Showing papers by "J. R. Siewert published in 2006"

Metabolic imaging predicts response, survival, and recurrence in adenocarcinomas of the esophagogastric junction.

Abstract: Purpose A previous study suggested that measurement of therapy-induced changes in tumor glucose metabolism by positron emission tomography (PET) with the glucose analog [18F]fluorodeoxyglucose (FDG) allows to select patients most likely to benefit from preoperative chemotherapy in adenocarcinomas of the esophagogastric junction (AEG). The aim of this study was to prospectively validate these findings by using an a priori definition of metabolic response. Patients and Methods Sixty-five patients with locally advanced AEGs were included. Tumor glucose utilization was quantitatively assessed by FDG-PET before chemotherapy and 14 days after initiation of therapy. Patients were classified as metabolic responders when the metabolic activity of the primary tumor had decreased by more than 35% at the time of the second PET. Results Metabolic responders showed a high histopathologic response rate (44%) with a 3-year survival rate of 70%. In contrast, prognosis was poor for metabolic nonresponders with a histopatho...

Adenocarcinoma of the esophago-gastric junction.

Abstract: Background:The border between the esophagus and stomach gives rise to many discrepancies in the current literature regarding the etiology, classification and surgical treatment of adenocarcinoma ar...

Prognostic significance of expression patterns of c-erbB-2, p53, p16INK4A, p27KIP1, cyclin D1 and epidermal growth factor receptor in oesophageal adenocarcinoma: a tissue microarray study

Abstract: Aims: To correlate immunohistochemical expression patterns and prognosis in oesophageal adenocarcinoma. Methods: The expression of c-erbB-2, p53, p16INK4A, p27KIP1, cyclin D1 and epidermal growth factor receptor (EGFR) was studied in a series of 137 primarily resected oesophageal adenocarcinoma samples. The expression analysis on protein level was performed on routine paraffin wax-embedded material, with immunohistochemical staining of the samples, assembled on a tissue microarray. The results were correlated with clinicopathological features (pT, pN and G) and survival. Results: 22 (16%) tumours showed an overexpression of the c-erbB-2 oncoprotein. Expression of EGFR was observed in 72 (55%) cases, accumulation of p53 in 68 (52%) cases and of cyclin D1 in 102 (77%) cases. Loss of p16INK4A expression was observed in 101 (76%) cases and low expression of p27KIP1 in 91 (71%) cases. Expression of these proteins did not correlate with tumour stage, grade, Lauren’s or World Health Organization classification or lymph node status. On univariate survival analysis, more advanced tumour stage (p = 0.002), lymph node involvement (p = 0.003), high tumour grade (p = 0.017) and lack of EGFR expression (p = 0.034) were found to be associated with poorer survival. On multiple regression analysis, only tumour stage (p = 0.03) and lymph node involvement (p = 0.004) were shown to have an association with the survival of the patient. Conclusion: The immunohistochemical expression of c-erbB-2 oncoprotein, cylin D1, p16INK4A, p27KIP1, p53 and EGFR in most oesophageal adenocarcinomas suggests their implication in the pathogenesis of this entity. None of the molecular markers assessed, however, was of prognostic value. Identification of any marker superior to or even approaching the prognostic value of conventional histopathological markers (pT and pN) was therefore not possible.

Prognostic significance of downregulated expression of the candidate tumour suppressor gene SASH1 in colon cancer

Abstract: The gene SASH1 (SAM- and SH3-domain containing 1) has originally been identified as a candidate tumour suppressor gene in breast cancer. SASH1 is a member of the SH3-domain containing expressed in lymphocytes (SLY1) gene family that encodes signal adapter proteins composed of several protein–protein interaction domains. The other members of this family are expressed mainly in haematopoietic cells, whereas SASH1 shows ubiquitous expression. We have used quantitative real-time PCR to investigate the expression of SASH1 in tissue samples from 113 patients with colon carcinoma, and compared the expression with 15 normal colon tissue samples. Moreover, nine benign adenomas and 10 liver metastases were analysed. Expression levels of SASH1 were strongly and significantly reduced in colon cancer of UICC stage II, III, and IV, as well as in liver metastases. Moreover, SASH1 was also found to be downregulated on protein levels by immunoblot analysis. However, SASH1 expression was not significantly deregulated in precancerous adenomas and in earlier stage lesions (UICC I). Overall, 48 out of 113 primary colon tumours showed SASH1 expression that was at least 10-fold lower than the levels found in normal colon tissue. Downregulation of SASH1 expression was correlated with the formation of metachronous distant metastasis, and multivariate analysis identified SASH1 downregulation as an independent negative prognostic parameter for patient survival. This study demonstrates for the first time that expression of a member of the SLY1-gene family has prognostic significance in human cancer.

