight of 43 animals had an identifiable tumor on histologic analysis. 89Zr-αGPC3 immuno-PET detected all 38 histologically confirmed tumors with a sensitivity of 100%, with the smallest tumor detected measuring 330 µm in diameter. Tumor-to-liver ratios of 89Zr-αGPC3 uptake were high, creating excellent spatial resolution for ease of tumor detection on PET/CT. Two of five tumors that were observed on PET/CT were not identified on histologic analysis, yielding a specificity of 60%. CONCLUSIONS: 89Zr-αGPC3 avidly accumulated in GPC3+ tumors with minimal off-target sequestration. 89Zr-αGPC3 immuno-PET yielded a sensitivity of 100% and detected sub-millimeter tumors. This technology may improve diagnostic sensitivity of small HCC and select GPC3+ tumors for targeted therapy. Human trials are warranted to assess its impact.

8.
PLoS One ; 18(3): e0282886, 2023.
Article in English | MEDLINE | ID: mdl-36943824

ABSTRACT

INTRODUCTION: In Nepal, abortion is legal on request through 12 weeks of pregnancy and up to 28 weeks for health and other reasons. Abortion is available at public facilities at no cost and by trained private providers. Yet, over half of abortions are provided outside this legal system. We sought to investigate the extent to which patients are denied an abortion at clinics legally able to provide services and factors associated with presenting late for care, being denied, and receiving an abortion after being denied. METHODS: We used data from a prospective longitudinal study with 1835 women aged 15-45. Between April 2019 and December 2020, we recruited 1,835 women seeking abortions at 22 sites across Nepal, including those seeking care at any gestational age (n = 537) and then only those seeking care at or after 10 weeks of gestation or do not know their gestational age (n = 1,298). We conducted interviewer-led surveys with these women at the time they were seeking abortion service (n = 1,835), at six weeks after abortion-seeking (n = 1523) and six-month intervals for three years. Using descriptive and multivariable logistic regression models, we examined factors associated with presenting for abortion before versus after 10 weeks gestation, with receiving versus being denied an abortion, and with continuing the pregnancy after being denied care. We also described reasons for the denial of care and how and where participants sought abortion care subsequent to being denied. Mixed-effects models was used to accounting clustering effect at the facility level. RESULTS: Among those recruited when eligibility included seeking abortion at any gestational age, four in ten women sought abortion care beyond 10 weeks or did not know their gestation and just over one in ten was denied care. Of the full sample, 73% were at or beyond 10 weeks gestation, 44% were denied care, and 60% of those denied continued to seek care after denial. Nearly three-quarters of those denied care were legally eligible for abortion, based on their gestation and pre-existing conditions. Women with lower socioeconomic status, including those who were younger, less educated, and less wealthy, were more likely to present later for abortion, more likely to be turned away, and more likely to continue the pregnancy after denial of care. CONCLUSION: Denial of legal abortion care in Nepal is common, particularly among those with fewer resources. The majority of those denied in the sample should have been able to obtain care according to Nepal's abortion law. Abortion denial could have significant potential implications for the health and well-being of women and their families in Nepal.


Subject(s)
Abortion, Induced , Abortion, Legal , Pregnancy , Humans , Female , Infant, Newborn , Longitudinal Studies , Prospective Studies , Nepal
9.
Gut ; 72(2): 325-337, 2023 02.
Article in English | MEDLINE | ID: mdl-35705369

