Malpractice litigation surrounding in vitro fertilization in the United States: a legal literature review.

IMPORTANCE: Analysis of malpractice lawsuits that involve in vitro fertilization (IVF) can provide insight into the breadth of legal challenges faced by IVF clinics and the patient harms and financial consequences that can result from alleged errors in practice. OBJECTIVE: We aimed to review malpractice litigations involving IVF and identify common themes in plaintiff allegations and defense arguments. EVIDENCE REVIEW: We queried Nexis Uni, Westlaw, and CourtListener legal databases to collect records from malpractice litigations involving IVF. The nature of the cases, allegations, and outcomes were abstracted from court documents. FINDINGS: Of the 447 cases identified in the query, 53 involved both malpractice and IVF, occurring between 1993 and 2022. Defendants included a reproductive endocrinologist in 19 (35.8%) cases, an academic institution in 17 (32.1%) cases, embryology personnel in 9 (17.0%) cases, and nursing staff in 2 (3.8%) cases. Twenty-four (45.3%) cases involved embryology errors (e.g., lost specimens and incorrect sperm donor), 11 (20.8%) preimplantation genetic testing errors (e.g., child born with genetic illness despite testing), 6 (11.3%) medical or surgical complications (e.g., ovarian hyperstimulation syndrome), 4 (7.5%) misdiagnoses (e.g., malignancy before cycle start), 3 (5.6%) misrepresentations of IVF outcomes, 2 (3.8%) medical eligibility screening issues (e.g., medical comorbidities in a gestational carrier), 2 (3.8%) confidentiality breaches, and 1 (1.9%) case of discrimination. The most common secondary claims were negligence (23 cases, 16.4% of all claims), breach of contract (13, 9.3%), lack of informed consent (11, 7.9%), and negligent infliction of emotional distress (11, 7.9%). Twenty-nine (54.7%) cases were decided in favor of the defending IVF clinic or provider, 13 (24.5%) cases were decided in favor of the plaintiff, and 11 (20.8%) involved ongoing proceedings. Financial awards ranged from $4171 to $14,975,000, with the largest monetary award resulting from a cryostorage accident class action lawsuit. CONCLUSION: In vitro fertilization malpractice claims are varied, with the most common issues involving embryology laboratory processes and genetic testing errors. Some errors may be avoidable with increased vigilance and implementation of stringent laboratory and clinical guidelines. Understanding jurisdiction-specific legislation and court processes may also assist IVF providers in navigating the malpractice litigation process. RELEVANCE: This comprehensive review of IVF litigation may have the potential to promote practices that protect both providers and patients.

HPP1 Ectodomain Shedding is Mediated by ADAM17 and is Necessary for Tumor Suppression in Colon Cancer.

BACKGROUND: Hyperplastic polyposis protein 1 (HPP1) encodes a tumor-suppressive transmembrane cleavable epidermal growth factor-like ligand. It is unclear as to whether cleavage and shedding of HPP1 are essential steps in achieving its tumor suppressive properties. ADAM proteins are key players in cellular ectodomain shedding processes with ADAM17 being well characterized and representing the most likely sheddase for HPP1. In this study, we explore the mechanisms and importance of ectodomain shedding in contributing to HPP1-mediated tumor suppression. METHODS: Baseline characterization of HPP1 ectodomain shedding and ADAM family member expression was performed in HCT116 colon cancer cells with forced overexpression of HPP1 and controls. Subsequent impact of attenuation of ADAM expression by short interfering RNA on HPP1 shedding was evaluated. Furthermore, we examined the functional impact of an uncleavable HPP1 mutant construct (HPP1-Δstalk) generated by site-directed mutagenesis. Cellular growth potential functions were analyzed by MTT and soft agar assays. RESULTS: Select proinflammatory cytokines enhanced HPP1 ectodomain shedding, whereas short interfering RNA-mediated knockdown of ADAM17 resulted in abrogation of HPP1 ectodomain shedding. ADAM17 knockdown concomitantly resulted in increased cell proliferation and anchorage-independent growth. HPP1-Δstalk-transfected cells exhibited significantly higher proliferation and reduced STAT1 activation relative to full-length HPP1, further suggesting a critical role for ectodomain shedding in HPP1-mediated tumor suppression. CONCLUSION: The tumor-suppressive properties of HPP1 in colorectal cancer require cleavage and shedding of its ectodomain which in turn are mediated by ADAM17. Further investigations into the regulation of HPP1 may lead to a greater understanding of epidermal growth factor-like ligand family biology and potential novel therapeutic strategies.