The importance of PET in the diagnosis and response evaluation of esophageal cancer.

Abstract: The major aims of imaging in esophageal cancer are to distinguish between locoregional and systemic disease (M-stage), to determine local tumor extension (T- and N-stage), to assess response to chemo- or chemoradiotherapy and to identify recurrence of cancer. The sensitivity of computed tomography (CT) for detection of distant metastases ranges between 90%. In esophageal cancer, F-18-fluorodeoxyglucose positron emission tomography (FDG-PET) has been shown to detect metastatic disease in approximately 20% of patients who are considered as having only locoregional disease on CT. In locoregional pretherapeutic tumor staging, FDG-PET specificity of 80% is sufficient, but FDG-PET sensitivity of 50% is rather low. However, the initial staging of regional lymph nodes is less important because at the moment there is no pretherapeutic therapy stratification based on lymph node category. The accuracy for correct identification of recurrence in esophageal cancer is higher for FDG-PET than for CT scan. Unfortunately until today no reliable essays for prediction of response or prognosis exist for esophageal cancer in clinical practice for patients with neoadjuvant treatment. Thus the identification of parameters predicting response and/or prognosis is crucial for the future. Post-therapeutic assessment of tumor response by FDG-PET has been shown to correlate with histopathologic tumor regression and patient survival. Furthermore, quantitative measurements of tumor FDG-uptake may allow an early metabolic response evaluation after only 2 weeks of therapy. An association of metabolic response with histopathologic tumor regression and patient outcome 2 weeks after initiation of preoperative chemotherapy may be shown for esophageal cancer.

Free peritoneal tumour cells are an independent prognostic factor in curatively resected stage IB gastric carcinoma

Abstract: Background: Several studies have shown that the cytological detection of free peritoneal tumour cells (FPTCs) in patients with gastric cancer indicates the presence of metastatic disease. The immunocytochemical detection of FPTCs, especially in early-stage tumours, has not been examined comprehensively. Method: Peritoneal lavage was performed in 351 patients before curative resection of a gastric carcinoma between 1987 and 2001, and an adequate sample was obtained from 346 patients. FPTCs were detected immunocytochemically using Ber-EP4 antibody. Median follow-up time was 70 months. Results: FPTCs were detected in the lavage fluid of 74 patients (21·4 per cent) and correlated with increasing pathological tumour depth (pT) and lymph node (pN) status (P < 0·001). The 5-year overall survival of patients with FPTCs was significantly worse than that of patients without FPTCs (35 versus 71·9 per cent; P < 0·001). FPTCs were present in 14 (8·5 per cent) of 164 patients with stage IA or IB tumours. Although the detection of FPTCs had no prognostic significance for stage IA tumours, the presence of FPTCs in those with stage IB tumours was associated with a worse prognosis (P < 0·001). Multivariate analysis identified the presence of FPTCs as an independent prognostic factor in the whole cohort and in the stage IB subgroup. Conclusion: Detection of FPTCs is associated with poor prognosis even in patients with early-stage gastric cancer and should be used for risk-group stratification. Copyright © 2006 British Journal of Surgery Society Ltd. Published by John Wiley & Sons, Ltd.

Preferred location for the development of esophageal adenocarcinoma within a segment of intestinal metaplasia.