ABSTRACT

OBJECTIVE: Programmed cell death protein 1 (PD-1) checkpoint inhibition and adoptive cellular therapy have had limited success in patients with microsatellite stable colorectal cancer liver metastases (CRLM). We sought to evaluate the effect of interleukin 10 (IL-10) blockade on endogenous T cell and chimeric antigen receptor T (CAR-T) cell antitumour function in CRLM slice cultures. DESIGN: We created organotypic slice cultures from human CRLM (n=38 patients' tumours) and tested the antitumour effects of a neutralising antibody against IL-10 (αIL-10) both alone as treatment and in combination with exogenously administered carcinoembryonic antigen (CEA)-specific CAR-T cells. We evaluated slice cultures with single and multiplex immunohistochemistry, in situ hybridisation, single-cell RNA sequencing, reverse-phase protein arrays and time-lapse fluorescent microscopy. RESULTS: αIL-10 generated a 1.8-fold increase in T cell-mediated carcinoma cell death in human CRLM slice cultures. αIL-10 significantly increased proportions of CD8+ T cells without exhaustion transcription changes, and increased human leukocyte antigen - DR isotype (HLA-DR) expression of macrophages. The antitumour effects of αIL-10 were reversed by major histocompatibility complex class I or II (MHC-I or MHC-II) blockade, confirming the essential role of antigen presenting cells. Interrupting IL-10 signalling also rescued murine CAR-T cell proliferation and cytotoxicity from myeloid cell-mediated immunosuppression. In human CRLM slices, αIL-10 increased CEA-specific CAR-T cell activation and CAR-T cell-mediated cytotoxicity, with nearly 70% carcinoma cell apoptosis across multiple human tumours. Pretreatment with an IL-10 receptor blocking antibody also potentiated CAR-T function. CONCLUSION: Neutralising the effects of IL-10 in human CRLM has therapeutic potential as a stand-alone treatment and to augment the function of adoptively transferred CAR-T cells.


Subject(s)
Carcinoma , Colorectal Neoplasms , Interleukin-10 , Liver Neoplasms , Receptors, Chimeric Antigen , Receptors, Interleukin-10 , Animals , Humans , Mice , Carcinoembryonic Antigen/immunology , Carcinoma/immunology , Carcinoma/secondary , CD8-Positive T-Lymphocytes/immunology , Colorectal Neoplasms/pathology , Immunotherapy, Adoptive , Interleukin-10/antagonists & inhibitors , Liver Neoplasms/immunology , Liver Neoplasms/secondary , Lymphocyte Activation , Receptors, Antigen, T-Cell/metabolism , Receptors, Chimeric Antigen/genetics , Receptors, Chimeric Antigen/metabolism , Receptors, Interleukin-10/antagonists & inhibitors , Antibodies, Blocking/immunology
10.
JAMA ; 328(17): 1689-1690, 2022 11 01.
Article in English | MEDLINE | ID: mdl-36318120

ABSTRACT

This Viewpoint discusses the US Supreme Court's decision in Dobbs v Jackson Women's Health Organization, describes how that decision threatens birth equity for some racial and social groups, and suggests a reproductive justice approach to address racial and social inequalities and ensure reproductive freedom and autonomy for all people.


Subject(s)
Abortion, Legal , Health Equity , Reproductive Rights , Supreme Court Decisions , Female , Humans , Pregnancy , Abortion, Legal/legislation & jurisprudence , Health Equity/legislation & jurisprudence , Health Equity/standards , Health Equity/trends , United States , Reproductive Rights/legislation & jurisprudence , Reproductive Rights/standards , Reproductive Rights/trends
11.
Undersea Hyperb Med ; 49(2): 171-177, 2022.
Article in English | MEDLINE | ID: mdl-35580484

ABSTRACT

Background: Clinicians often rely on measurement of carboxyhemoglobin (COHb) to confirm or rule out a diagnosis of carbon monoxide (CO) poisoning. Methods: We report two cases of false negative COHb in patients with CO poisoning and one case of false positive COHb in a patient without CO poisoning. Results: In the first case, a 20-year-old male developed headache, confusion, and near-syncope while operating a gasoline-powered pressure washer in an enclosed space. In the emergency department (ED), his COHb was 1.8%, but this level was disregarded, and he was referred for hyperbaric oxygen. His COHb just before hyperbaric oxygen was 4.1%, and later analysis of his blood collected at ED arrival revealed a COHb of 20.1%. The referral ED blood gas machine calibration and controls were within specification. In the second case, a 45-year-old male presented with several others to the ED with symptoms of CO poisoning after exposure at a conference. All others had elevated COHb levels, but his COHb was 2%. He was discharged but returned shortly with continued symptoms and requested his COHb be repeated. The repeat COHb was 17% (84 minutes after the first). After three hours of oxygen, his COHb was 7%. In the final case, an 83-year-old non-smoking male presented to an ED with breathlessness and tachypnea and was diagnosed with COVID-19 pneumonia. His COHb was 7.1%, but he reported living in an all-electric home. Another adult who lived with him and rode with him to the ED was asymptomatic and had a COHb of 3%. Later, COHb of 1.9% was measured from blood collected at ED arrival, and gas chromatography/mass spectrometry confirmed this result (2%). Conclusions: COHb levels are not always accurate. Clinicians should use clinical judgment to manage their patients, including rejecting laboratory values that do not fit the clinical situation.


