SARS-CoV-2/COVID-19 and its relationship with NOD2 and ubiquitination.

COVID-19 infection activates the immune system to cause autoimmune and autoinflammatory diseases. We provide a comprehensive review of the relationship between SARS-CoV-2, NOD2 and ubiquitination. COVID-19 infection partly results from host inborn errors and genetic factors and can lead to autoinflammatory disease. The interaction between defective NOD2 and viral infection may trigger NOD2-associated disease. SARS-CoV-2 can alter UBA1 and abnormal ubiquitination leading to VEXAS syndrome. Both NOD2 and ubiquitination play important roles in controlling inflammatory process. Receptor interacting protein kinase 2 is a key component of the NOD2 activation pathway and becomes ubiquitinated to recruit downstream effector proteins. NOD2 mutations result in loss of ubiquitin binding and increase ligand-stimulated NOD2 signaling. During viral infection, mutations of either NOD2 or UBA1 genes or in combination can facilitate autoinflammatory disease. COVID-19 infection can cause autoinflammatory disease. There are reciprocal interactions between SARS-CoV-2, NOD2 and ubiquitination.

Scarlet fever associated with hepatitis in pediatrics. A case report. / Scarlet fever associated with hepatitis in pediatrics. A case report.

INTRODUCTION: Scarlet fever is a common illness in pediatrics caused by group A beta-hemolytic strep tococcus (GABHS), which usually occurs after an episode of pharyngitis, and has an overall excellent prognosis. Hepatitis secondary to scarlet fever is a rare complication described in adults and even less frequently in children. Our objective was to describe a case of hepatitis secondary to scarlet fever in a pediatric patient. CLINICAL CASE: A 12-year-old male with scarlet fever presented with a 4-day history of jaundice, dark urine, and decreased appetite. Laboratory tests revealed elevated liver enzy mes and total and direct bilirubin levels, and negative studies for hepatitis A, B and C, Epstein Barr virus, parvovirus B19, adenovirus, cytomegalovirus, human herpes virus-6, and herpes simplex virus 1 and 2. Abdominal ultrasound examination was normal. DISCUSSION: The pathogenesis of scarlet fever associated hepatitis remains unclear. Streptococcal pyrogenic exotoxin mediated cellular injury via cytokine production has been proposed as a possible mechanism of hepatotoxicity in GABHS infections. CONCLUSION: Hepatitis secondary to scarlet fever remains a rare but benign entity, with complete recovery expected over weeks to months.

[Pancreatitis, genes and islet cells auto transplant; updates and new horizons]. / Pancreatitis, genes y autotrasplante de islotes; actualizaciones y nuevos horizontes.

Pancreatitis is an inflammation of the pancreas that can progress from an acute presentation to an acute recurring presentation and eventually to chronic pancreatitis, which is characterized by irreversible morphological changes and scarring of the pancreas. The entity known as hereditary pancreatitis has been recognized in the literature for years and certainly the discovery of the PRSS1 gene in 1996 marked the beginning of a new era of genetic discoveries associated with the disease. Since then, multiple genes have been described as the causing agents of pancreatitis or disease modifiers, some of the most important ones being the PRSS1, SPINK1, CFTR, CASR, CTRC, CLDN2, and CPA1. The patient selection process for genetic testing should be guided by the current experts' recommendations and should meet specific corresponding criteria. Once the diagnosis has been made, treatment should be tailored to each patient's particular needs. Certainly, the advent of the total pancreatectomy with auto islet cell transplantation, which has the main goal to improve the pain caused by the chronic pancreatitis and simultaneously reduce the severity of the pancreatectomy induced diabetes, is an attractive alternative in the treatment and management of patient with a diagnosis of hereditary pancreatitis. However, strict criteria and an interdisciplinary management are essential since this surgery is irreversible and carries lifetime health consequences that all patients must be aware of and the medical team must be able to early recognize these and treat accordingly. However, there are many potential areas in this field for more, better and forefront research to be developed aiming for a better understanding of the disease process and for the development of a cure.

Pilot study to assess toxicity and pharmacokinetics of docetaxel in patients with metastatic breast cancer and impaired liver function secondary to hepatic metastases.