Abstract: Barrett’s metaplasia is the predominant precursor for the development of esophageal adenocarcinoma. This precancerous lesion has become the focus of various surveillance programs aimed at detecting earlier and therefore potentially curable lesions. However, sampling error by missing invasive cancer lesions is a common problem. This study aimed to identify preferred locations within a segment of Barrett’s mucosa for the development of esophageal adenocarcinoma. The study group consisted of 213 patients with histologically proven esophageal adenocarcinoma. Of those, there were 134 cases of early cancer and 79 cases of locally advanced lesions. These patients received neoadjuvant chemotherapy. The frequency of intestinal metaplasia and the location of the tumor occurrence within the segment of intestinal metaplasia were assessed. Intestinal metaplasia was found in 83% of the early lesions and in 98% of the advanced tumors after neoadjuvant chemotherapy. In 82.2% of the cases, the tumor was located at the distal margin of the intestinal metaplasia in patients with early tumor manifestations. The remaining tumor mass after neoadjuvant therapy also was located predominantly at the distal margin of the segment of intestinal metaplasia (85% of the cases). The results demonstrate that almost all adenocarcinomas of the esophagus are based on the development of a segment of intestinal metaplasia. The distal margin of Barrett’s mucosa seems to be the most vulnerable location for the development of invasive cancer.

Expression of cyclo‐oxygenase 1 and 2, prostaglandin E synthase and transforming growth factor β1, and their relationship with vascular endothelial growth factors A and C, in primary adenocarcinoma of the small intestine

Abstract: Background: Primary adenocarcinomas of the small intestine are rare. The prostaglandin biosynthetic pathway plays a major role in carcinogenesis and is linked with angiogenesis in various tumours. Promotion of tumour growth by transforming growth factor (TGF) β may be mediated through the prostaglandin pathway. Methods: Expression of cyclo-oxygenase (COX) 1 and 2, prostaglandin E synthase (PGES), TGF-β1 and vascular endothelial growth factor (VEGF) A and C genes was analysed in 54 primary adenocarcinomas of the small intestine and corresponding normal intestinal mucosa. All patients had undergone surgical resection without previous antineoplastic therapy. Target gene expression was analysed at the mRNA level by reverse transcriptase–polymerase chain reaction and correlated with clinicopathological parameters as well as survival. COX-2 protein expression was examined by immunohistochemistry. Results: Expression of COX-2 protein was detected immunohistochemically in 98 per cent of the carcinomas. COX-1, COX-2, VEGF-A, VEGF-C, PGES and TGF-β1 mRNA expression varied markedly in different tumours, but all were overexpressed compared with levels in normal intestinal mucosa. There were significant associations between levels of COX-1, COX-2, TGF-β1 and PGES mRNAs and those of VEGF-A and VEGF-C. Conclusion: Correlations between levels of mRNA for COX-1, COX-2, TGF-β1 and PGES and those for proangiogenic factors VEGF-A and VEGF-C suggest a role for these factors in the propagation of primary adenocarcinomas of the small intestine. Copyright © 2006 British Journal of Surgery Society Ltd. Published by John Wiley & Sons, Ltd.

Blood interleukin 12 as preoperative predictor of fatal postoperative sepsis after neoadjuvant radiochemotherapy.

Abstract: INTRODUCTION: The value of preoperative whole-blood interleukin (IL) 12 levels in predicting death from postoperative sepsis was evaluated, in patients stratified by underlying malignancy, neoadjuvant tumour treatment and surgical procedure. METHODS: Blood samples were collected from 1444 patients before major surgery. Whole blood was incubated with Escherichia coli lipopolysaccharide (LPS) and IL-12 production in supernatants was assessed by enzyme-linked immunosorbent assay. The prognostic impact of ability to synthesize IL-12 before surgery was investigated in patient subgroups with respect to sepsis-related mortality using multivariate binary logistic regression analysis. RESULTS: IL-12 synthesizing capability in patients who survived sepsis was significantly higher than that in patients who developed fatal sepsis (P = 0.006). In multivariate analysis only IL-12 was associated with a lethal outcome from postoperative sepsis (P = 0.006). The prognostic impact of IL-12 was evident in patients with underlying malignancy (P = 0.011) and in those who had undergone neoadjuvant tumour treatment (P = 0.008). When patients were analysed according to the type of neoadjuvant therapy, preoperative ability to synthesize IL-12 had a significant prognostic impact in patients who had neoadjuvant radiochemotherapy (P = 0.026), but not in those who had neoadjuvant chemotherapy. CONCLUSION: IL-12 production after stimulation of whole blood with LPS appears to be useful for the preoperative assessment of risk of sepsis-related death after operation in patients who have undergone neoadjuvant radiochemotherapy.

Delays in diagnosis and therapy of gastric cancer and esophageal adenocarcinoma.