Subject(s)
COVID-19 , Carbon Monoxide Poisoning , Adult , Aged, 80 and over , Carbon Monoxide , Carbon Monoxide Poisoning/complications , Carbon Monoxide Poisoning/diagnosis , Carbon Monoxide Poisoning/therapy , Carboxyhemoglobin/analysis , Humans , Male , Middle Aged , Oxygen , Syncope , Young Adult
12.
Int J Gynaecol Obstet ; 159(1): 160-165, 2022 Oct.
Article in English | MEDLINE | ID: mdl-35152426

ABSTRACT

OBJECTIVE: Although abortion in Nepal is broadly legal and free of charge, many women seek abortion care outside the legal system, including from pharmacies. We evaluated the prevalence of, and factors associated with, prior unsuccessful abortion attempts among women presenting to 14 randomly-selected government approved abortion health facilities across Nepal. METHODS: Eligible participants were recruited in 2019 by trained research staff from certified abortion facilities. Participants (n = 1160) completed research staff-administered baseline surveys. We used multivariable mixed-effects logistic regression models to evaluate factors associated with having attempted pharmacy abortion prior to coming to the health facility. RESULTS: Almost one in seven (14%) women had tried to end their pregnancy before presenting to a participating clinic, often (9%) using medication obtained from a pharmacy. Women who lived farther from the clinic (aOR 1.28 per log hours travel time, 95% CI 1.10-1.49) and who reported financial difficulty in accessing the clinic (19% vs. 10%, aOR 2.10, 95% CI 1.20-3.70) had increased odds of having tried to access abortion through a pharmacy. CONCLUSION: Integrating pharmacies into the legal network of abortion providers may improve access to safe care, particularly for rural women with financial and practical travel limitations.


Subject(s)
Abortion, Induced , Pharmacies , Pharmacy , Abortion, Legal , Female , Government , Health Services Accessibility , Humans , Male , Nepal/epidemiology , Pregnancy
13.
Br J Surg ; 109(3): 256-266, 2022 02 24.
Article in English | MEDLINE | ID: mdl-35037019

ABSTRACT

BACKGROUND: This individual-patient data meta-analysis investigated the effects of enhanced recovery after surgery (ERAS) protocols compared with conventional care on postoperative outcomes in patients undergoing pancreatoduodenectomy. METHODS: The Cochrane Library, MEDLINE, Embase, Scopus, and Web of Science were searched systematically for articles reporting outcomes of ERAS after pancreatoduodenectomy published up to August 2020. Comparative studies were included. Main outcomes were postoperative functional recovery elements, postoperative morbidity, duration of hospital stay, and readmission. RESULTS: Individual-patient data were obtained from 17 of 31 eligible studies comprising 3108 patients. Time to liquid (mean difference (MD) -3.23 (95 per cent c.i. -4.62 to -1.85) days; P < 0.001) and solid (-3.84 (-5.09 to -2.60) days; P < 0.001) intake, time to passage of first stool (MD -1.38 (-1.82 to -0.94) days; P < 0.001) and time to removal of the nasogastric tube (3.03 (-4.87 to -1.18) days; P = 0.001) were reduced with ERAS. ERAS was associated with lower overall morbidity (risk difference (RD) -0.04, 95 per cent c.i. -0.08 to -0.01; P = 0.015), less delayed gastric emptying (RD -0.11, -0.22 to -0.01; P = 0.039) and a shorter duration of hospital stay (MD -2.33 (-2.98 to -1.69) days; P < 0.001) without a higher readmission rate. CONCLUSION: ERAS improved postoperative outcome after pancreatoduodenectomy. Implementation should be encouraged.


Enhanced recovery protocols consist of interdisciplinary interventions aimed at standardizing care and reducing the impact of surgical stress. They often include a short period of preoperative fasting during the night before surgery, early removal of lines and surgical drains, early food intake and mobilization out of bed on the day of surgery. This study gives a summary of reports assessing such care protocols in patients undergoing pancreatic head surgery, and assesses the impact of these protocols on functional recovery in an analysis of individual-patient data. The study revealed the true benefits of enhanced recovery protocols, including shorter time to food intake, earlier bowel activity, fewer complications after surgery, and a shorter hospital stay compared with conventional care.