BACKGROUND: Limited clinical data are available regarding the safety of docetaxel in metastatic breast cancer patients with liver dysfunction. METHODS: Eligible patients had breast cancer with impaired liver function secondary to hepatic metastases and were candidates for docetaxel therapy. They were assigned to one of five groups on the basis of total bilirubin, alanine aminotransferase, aspartate aminotransferase, and alkaline phosphatase levels. All other causes of liver dysfunction were excluded, and bile duct obstruction was corrected, if possible, prior to study entry. Patients received docetaxel every three weeks. The chemotherapy dose was chosen on the basis of the patient's level of hepatic dysfunction and escalated as tolerated. The primary outcome of this study was safety. The secondary outcomes were pharmacokinetic data and efficacy in terms of time to disease progression. RESULTS: Twenty-three patients were enrolled. No unexpected toxicities occurred. Grade 3/4 fatigue (65%), neutropenia (30%), myalgias (26%), neutropenic fever (26%), vomiting (9%), and rash (9%) were the most common serious adverse events. The median time to progression was three months (range 1-18 months). Pharmacokinetic results indicated that patients with more severe hepatic dysfunction may have been underdosed based on our conservative dosing strategy. CONCLUSIONS: Docetaxel can be administered to patients with metastatic breast cancer and liver dysfunction after dose attenuation. However, because of a narrow therapeutic index in this clinical setting, therapy should be closely monitored with subsequent dose escalation when possible.

High level of novelty under the hood of convergent evolution.

Little is known about the extent to which species use homologous regulatory architectures to achieve phenotypic convergence. By characterizing chromatin accessibility and gene expression in developing wing tissues, we compared the regulatory architecture of convergence between a pair of mimetic butterfly species. Although a handful of color pattern genes are known to be involved in their convergence, our data suggest that different mutational paths underlie the integration of these genes into wing pattern development. This is supported by a large fraction of accessible chromatin being exclusive to each species, including the de novo lineage-specific evolution of a modular optix enhancer. These findings may be explained by a high level of developmental drift and evolutionary contingency that occurs during the independent evolution of mimicry.

A phase 1 study of weekly everolimus (RAD001) in combination with docetaxel in patients with metastatic breast cancer.

BACKGROUND: Inhibition of mammalian target of rapamycin with everolimus may improve the efficacy of taxanes. Everolimus and docetaxel are both metabolized by CYP3A4, which could result in a pharmacokinetic (PK) interaction. METHODS: Fifteen patients with metastatic breast cancer were treated with docetaxel (doses of 40-75 mg/m(2) intravenously on day 1 of a 21-day cycle) in combination with everolimus (doses ranging from 20 to 50 mg orally on days 1 and 8 of a 21-day cycle) in a phase 1 trial using the continuous reassessment method to determine maximum tolerated dose. The first 2 patients developed a dose-limiting toxicity (neutropenic infection), prompting a mandatory dose reduction and PK evaluation of both everolimus and docetaxel for patients enrolled in subsequent dosing cohorts. RESULTS: Fifteen patients were treated. Dose-limiting toxicity included grade 3 mucositis (n = 1), prolonged grade 4 neutropenia (n = 1), and grade 3 infection/febrile neutropenia (n = 3). Day 8 of everolimus was commonly held for neutropenia despite a dose reduction in docetaxel to 40 mg/m(2). Eleven patients underwent complete PK evaluation for everolimus, and 9 patients underwent complete PK evaluation for both everolimus and docetaxel. Widely variable changes in clearance were seen for both drugs, and the study was terminated because of lack of efficacy and concerns regarding toxicity seen with the combination. CONCLUSIONS: Weekly everolimus in combination with docetaxel every 3 weeks was associated with excessive neutropenia and variable clearance of both drugs, making combination therapy unpredictable, even at low doses of both drugs.

Comparison of molecular subtyping with BluePrint, MammaPrint, and TargetPrint to local clinical subtyping in breast cancer patients.