Abstract: BACKGROUND AND STUDY AIMS: In the past, there were long delays in the diagnosis of patients with cancer of the stomach or esophagus The objective of this study was to describe current delays in the diagnosis and treatment of gastric and esophageal adenocarcinoma and to compare the findings with those from an historical control population treated at the same institutions 10 years earlier PATIENTS AND METHODS: Patients with biopsy-proven gastric cancer or esophageal adenocarcinoma who were treated at two academic medical centers in Germany between April and October 2003 were consecutively screened for eligibility to take part in the study Medical charts for each patient were reviewed Additional data were obtained via structured interviews Main outcome measures were the total delay, and the delays related to patients themselves, to doctors, and to the hospital Data were compared with those from a historic control group assessed in 1993 RESULTS: The median total delay for patients with gastric cancer (n =104) was 35 months (range 03 - 296), and in patients with esophageal adenocarcinoma (n = 22) the total delay was significantly shorter (median 22 months, range 12 - 117; P< 005) Comparing these findings with those from an historic cohort of patients with gastric cancer (n = 100) revealed a significant decrease in the total delay (35 versus 80 months, P< 0001) CONCLUSIONS: The current findings indicate that delays in the diagnosis and treatment of gastric cancer have become significantly shorter within the last 10 years as our understanding of and ability to treat this form of cancer have improved

Therapeutische Strategien bei lokoregionalen Rezidiven gastrointestinaler Tumoren

Abstract: Lokoregionale Rezidive stellen ein relevantes Problem in der chirurgischen Onkologie dar. Intraluminale Lokalrezidive sind in vielen Fallen Ausdruck einer unzureichenden Primarresektion, die mit nicht ausreichenden Sicherheitsabstanden durchgefuhrt wurde. Die Nachresektion mit ausreichenden Sicherheitsabstanden stellt, wann immer moglich, das Therapieverfahren der Wahl dar. Das Auftreten eines Rezidivs im Tumorbett ist nach optimaler primarer Resektion Ausdruck einer bereits primar lokal weit fortgeschrittenen Erkrankung. Die Indikation zur Nachresektion ist hier immer sehr kritisch abzuwagen. Aussicht auf langerfristige Tumorkontrolle besteht nur, wenn die Zweitresektion residualtumorfrei durchgefuhrt werden kann und wenn sie sinnvoll in ein multimodales Behandlungskonzept eingebettet ist. Fur Rezidive im Bereich der Lymphabstrombahn, der sog. 4. Dimension, besteht in der Regel keine zweite kurative Behandlungsoption.

Verfahren zum temporären Bauchdeckenverschluss bei Trauma und Sepsis

Abstract: Die Verfahren eines temporaren Bauchdeckenverschlusses unterscheiden sich grundsatzliche durch vakuumassistierte und konventionelle Technik. Die vakuumassistierten Verfahren erscheinen bezuglich der Zielgrosen Letalitat, Moglichkeit zum Sekundarverschluss wahrend des primaren stationaren Aufenthaltes und Haufigkeit der Ausbildung einer enterokutanen Fistel den konventionellen uberlegen. Dieses gilt insbesondere im Rahmen der traumatologisch bedingten Indikationen. Die klassischen Verfahren haben ihre speziellen Indikationen; so stellen das Skin-only-closure-Verfahren und der Tuchklemmenverschluss typische uberbruckende Verfahren insbesondere bei gleichzeitiger Durchfuhrung eines abdominellen Packings dar. Die Bogota Bag findet ihren Anwendungsbereich insbesondere bei Vorliegen eines schwerwiegenden abdominellen Kompartmentsyndroms und bei massivem Volumenbedarf der Intestinalorgane. Als einziges Verfahren ermoglicht es die relativ problemlose Ausleitung eines temporaren Ileostomas durch den Bauchdeckenverschluss, wie es bei sehr grosen Substanzverlusten gelegentlich erforderlich ist. Die drei vakuumassistierten Verfahren unterscheiden sich geringfugig. Das KCI Abdominal Dressing® ist ein technisch ausgereiftes Verfahren, allerdings auch das kostenintensivste hier beschriebene System. Unter einsatzmedizinischen Gesichtspunkten ist es nicht geeignet. Der Vorteil der klassischen Vakuumversieglung in Kombination mit einem auf Faszienniveau eingenahten Vicrylnetz besteht in der problemlosen Umwandlung zu einem permanenten Laparostoma. Wir bevorzugen deshalb dieses Verfahren, insbesondere da es auch unter Einsatzbedingungen gut anwendbar ist.