Subject(s)
Enhanced Recovery After Surgery , Pancreaticoduodenectomy , Humans , Length of Stay , Pancreaticoduodenectomy/adverse effects , Patient Readmission , Postoperative Complications/prevention & control , Recovery of Function
14.
Surg Endosc ; 36(2): 889-895, 2022 02.
Article in English | MEDLINE | ID: mdl-33608766

ABSTRACT

BACKGROUND: Robotic hepatectomy (RH) is increasingly utilized for minor and major liver resections. The IWATE criteria were developed to classify minimally invasive liver resections by difficulty. The objective of this study was to apply the IWATE criteria in RH and to describe perioperative and oncologic outcomes of RH over the last decade at our institution. METHODS: Perioperative and oncologic outcomes of patients who underwent RH between 2011 and 2019 were retrospectively collected. The difficulty level of each operation was assessed using the IWATE criteria, and outcomes were compared at each level. Univariate linear regression was performed to characterize the relationship between IWATE criteria and perioperative outcomes (OR time, EBL, and LOS), and a multivariable model was also developed to address potential confounding by patient characteristics (age, sex, BMI, prior abdominal surgery, ASA class, and simultaneous non-hepatectomy operation). RESULTS: Two hundred and twenty-five RH were performed. Median IWATE criteria for RH were 6 (IQR 5-9), with low, intermediate, advanced, and expert resections accounting for 23% (n = 51), 34% (n = 77), 32% (n = 72), and 11% (n = 25) of resections, respectively. The majority of resections were parenchymal-sparing approaches, including anatomic segmentectomies and non-anatomic partial resections. 30-day complication rate was 14%, conversion to open surgery occurred in 9 patients (4%), and there were no deaths within 30 days postoperatively. In the univariate linear regression analysis, IWATE criteria were positively associated with OR time, EBL, and LOS. In the multivariable model, IWATE criteria were independently associated with greater OR time, EBL, and LOS. Two-year overall survival for hepatocellular carcinoma and intrahepatic cholangiocarcinoma was 94% and 50%, respectively. CONCLUSION: In conclusion, the IWATE criteria are associated with surgical outcomes after RH. This series highlights the utility of RH for difficult hepatic resections, particularly parenchymal-sparing resections in the posterosuperior sector, extending the indication of minimally invasive hepatectomy in experienced hands and potentially offering select patients an alternative to open hepatectomy or other less definitive liver-directed treatment options.


Subject(s)
Bile Duct Neoplasms , Laparoscopy , Liver Neoplasms , Robotic Surgical Procedures , Bile Duct Neoplasms/surgery , Bile Ducts, Intrahepatic/pathology , Hepatectomy/adverse effects , Humans , Laparoscopy/adverse effects , Length of Stay , Postoperative Complications/epidemiology , Postoperative Complications/etiology , Postoperative Complications/surgery , Retrospective Studies , Robotic Surgical Procedures/adverse effects
15.
J Nucl Med ; 63(7): 1033-1038, 2022 07.
Article in English | MEDLINE | ID: mdl-34772791