PURPOSE: To compare breast cancer subtyping with the three centrally assessed microarray-based assays BluePrint, MammaPrint, and TargetPrint with locally assessed clinical subtyping using immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH). METHODS: BluePrint, MammaPrint, and TargetPrint were all performed on fresh tumor samples. Microarray analysis was performed at Agendia Laboratories, blinded for clinical and pathological data. IHC/FISH assessments were performed according to local practice at each institution; estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) assessments were performed on 132 samples, and Ki-67 on 79 samples. RESULTS: The concordance between BluePrint and IHC/FISH subtyping was 94 % for the Luminal-type, 95 % for the HER2-type, and 94 % for the Basal-type subgroups. The concordance of BluePrint with subtyping using mRNA single gene readout (TargetPrint) was 96 % for the Luminal-type, 97 % for the HER2-type, and 98 % for the Basal-type subgroups. The concordance for substratification into Luminal A and B using MammaPrint and Ki-67 was 68 %. The concordance between TargetPrint and IHC/FISH was 97 % for ER, 80 % for PR, and 95 % for HER2. CONCLUSIONS: The implementation of multigene assays such as TargetPrint, BluePrint, and MammaPrint may improve the clinical management of breast cancer patients. High discordance between Luminal A and B substratification based on MammaPrint versus locally assessed Ki-67 or grade indicates that chemotherapy decisions should not be based on the basis of Ki-67 readout or tumor grade alone. TargetPrint serves as a second opinion for those local pathology settings where high-quality standardization is harder to maintain.

Hereditary pancreatitis: An updated review in pediatrics.

Hereditary Pancreatitis (HP) has emerged as a significant cause of acute, acute recurrent and chronic pancreatitis in the pediatric population. Given that it presents similarly to other causes of pancreatitis, a positive family history and/or isolation of a gene mutation are vital in its designation. Inheritance patterns remain complex, but mutations involving the PRSS1, SPINK1, CFTR and CTRC genes are commonly implicated. Since being first described in 1952, dozens of genetic alterations that modify the action of pancreatic enzymes have been identified. Among children, these variants have been isolated in more than 50% of patients with chronic pancreatitis. Recent research has noted that such mutations in PRSS1, SPINK1 and CFTR genes are also associated with a faster progression from acute pancreatitis to chronic pancreatitis. Patients with HP are at increased risk of developing diabetes mellitus, exocrine pancreatic insufficiency, and pancreatic adenocarcinoma. Management follows a multi-disciplinary approach with avoidance of triggers, surveillance of associated conditions, treatment of pancreatic insufficiency and use of endoscopic and surgical interventions for complications. With significant sequela, morbidity and a progressive nature, a thorough understanding of the etiology, pathophysiologic mechanisms, diagnostic evaluation, current management strategies and future research considerations for this evolving disease entity in pediatrics is warranted.

Heliconius butterflies: a window into the evolution and development of diversity.

Butterflies have become prominent models for studying the evolution and development of phenotypic variation. In Heliconius, extraordinary within species divergence and between species convergence in wing color patterns has driven decades of comparative genetic studies. However, connecting genetic patterns of diversification to the molecular mechanisms of adaptation has remained elusive. Recent studies are bridging this gap between genome and function and have driven substantial advances in deciphering the genetic architecture of diversification in Heliconius. While only a handful of large-effect genes were initially identified in the diversification of Heliconius color patterns, recent experiments have begun to unravel the underlying gene regulatory networks and how these have evolved. These results reveal an evolutionary story of many interacting loci and partly independent genetic architectures that underlie convergent evolution.

Chemotherapy resistance in metastatic breast cancer: the evolving role of ixabepilone.

Resistance to chemotherapy is a major obstacle to the effective treatment of many tumor types. Although many anticancer therapies can alter tumor growth, in most cases the effect is not long lasting. Consequently, there is a significant need for new agents with low susceptibility to common drug resistance mechanisms in order to improve response rates and potentially extend survival. Approximately 30% of the women diagnosed with early-stage disease in turn progress to metastatic breast cancer, for which therapeutic options are limited. Current recommendations for first-line chemotherapy include anthracycline-based regimens and taxanes (paclitaxel and docetaxel). They typically give response rates of 30 to 70% but the responses are often not durable, with a time to progression of 6 to 10 months. Patients with progression or resistance may be administered capecitabine, gemcitabine, vinorelbine, albumin-bound paclitaxel, or ixabepilone, while other drugs are being evaluated. Response rates in this setting tend to be low (20 to 30%); the median duration of responses is <6 months and the results do not always translate into improved long-term outcomes. The present article reviews treatment options in taxane-resistant metastatic breast cancer and the role of ixabepilone in this setting.

Implications of anthracycline-resistant and taxane-resistant metastatic breast cancer and new therapeutic options.