[Response prediction--early response evaluation. Consequences for surgical oncology].

Abstract: Response to perioperative chemotherapy or chemoradiation can hardly be predicted on the basis of molecular marker analyses. In contrast, by means of metabolic and molecular imaging using positron emission tomography, response can be assessed as early as 14 days after the start chemotherapy for many tumors. There is no doubt that the prognosis of patients with surgically resected tumors is much better in the case of a response to chemotherapy or chemoradiation. Important consequences can be deduced from this regarding the indications for perioperative therapies, the radicality of surgery or the surgical indications per se. In the following, we delineate the current knowledge on response prediction and early response evaluation in selected tumor entities and draw possible conclusions for clinical practice and future clinical studies.

Impact of disseminated tumor cells in gastrointestinal cancer

Abstract: The detection of epithelial cells by sensitive immunological and molecular methods in blood, lymph nodes or bone marrow of gastrointestinal cancer patients may open a new approach to clinical metastasis research. The phenotypic and genomic characterization of these cells is of great value in the prediction of the further course of the disease and the monitoring of response to treatment. In addition, the role of ultrastaging in blood, lymph nodes and bone marrow of cancer patients for the indication of multimodal therapy is discussed in this review. The impact of prognostic or predictive factors for new treatment protocols in patients with gastrointestinal cancer was evaluated as well as the correlation with clinical factors.

Possible individualized therapy by early assessment of response during neoadjuvant radiochemotherapy in esophageal squamous cell carcinoma patients by 18-FDG-PET

Abstract: 4060 Background: Response evaluation by positron emission tomography with the glucose analog [18F]-fluorodeoxyglucose (FDG-PET) has been used in patients with esophageal squamous cell carcinoma (ESCC) after neoadjuvant radiochemotherapy (RTx/CTx). This prospective study was undertaken to compare FDG-PET assessment of tumor response during RTx/CTx with histopathology in patients with ESCC, and to correlate the findings with survival. Methods: Patients (n=61) with histologically proven intrathoracic ESCC (cT3, cN0/+, cM0) underwent preoperative, simultaneous RTx/CTx followed by esophagectomy between 1996 and 2005. The patients underwent FDG-PET prior to and 2 weeks after the begin of RTx/CTx (20Gray). Histopathological response was quantified as the percentage of residual tumor cells. The threshold pre-therapy-to-during-therapy decrease in standardized uptake value by FDG-PET used to define metabolic responders (ΔSUVR) was -30%. Results: Receiving-operator-curve analysis (ROC) for determination of metabolic...

Penetrierende Beckenverletzung

Abstract: Durch eine Zunahme der Kriminalitat und dem damit verbundenen Waffengebrauch werden Chirurgen im Inland sowie Militarchirurgen im Einsatz in Krisengebieten vermehrt mit penetrierenden Verletzungen des Beckens konfrontiert. Penetrierende Verletzungen der Iliakalgefase sind mit einer hohen Mortalitat verknupft; die Mehrzahl dieser Patienten erreicht die medizinische Behandlung im profunden Ausblutungsschock. Assoziierte Darmverletzungen, die in uber 20% vorhanden sind, fuhren zu einer zeitgleichen Kontamination des Operationsgebietes. Die Versorgungsoptionen fur Gefase beinhalten die einfache Rekonstruktion von Vene oder Arterie, die Ligatur der Vene, die temporare Shunteinlage oder das Kunststoffinterponat der Arterie. Bei anderweitig nicht kontrollierbarer Blutung stellt die Ligatur der Iliakalarterie eine lebensrettende Option dar. Fruhzeitige Konversion in den Damage-Control-Modus und verbundene Versorgungstechniken konnen verhindern, dass diese schwerstverletzten Patienten in die Koagulopathie abgleiten.