ABSTRACT

Hepatocellular carcinoma (HCC) is a significant cause of morbidity and mortality worldwide, with limited therapeutic options for advanced disease. Targeted α-therapy is an emerging class of targeted cancer therapy in which α-particle-emitting radionuclides, such as 227Th, are delivered specifically to cancer tissue. Glypican-3 (GPC3) is a cell surface glycoprotein highly expressed on HCC. In this study, we describe the development and in vivo efficacy of a 227Th-labeled GPC3-targeting antibody conjugate (227Th-octapa-αGPC3) for treatment of HCC in an orthotopic murine model. Methods: The chelator p-SCN-Bn-H4octapa-NCS (octapa) was conjugated to a GPC3-targeting antibody (αGPC3) for subsequent 227Th radiolabeling (octapa-αGPC3). Conditions were varied to optimize radiolabeling of 227Th. In vitro stability was evaluated by measuring the percentage of protein-bound 227Th by γ-ray spectroscopy. An orthotopic athymic Nu/J murine model using HepG2-Red-FLuc cells was developed. Biodistribution and blood clearance of 227Th-octapa-αGPC3 were evaluated in tumor-bearing mice. The efficacy of 227Th-octapa-αGPC3 was assessed in tumor-bearing animals with serial measurement of serum α-fetoprotein at 23 d after injection. Results: Octapa-conjugated αGPC3 provided up to 70% 227Th labeling yield in 2 h at room temperature. In the presence of ascorbate, at least 97.8% of 227Th was bound to αGPC3-octapa after 14 d in phosphate-buffered saline. In HepG2-Red-FLuc tumor-bearing mice, highly specific GPC3 targeting was observed, with significant 227Th-octapa-αGPC3 accumulation in the tumor over time and minimal accumulation in normal tissue. Twenty-three days after treatment, a significant reduction in tumor burden was observed in mice receiving a 500 kBq/kg dose of 227Th-octapa-αGPC3 by tail-vein injection. No acute off-target toxicity was observed, and no animals died before termination of the study. Conclusion:227Th-octapa-αGPC3 was observed to be stable in vitro; maintain high specificity for GPC3, with favorable biodistribution in vivo; and result in significant antitumor activity without significant acute off-target toxicity in an orthotopic murine model of HCC.


Subject(s)
Carcinoma, Hepatocellular , Liver Neoplasms , Animals , Carcinoma, Hepatocellular/drug therapy , Carcinoma, Hepatocellular/radiotherapy , Cell Line, Tumor , Glypicans/chemistry , Glypicans/metabolism , Humans , Liver Neoplasms/drug therapy , Liver Neoplasms/radiotherapy , Mice , Tissue Distribution , Tumor Burden , Xenograft Model Antitumor Assays
16.
Contraception ; 104(1): 73-76, 2021 07.
Article in English | MEDLINE | ID: mdl-33811840

ABSTRACT

OBJECTIVE: To estimate obstetrician-gynecologists' (ob-gyns) willingness to provide medication abortion if the in-person dispensing requirement for mifepristone were removed. STUDY DESIGN: We analyzed a subsample (n = 868) from a 2016 to 2017 national survey of ob-gyns, focusing on questions related to provision of medication abortion. RESULTS: In the survey, 164 (19%) ob-gyns reported providing medication abortion in the prior year. When we asked those not providing medication abortion if they would offer the method to their patients if the in-person dispensing requirement for mifepristone were removed, 171 (24%) ob-gyns reported they would, suggesting a potential doubling of providers (+104%, 95% confidence interval (CI): 97%-112%). The largest theoretical increases were in the Midwest (+189%, 95% CI: 172%-207%) and South (+118%, 95% CI: 103%-134%). In multivariable regression analysis, female ob-gyns and those in university faculty practices had higher odds of reporting they would start providing medication abortion if the dispensing requirement were removed, while those in practice >10 years had lower odds. CONCLUSIONS: Removal of the in-person dispensing requirement could increase provision of medication abortion, including in regions with limited abortion access. IMPLICATIONS: In order to improve access to medication abortion, the mifepristone Risk Evaluation and Mitigation Strategy should be modified or removed to allow clinicians to prescribe the medication with dispensing by pharmacies, including mail-order pharmacies.


Subject(s)
Abortion, Induced , Gynecology , Obstetrics , Pharmacies , Attitude of Health Personnel , Female , Health Personnel , Humans , Mifepristone , Pregnancy
17.
Womens Health Issues ; 31(3): 227-235, 2021.
Article in English | MEDLINE | ID: mdl-33832830