Patients with advanced or metastatic breast cancer commonly develop disease resistant to chemotherapy (typically anthracyclines and taxanes), which presents a major obstacle to therapy and leaves few effective treatment options. Drug resistance can occur due to various mechanisms including modification of drug efflux membrane transporters such as P-glycoprotein, as well as alterations in beta-tubulin. The novel epothilone B analog, ixabepilone, which has low susceptibility to various drug-resistance mechanisms, has demonstrated preclinical activity in drug-resistant breast cancer. The clinical activity of ixabepilone was evaluated in metastatic breast cancer patients with highly pretreated and/or resistant/refractory disease. Results were reviewed from three phase II trials in which ixabepilone was administered as monotherapy and one phase III trial that evaluated ixabepilone in combination with capecitabine. As a single agent, ixabepilone demonstrated activity in women who were heavily pretreated and resistant to an anthracycline, a taxane, and/or capecitabine. The combination of ixabepilone and capecitabine was significantly more active than capecitabine alone in patients with prior treatment or resistance to anthracyclines and taxanes. Treatment-related adverse events were generally low grade except for grade 3/4 toxicities, including neutropenia (53-54%) and reversible peripheral sensory neuropathy (14-16%). Ixabepilone has significant activity in patients with heavily pretreated metastatic breast cancer who are disease resistant or refractory to anthracyclines and taxanes. Further clinical evaluation of this agent in patients with drug-resistant breast cancer and in specific patient subsets is warranted.

Meandering Main Pancreatic Duct in Association with Choledochal Cysts and Acute Pancreatitis in Pediatrics.

Meandering main pancreatic duct (MMPD) is an uncommon anomaly of the main pancreatic duct characterized by an abnormal curvature at the pancreatic head region. This variant can be diagnosed on imaging, particularly magnetic resonance cholangiopancreatography (MRCP). Although its clinical significance remains debatable, recent research suggests an association with recurrent acute pancreatitis. To our knowledge, no pediatric cases of acute or recurrent acute pancreatitis have been attributed to the presence of MMPD. In this article, we report on two patients. The first case is of a 15-year-old girl with MMPD discovered on investigation of idiopathic acute pancreatitis. The second case is of a 5-year-old boy who presented with his second episode of acute pancreatitis. In this patient, MRCP imaging revealed MMPD and type IVA choledochal cyst. With appropriate care, both patients experienced clinical improvement with resolution of abdominal pain. This article highlights MMPD as a distinct entity that should be considered in pediatric patients with recurrent attacks of acute pancreatitis. This report also describes the first association of MMPD with choledochal cysts. [Pediatr Ann. 2019;48(10):e412-e416.].

The Mesentery, Systemic Inflammation, and Crohn's Disease.

Initially thought to be a structure that only provided support to the abdominal contents, the mesentery has now gained special attention in the scientific community. The new approach of studying the mesentery as an individual organ has highlighted its importance in the development of local and systemic inflammatory diseases and its potential role in Crohn's disease. Its topographical relationship with the intestine in the setting of active inflammation and "creeping fat" is possibly one of the most important arguments for including the mesentery as an important factor in the pathogenesis of Crohn's disease. In this review, we discuss the importance of the mesentery from the anatomical and embryological standpoints. We also will summarize data on mesenteric inflammation in patients with Crohn's disease. The significance of the mesentery in systemic inflammatory syndromes will be discussed, and we provide an overview of primary inflammatory disorders of the mesentery. Finally, we discuss surgical approaches for patients requiring resection for Crohn's disease that incorporate mesenteric factors, pointing out recent data suggesting that these have the potential for improving outcomes and reducing disease recurrence.10.1093/ibd/izy201_video1izy201.video15794169491001.

Hypophosphatemia in a Malnourished Child: When Renal Fanconi Syndrome Does Not Stand for Refeeding Syndrome.

Refeeding syndrome is diagnosed based on the onset of multiple laboratory abnormalities (most commonly hypophosphatemia) and clinical signs in the setting of nutrition rehabilitation of malnourished patients. Because definitions are not uniform, a broad differential diagnosis should always include renal tubular dysfunction. Our report details a 3 year-old child with undiagnosed renal tubular dysfunction who presented with the clinical picture of refeeding syndrome with refractory electrolyte abnormalities. A diagnosis of renal Fanconi syndrome was made after urinalysis that revealed glucosuria and urine electrolyte losses. Thus, urinalysis can aid in making a positive diagnosis of refeeding syndrome.

Interplay between Developmental Flexibility and Determinism in the Evolution of Mimetic Heliconius Wing Patterns.