Correction: DeltaNp63alpha-Mediated Induction of Epidermal Growth Factor Receptor Promotes Pancreatic Cancer Cell Growth and Chemoresistance.

[This corrects the article DOI: 10.1371/journal.pone.0026815.].

The Tumor Suppressive Effects of HPP1 Are Mediated Through JAK-STAT-Interferon Signaling Pathways.

HPP1, a novel tumor suppressive epidermal growth factor (EGF)-like ligand, mediates its effects through signal transducer and activators of transcription (STAT) activation. We previously demonstrated the importance of STAT1 activation for HPP1 function; however the contribution of STAT2 remains unclear. We sought to delineate the components of JAK-STAT-interferon (IFN) signaling specifically associated with HPP1s biological effects. Using stable HPP1-HCT116 transfectants, expression analyses were performed by polymerase chain reaction (PCR)/western blotting while expression knockdowns were achieved using siRNA. Growth parameters evaluated included proliferation, cell cycle distribution, and anchorage-independent growth. STAT dimerization, translocation, and DNA binding were examined by reporter assays, fluorescent microscopy, and chromatin immunoprecipitation (ChIP), respectively. Forced expression of HPP1 in colon cancer cell lines results in the upregulation of total and activated levels of STAT2. We have also determined that JAK1 and JAK2 are activated in response to HPP1 overexpression, and are necessary for subsequent STAT activation. Overexpression of HPP1 was associated with significant increases in STAT1:STAT1 (p=0.007) and STAT1:STAT2 (p=0.036) dimer formation, as well as subsequent nuclear translocation. By ChIP, binding of activated STAT1 and STAT2 to the interferon-signaling regulatory element promoter sites of the selected genes, protein kinase RNA-activated (PKR), IFI44, and OAS1 was demonstrated. STAT2 knockdown resulted in partial abrogation of HPP1s growth suppressive activity with increased proliferation (p<0.0001), reduced G1/G0 phase cell cycle fraction, and a restoration of growth potential in soft agar (p<0.01). Presumably as a consequence of upregulation of IFN signaling elements, HPP1 overexpression resulted in an acquisition of exogenous IFN sensitivity. Physiologic doses of IFN-α resulted in a significant reduction in proliferation (p<0.001) and increase in G1/G0 cell cycle arrest in HPP1 transfectants. STAT2 is necessary for HPP1-associated growth suppression, and mediates these effects through activation of IFN-α pathways. Given the interest in therapeutic targeting of oncogenic erbB proteins, further understanding of HPP1s role as a tumor suppressive EGF-like ligand is warranted.

The Nedd8-activating enzyme inhibitor MLN4924 thwarts microenvironment-driven NF-κB activation and induces apoptosis in chronic lymphocytic leukemia B cells.

BACKGROUND: Stromal-mediated signaling enhances NF-κB pathway activity in chronic lymphocytic leukemia (CLL) B cells, leading to cell survival and chemoresistance. Ubiquitination of IκBα may partially account for constitutive activation of NF-κB. MLN4924 is an investigational agent that inhibits the Nedd8-activating enzyme, thereby neutralizing Cullin-RING ubiquitin ligases and preventing degradation of their substrates. EXPERIMENTAL DESIGN: We conducted a preclinical assessment of MLN4924 in CLL. Primary CLL cells were cocultured in vitro with CD40L-expressing stroma to mimic the prosurvival conditions present in lymphoid tissue. The effect of MLN4924 on CLL cell apoptosis, NF-κB pathway activity, Bcl-2 family members, and cell cycle was assessed by flow cytometry, Western blotting, PCR, and immunocytochemistry. RESULTS: CD40L-expressing stroma protected CLL cells from spontaneous apoptosis and induced resistance to multiple drugs, accompanied by NF-κB activation and Bim repression. Treatment with MLN4924 induced CLL cell apoptosis and circumvented stroma-mediated resistance. This was accompanied by accumulation of phospho-IκBα, decreased nuclear translocation of p65 and p52 leading to inhibition of both the canonical and noncanonical NF-κB pathways, and reduced transcription of their target genes, notably chemokines. MLN4924 promoted induction of Bim and Noxa in the CLL cells leading to rebalancing of Bcl-2 family members toward the proapoptotic BH3-only proteins. siRNA-mediated knockdown of Bim or Noxa decreased sensitivity to MLN4924. MLN4924 enhanced the antitumor activity of the inhibitors of B-cell receptor (BCR)-associated kinases. CONCLUSIONS: MLN4924 disrupts NF-κB activation and induces Bim expression in CLL cells, thereby preventing stroma-mediated resistance. Our data provide rationale for further evaluation of MLN4924 in CLL.