ABSTRACT

PURPOSE: Utah law requires patients to have a face-to-face "informed consent" visit at least 72 hours prior to abortion. Planned Parenthood Association of Utah (PPAU) offers this visit via telemedicine as an alternative to an in-person visit, which can require burdensome travel. This novel study identifies factors associated with using telemedicine for informed consent, patients' reasons for using it, and experiences with it, compared to in-person informed consent. METHODS: In 2017 and 2018, patients 18 years and older seeking abortion at PPAU completed a self-administered online survey about their experiences with the informed consent visit. We used linear and logistic regression models to compare participants' demographic characteristics by informed consent visit type, and descriptive statistics to describe reasons for using each visit type and experiences with the visit. Multivariable logistic regression models examined associations between visit type and satisfaction. RESULTS: Responses from 166 telemedicine patients and 217 in-person informed consent patients indicate that telemedicine participants would have had to travel significantly further than in-person participants traveled to attend the visit at the clinic (mean of 65 miles versus 21 miles, p < .001). In multivariable analyses, telemedicine participants had higher odds of being "very satisfied" with the visit (aOR, 2,89; 95% CI: 1.93-4.32) and "very comfortable" asking questions during the visit (aOR, 3.76; 95% CI: 2.58-5.49), compared to participants who attended in-person visits. CONCLUSIONS: Telemedicine offers a convenient, acceptable option for mandated pre-abortion informed consent visits and reduces the burden of additional travel and associated barriers for some patients, particularly those who live further away from clinics.


Subject(s)
Personal Satisfaction , Telemedicine , Demography , Female , Humans , Informed Consent , Patient Satisfaction , Pregnancy , Utah
19.
Sci Rep ; 11(1): 3731, 2021 02 12.
Article in English | MEDLINE | ID: mdl-33580090

ABSTRACT

Glypican-3 (GPC3) is a tumor associated antigen expressed by hepatocellular carcinoma (HCC) cells. This preclinical study evaluated the efficacy of a theranostic platform using a GPC3-targeting antibody αGPC3 conjugated to zirconium-89 (89Zr) and yttrium-90 (90Y) to identify, treat, and assess treatment response in a murine model of HCC. A murine orthotopic xenograft model of HCC was generated. Animals were injected with 89Zr-labeled αGPC3 and imaged with a small-animal positron emission/computerized tomography (PET/CT) imaging system (immuno-PET) before and 30 days after radioimmunotherapy (RIT) with 90Y-labeled αGPC3. Serum alpha fetoprotein (AFP), a marker of tumor burden, was measured. Gross tumor volume (GTV) and SUVmax by immuno-PET was measured using fixed intensity threshold and manual segmentation methods. Immuno-PET GTV measurements reliably quantified tumor burden prior to RIT, strongly correlating with serum AFP (R2 = 0.90). Serum AFP was significantly lower 30 days after RIT in 90Y-αGPC3 treated animals compared to those untreated (p = 0.01) or treated with non-radiolabeled αGPC3 (p = 0.02). Immuno-PET GTV measurements strongly correlated with tumor burden after RIT (R2 = 0.87), and GTV of animals treated with 90Y-αGPC3 was lower than in animals who did not receive treatment or were treated with non-radiolabeled αGPC3, although this only trended toward statistical significance. A theranostic platform utilizing GPC3 targeted 89Zr and 90Y effectively imaged, treated, and assessed response after radioimmunotherapy in a GPC3-expressing HCC xenograft model.


Subject(s)
Carcinoma, Hepatocellular/therapy , Drug Delivery Systems/methods , Glypicans/immunology , Animals , Carcinoma, Hepatocellular/metabolism , Carcinoma, Hepatocellular/pathology , Cell Line, Tumor , Glypicans/metabolism , Humans , Liver Neoplasms/metabolism , Liver Neoplasms/pathology , Liver Neoplasms/therapy , Mice , Mice, Nude , Positron-Emission Tomography/methods , Precision Medicine/methods , Radioimmunotherapy , Radioisotopes/pharmacology , Radiopharmaceuticals , Tissue Distribution , Xenograft Model Antitumor Assays , Yttrium Radioisotopes/pharmacology , Zirconium/pharmacology
20.
Am J Hosp Palliat Care ; 38(8): 1053-1056, 2021 Aug.
Article in English | MEDLINE | ID: mdl-32940545

ABSTRACT

Lower severe edema is a common condition faced by advanced cancer patients with an impact on comfort, quality of life, and care planning. Diuresis and mechanical interventions are the mainstream options for the treatment of edema, but, although effective, may not be indicated for frail, bed-bound, and dependent patients cared for in the community setting.We present a case report of a young female with severe edema to her right lower limb, which accepted controlled subcutaneous fluid drainage at her home. Subcutaneous fluid drainage at home was effective, safe, and feasible and improved the patient's comfort and well-being.


Subject(s)
Edema , Quality of Life , Drainage , Edema/etiology , Edema/therapy , Female , Humans , Lower Extremity , Palliative Care
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