To what extent can we predict how evolution occurs? Do genetic architectures and developmental processes canalize the evolution of similar outcomes in a predictable manner? Or do historical contingencies impose alternative pathways to answer the same challenge? Examples of Müllerian mimicry between distantly related butterfly species provide natural replicates of evolution, allowing us to test whether identical wing patterns followed parallel or novel trajectories. Here, we explore the role that the signaling ligand WntA plays in generating mimetic wing patterns in Heliconius butterflies, a group with extraordinary mimicry-related wing pattern diversity. The radiation is relatively young, and numerous cases of wing pattern mimicry have evolved within the last 2.5-4.5 Ma. WntA is an important target of natural selection and is one of four major effect loci that underlie much of the pattern variation in the group. We used CRISPR/Cas9 targeted mutagenesis to generate WntA-deficient wings in 12 species and a further 10 intraspecific variants, including three co-mimetic pairs. In all tested butterflies, WntA knockouts affect pattern broadly and cause a shift among every possible scale cell type. Interestingly, the co-mimics lacking WntA were very different, suggesting that the gene networks that pattern a wing have diverged considerably among different lineages. Thus, although natural selection channeled phenotypic convergence, divergent developmental contexts between the two major Heliconius lineages opened different developmental routes to evolve resemblance. Consequently, even under very deterministic evolutionary scenarios, our results underscore a surprising unpredictability in the developmental paths underlying convergence in a recent radiation.

Clinical development of ixabepilone and other epothilones in patients with advanced solid tumors.

Chemotherapy efficacy in patients with solid tumors is influenced by primary and acquired multidrug resistance (MDR). Epothilones represent a novel class of microtubule inhibitors with lower susceptibility to drug resistance and efficacy in taxane-resistant tumors. While other epothilones are currently under investigation, ixabepilone is the first epothilone B analogue approved by the U.S. Food and Drug Administration. Ixabepilone has been shown to have preclinical activity in chemotherapy-sensitive and chemotherapy-resistant tumor models, and synergistic antitumor activity with other chemotherapeutic and targeted agents. Single-agent ixabepilone has demonstrated clinical activity in multiple solid tumors including advanced breast, lung, prostate, pancreatic, renal cell, and ovarian cancers. Most notably, efficacy has been demonstrated in patients with metastatic breast cancer (MBC) progressing after treatment with anthracyclines and taxanes. A phase III trial in anthracycline- and taxane-resistant MBC showed superior disease control with ixabepilone plus capecitabine versus capecitabine monotherapy, resulting in its approval. Ixabepilone is also active in chemotherapy-naïve and taxane-resistant hormone-refractory prostate cancer and platinum-resistant non-small cell lung cancer. Neutropenia and peripheral sensory neuropathy are the most common adverse events associated with treatment. This review discusses the challenges of MDR and the data that support the use of epothilones in this setting, focusing on ixabepilone.

Comparison of ductal lavage and random periareolar fine needle aspiration as tissue acquisition methods in early breast cancer prevention trials.

PURPOSE: Short-term phase I and phase II breast cancer prevention trials require tissue acquisition at baseline and after intervention to evaluate modulation of potential biomarkers. Currently used tissue acquisition methods include ductal lavage (DL), random periareolar fine needle aspiration (RPFNA), and core needle biopsy. The optimum method to retrieve adequate samples and the most accepted method by study participants is not known. EXPERIMENTAL DESIGN: We compared RPFNA and DL as breast tissue acquisition methods for short-term breast cancer prevention trials by evaluating sample adequacy and tolerability in subjects who participated in two prospective phase II breast cancer prevention trials. Eighty-six women at increased risk for breast cancer were included in this study and underwent baseline DL and RPFNA. High risk was defined as having a 5-year Gail score of >1.67% or a history of atypical hyperplasia (AH), lobular carcinoma, or breast cancer. RESULTS: Median age was 54.5 years (range, 39-75 years); 75% of the women were postmenopausal. About 51% of the women yielded nipple aspiration fluid, and breast fluid samples via DL were retrieved in 73% of these subjects. Of these samples, 71% were adequate samples (greater than 10 epithelial cells). However, when the entire cohort was considered, only 31% of the subjects had adequate samples. RPFNA was also attempted in all subjects, and sample retrieval rate was 100%. Out of these, 96% of the subjects had adequate samples. In DL samples, AH rate was 3.7% was and hyperplasia (H) rate was 11.1%. In RPFNA samples, AH rate was 12.9%, and H rate was 24.7%. Cytology findings in RPFNA samples correlated with age, menopausal status, and breast cancer risk category (previous history of lobular carcinoma in situ). Both procedures were well tolerated, and no complications occurred among participants. CONCLUSIONS: Considering that the main end point for short-term prevention trials is the modulation of biomarkers, it is important to optimize adequate sample acquisition; therefore, RPFNA is a more practical option for future phase I and II breast cancer prevention trials compared with DL.