Defining optimum treatment of patients with pancreatic adenocarcinoma using regret-based decision curve analysis.

OBJECTIVE: To use regret decision theory methodology to assess three treatment strategies in pancreatic adenocarcinoma. BACKGROUND: Pancreatic adenocarcinoma is uniformly fatal without operative intervention. Resection can prolong survival in some patients; however, it is associated with significant morbidity and mortality. Regret theory serves as a novel framework linking both rationality and intuition to determine the optimal course for physicians facing difficult decisions related to treatment. METHODS: We used the Cox proportional hazards model to predict survival of patients with pancreatic adenocarcinoma and generated a decision model using regret-based decision curve analysis, which integrates both the patient's prognosis and the physician's preferences expressed in terms of regret associated with a certain action. A physician's treatment preferences are indicated by a threshold probability, which is the probability of death/survival at which the physician is uncertain whether or not to perform surgery. The analysis modeled 3 possible choices: perform surgery on all patients; never perform surgery; and act according to the prediction model. RESULTS: The records of 156 consecutive patients with pancreatic adenocarcinoma were retrospectively evaluated by a single surgeon at a tertiary referral center. Significant independent predictors of overall survival included preoperative stage [P = 0.005; 95% confidence interval (CI), 1.19-2.27], vitality (P < 0.001; 95% CI, 0.96-0.98), daily physical function (P < 0.001; 95% CI, 0.97-0.99), and pathological stage (P < 0.001; 95% CI, 3.06-16.05). Compared with the "always aggressive" or "always passive" surgical treatment strategies, the survival model was associated with the least amount of regret for a wide range of threshold probabilities. CONCLUSIONS: Regret-based decision curve analysis provides a novel perspective for making treatment-related decisions by incorporating the decision maker's preferences expressed as his or her estimates of benefits and harms associated with the treatment considered.

Targeting early deaths following pancreaticoduodenectomy to improve survival.

INTRODUCTION: There is increasing focus on disease-specific outcomes. This study was undertaken to analyze early mortality after pancreaticoduodenectomy as part of a strategy to improve long-term outcome. METHODS: One thousand thirty-one patients who underwent pancreaticoduodenectomy from 1992 to 2010 were studied. Median data are reported. RESULTS: Fifty-eight (5.6%) patients died within 90 days after pancreaticoduodenectomy. All patients had at least one significant comorbidity, commonly cardiorespiratory in nature (76%). Sixty percent of patients had depressed serum albumin levels, and 43% were jaundiced. The American Society of Anesthesiologists class was: 17% class II, 72% class III, and 10% class IV. Seventy-four percent had malignant disease. Twenty-two percent of patients underwent a major vascular resection at the time of pancreaticoduodenectomy. Causes of death were vascular/bleeding related (26%), cardiorespiratory causes (17%), multiorgan failure (12%), leak/perforation (10%), cancer progression (9%), infection (7%), or indeterminate (19%). CONCLUSIONS: Death within 90 days after pancreaticoduodenectomy is uncommon, occurs in relatively older deconditioned patients, and is generally not causally related to underlying malignancy. Early death is generally associated with vascular or bleeding complications. Strategies to minimize early death should focus on careful patient selection and prompt recognition and management of herald bleeding or vascular thrombosis, as it can often result in perioperative death following pancreaticoduodenectomy.

Complementary strand microRNAs mediate acquisition of metastatic potential in colonic adenocarcinoma.