Akutes Abdomen, Peritonitis, Ileus und traumatisiertes Abdomen

Abstract: Das akute Abdomen stellt die klassische chirurgische Notfallsituation dar und hat daher grose klinische Bedeutung. Es erfordert eine unverzugliche klinische und apparative Diagnostik und eine rasche Entscheidung uber operatives oder konservatives Vorgehen. Hauptursachen sind entzundliche oder obstruktive Erkrankungen des Gastrointestinaltraktes, deren Lokalisation und Ausmas oft erst intraoperativ genau erkennbar sind. Die Peritonitis nimmt dabei eine Sonderstellung ein, da sie neben der lokalen intraabdominellen Infektion durch schwere septische Allgemeinreaktionen gekenn-zeichnet ist. Dieses erfordert eine z. T. wiederholte aggressive chirurgische Intervention; trotzdem ist die Peritonitis in ihrer generalisierten Verlaufsform mit einer Letalitat von 20–60 % belastet. Der zweite typische abdominelle Notfall ist der Ileus, dessen mechanische Form von dramatischen Schmerzen begleitet sein kann. Die Abgrenzung der paralytischen Form ist wesentlich, um Fehler bei der Indikationsstellung zur Operation zu vermeiden. Eine Traumatisierung des Abdo-mens gefahrdet den Verletzten in erster Linie durch intraabdominelle Blutungen aus Organrupturen. Die rasche Erkennung und Versorgung der Blutung und eventueller Begleitverletzungen steht daher ganz im Vordergrund des chirurgischen Handelns.

Minimal-symptomatische Leistenhernie

Abstract: Viele Männer mit dem Befund einer Leistenhernie haben eine nur minimale Symptomatik. Eine Leistenhernienoperation wird bei diesen Patienten unter der Vorstellung indiziert, eine spätere Komplikation zu verhindern (akute Inkarzeration mit Obstruktion oder Strangulation von Bruchsackinhalt). Allerdings ist der Spontanverlauf („natural history“) dieser mit minimaler Symptomatik einhergehenden Leistenhernien nicht hinreichend untersucht: Es ist unklar, ob das Aufschieben einer Leistenhernienoperation gefahrlos möglich ist und die einstweilige Beobachtung damit eine akzeptable Option darstellt. Diese Fragestellung ist in einer randomisierten klinischen Studie untersucht worden, deren Ergebnisse jetzt im Journal of the American Medical Association (JAMA) publiziert worden sind [2]. Zwischen Januar 1999 und Dezember 2004 wurden an fünf nordamerikanischen Zentren1 insgesamt 720 Männer mit „minimal-symptomatischer Leistenhernie“ zur Operation

Einfluss des Längenpolymorphismus am Promotor der Thymidylatsynthase auf die Prognose des lokal fortgeschrittenen Magenkarzinoms

Abstract: Purpose: We evaluated DNA polymorphisms in the thymidylate synthase (TS) for an association with response and survival in locally advanced gastric cancer treated with primary resection or 5-FU based preoperative chemotherapy (CTx). Recently we found an association with prognosis, but not response in neadjuvant treated gastric cancer. Experimental Design: The DNA of 205 patients completely resected patients (102 with CTx; 103 without CTx) was isolated from blood or from nontumorous tissues. Genotyping of the tandem repeat polymorphism in the promoter region of the TS gene was performed by PCR. Results: 53 (52 %) of the patients with primary resection had the 2R/3R genotype, 28 (27 %) the 3R/3R and 22 (21 %) the 2R/2R genotype. 46 (45 %) of the patients with neoadjuvant CTx showed the 2R/3R genotype, 29 (28 %) the 3R/3R genotype and 27 (27 %) the 2R/2R genotype (p = 0.60). In the CTx-group, the TS genotypes were not associated with clinical (p = 0.93) or histopathological response (p = 0.71), but were significantly related to survival (Median survival in months: 3R/3R: 35,2; 2R/3R: n.r; 2R/2R: n.r.; p = 0.003). In contrast there is no survival difference in the primary resected patients regarding the genotype (3R/3R: 33,3; 2R/3R: 47,6; 2R/2R: 32,0; p = 0.83). Comparing survival between completely resected patients with and without CTx in the respective TS genotype groups, a significant survival benefit for the patients with CTx was found for the 2R/2R (n = 49; p = 0.002) and 2R/3R genotypes (n = 99; p = 0.004), but not for the 3R/3R genotype (n = 57; p = 0.93). Conclusion: Our results show that patients’ prognosis after CTx was associated with the TS genotype. Patients with the 3R/3R genotype did not benefit from CTx. Thus a different CTx or primary surgery might be more appropriate for these patients.