Cryptosporidium diagnosed on endoscopic biopsy in a paediatric patient with inflammatory bowel disease.

Cryptosporidium, a parasitic infection commonly associated with diarrhoea, may be difficult to differentiate from a flare in patients with inflammatory bowel disease and can lead to unnecessary therapy and increase in morbidity and mortality. We report the case of a paediatric patient who had substantial stool output requiring significant fluid resuscitation and who was later diagnosed with cryptosporidium on endoscopic biopsy. Diagnostic work up for cryptosporidium should be strongly considered when a patient presents with a flare involving massive stool output.

The Characterization of Monoclonal Antibodies to Mouse TLT-1 Suggests That TLT-1 Plays a Role in Wound Healing.

Platelets play a vital role in hemostasis and inflammation. The membrane receptor TREM-like transcript-1 (TLT-1) is involved in platelet aggregation, bleeding, and inflammation, and it is localized in the α-granules of platelets. Upon platelet activation, TLT-1 is released from α-granules both in its transmembrane form and as a soluble fragment (sTLT-1). Higher levels of sTLT-1 have been detected in the plasma of patients with acute inflammation or sepsis, suggesting an important role for TLT-1 during inflammation. However, the roles of TLT-1 in hemostasis and inflammation are not well understood. We are developing the mouse model of TLT-1 to mechanistically test clinical associations of TLT-1 in health and disease. To facilitate our studies, monoclonal murine TLT-1 (mTLT-1) antibodies were produced by the immunization of a rabbit using the negatively charged region of the mTLT-1 extracellular domain 122PPVPGPREGEEAEDEK139. In the present study, we demonstrate that two selected clones, 4.6 and 4.8, are suitable for the detection of mTLT-1 by western blot, immunoprecipitation, immunofluorescent staining, flow cytometry and inhibit platelet aggregation in aggregometry assays. In addition, we found that the topical administration of clone 4.8 delayed the wound healing process in an experimental burn model. These results suggest that TLT-1 plays an important role in wound healing and because both clones specifically detect mTLT-1, they are suitable to further develop TLT-1 based models of inflammation and hemostasis in vivo.

Weekly paclitaxel improves pathologic complete remission in operable breast cancer when compared with paclitaxel once every 3 weeks.

PURPOSE: To determine the impact a change in schedule of paclitaxel administration from once every 3 weeks to frequent administration would have on the pathologic complete response (pCR) rate in the breast and lymph nodes for patients with invasive breast cancer treated with primary systemic chemotherapy (PST). PATIENTS AND METHODS: Patients with clinical stage I-IIIA breast cancer were randomly assigned to receive PST of paclitaxel doses administered either weekly (for a total of 12 doses of paclitaxel) or once every 3 weeks (four cycles), followed by four cycles of fluorouracil/doxorubicin/cyclophosphamide (FAC) in standard doses every 3 weeks. Two different doses of paclitaxel were used based on lymph node status defined by ultrasound and fine needle aspiration. Clinical response and extent of residual disease in the breast and lymph nodes was assessed after completion of all chemotherapy. RESULTS: A total of 258 patients were randomly assigned to receive doses of paclitaxel administered either weekly or once every 3 weeks, followed by FAC. Of these 258 patients, 110 patients had histologic lymph node involvement and 148 patients had clinical N0 disease. Weekly paclitaxel followed by FAC was administered to 127 patients and once-every-3-weeks paclitaxel followed by FAC was administered to 131 patients. Clinical response to treatment was similar between groups (P = .25). Patients receiving weekly paclitaxel had a higher pCR rate (28.2%) than patients treated with once-every-3-weeks paclitaxel (15.7%; P = .02), with improved breast conservation rates (P = .05). CONCLUSION: The change in schedule of paclitaxel from once every 3 weeks to a more frequent administration significantly improved the ability to eradicate invasive cancer in the breast and lymph nodes.