BACKGROUND: Altered expression of specific microRNAs (miRNA) is known to occur during colorectal carcinogenesis. However, little is known about the genome-wide alterations in miRNA expression during the neoplastic progression of primary colorectal cancers. METHODS: Using a miRNA array platform, we evaluated the expression of 668 miRNA in primary colonic adenocarcinomas. Biological functions of selected miRNA were evaluated with in vitro invasion assays. RESULTS: RNA was extracted for miRNA analysis from 65 primary colon cancers. We identified a seven-miRNA expression signature that differentiated stage I and stage IV primary colon cancers. We then demonstrated this signature was able to discriminate between stage II and III primary colon cancers. Six differentially expressed miRNA were downregulated in association with the development of metastases, and all 7 miRNA were complementary strand miRNA. We transfected HCT-116, a highly invasive colon cancer cell line, with corresponding downregulated miRNA and demonstrated that overexpression of three miRNA (miR200c*, miR143*, and miR424*) significantly abrogated invasive potential. CONCLUSION: We have identified a seven-miRNA signature that is associated with metastatic potential in the primary tumor. Forced overexpression of three downregulated miRNA resulted in attenuation of in vitro invasion, suggesting direct tumor suppressive function and further supporting the biological importance of complementary strand miRNA.

Robotic lobectomy: flattening the learning curve.

Early experience with robotic technology in pulmonary resection has emphasized a steep learning curve. We initiated a robotic thoracic surgical program with the goal of minimizing complications, operative times, and hospital stays. We implemented robotic lobe resections at our institution with the intent of performing an operationally analogous procedure to that of the open technique. Specifically, we used single docking of the robotic cart, innovative retraction, single interspace port placement, and dockings specific to the resected lobe. We reviewed outcomes for patients undergoing robotic lobectomy at our institution. Data is presented as mean ± standard deviation. 20 patients (69 ± 12 years) underwent robotic lobe resections. American Joint Committee on Cancer staging for 14 patients undergoing resections for non-small cell lung cancers were Stage I (10), Stage II (2), and Stage III (2). Operative times for 20 patients undergoing robotic lobectomies were 203 ± 53 min. Median postoperative hospital stay was 3 days. Conversions to open procedures were required in two patients secondary to failure to progress (1) and bleeding (1). Complications occurred in four (20%) patients and included atelectasis (2), myocardial infarction (1), and atrial fibrillation (1). No fatalities occurred. The perception that robotic pulmonary resection involves a steep learning curve may not be universally accurate; our operative times and hospital stays are consistent with those reported by established programs. For surgeons experienced in open and thoracoscopic lobectomy, appropriate patient selection coupled with the specific robotic techniques described may flatten the learning curve.

DeltaNp63alpha-mediated induction of epidermal growth factor receptor promotes pancreatic cancer cell growth and chemoresistance.

Pancreatic ductal adenocarcinoma (PDAC) is highly resistant to current chemotherapy regimens, in part due to alterations in the p53 tumor suppressor pathway. p53 homolog p63 is a transcription factor essential for the development and differentiation of epithelial surfaces. However its function in cancer is controversial and its role in PDAC is not known. We discovered that ΔNp63α was the predominantly expressed p63 variant in pancreatic cancer cell lines. ΔNp63α protein and mRNA levels were high in T3M4, BxPC3 and COLO-357 pancreatic cancer cells and low in ASPC-1 and PANC-1 cells. Overexpression of ΔNp63α in PANC-1 cells and shRNA-mediated knockdown in T3M4 cells indicated that ΔNp63α promoted anchorage-dependent and -independent growth, motility and invasion, and enhanced resistance to cisplatin-induced apoptosis. Epidermal growth factor receptor (EGFR) signaling pathways contribute to the biological aggressiveness of PDAC, and we found that the motogenic effects of ΔNp63α were augmented in presence of EGF. Ectopic expression of ΔNp63α resulted in upregulation of EGFR and ß1-integrin in PANC-1 cells. Conversely, ΔNp63α knockdown had an opposite effect in T3M4 cells. ΔNp63α potentiated EGF-mediated activation of ERK, Akt and JNK signaling. Chromatin immunoprecipitation and functional reporter assays demonstrated that ΔNp63α activated EGFR transcription. 14-3-3σ transcription was also positively regulated by ΔNp63α and we have previously shown that 14-3-3σ contributes to chemoresistance in pancreatic cancer cell lines. Conversely, shRNA-mediated knockdown of 14-3-3σ led to abrogation of the ΔNp63α effects on cell proliferation and invasion. Thus, p53 homolog ΔNp63α enhances the oncogenic potential of pancreatic cancer cells through trans-activation of EGFR and 14-3-3σ.