Multimodal Treatment of Metastatic Rectal Cancer in a Young Patient: Case Report and Literature Review.

Metastatic colorectal cancer requires a multidisciplinary and individualized approach. Herein, we reported the case of a young woman diagnosed with metastatic rectal cancer who received an individualized multimodal treatment strategy that resulted in a remarkable survival. There were several particular aspects of this case, such as the early onset of the disease, the successful use of conversion therapy, the application of liquid biopsy to guide treatment, and the specific nature of the bone metastasis. To offer more insights for navigating such challenges in patients with metastatic colorectal cancer, we have conducted a literature review to find more data related to the particularities of this case. The incidence of early onset colorectal cancer is on the rise. Data suggests that it differs from older-onset colorectal cancer in terms of its pathological, epidemiological, anatomical, metabolic, and biological characteristics. Conversion therapy and surgical intervention provide an opportunity for cure and improve outcomes in metastatic colorectal cancer. It is important to approach each case individually, as every patient with limited liver disease should be considered as a candidate for secondary resection. Moreover, liquid biopsy has an important role in the individualized management of metastatic colorectal cancer patients, as it offers additional information for treatment decisions.

Endoscopic Ultrasound-Guided Fiducial Placement for Stereotactic Body Radiation Therapy in Patients with Pancreatic Cancer.

Accurate delivery of stereotactic body radiotherapy (SBRT) to pancreatic tumors relies on successful EUS-guided placement of fiducial markers. The aim of this study is to report the technical feasibility and safety of EUS-guided fiducial placement and to evaluate the characteristics and technical benefit of SBRT in a cohort of patients with pancreatic cancer (PC). A retrospective chart review was performed for all (n = 82) PC patients referred for EUS-guided fiducial placement by a single endosonographer at a tertiary cancer center. Data regarding EUS-related technical details, SBRT characteristics, adverse events, and continuous visibility of fiducials were recorded and analyzed. Most patients included in the study had either locally advanced disease (32 patients, 39%) or borderline resectable disease (29 patients, 35%). Eighty-two PC patients underwent the placement of 230 fiducial markers under EUS guidance. The technical success rate of the fiducial placement was 98%. No immediate EUS-related adverse events were reported. The average time to the simulation CT after fiducial placement was 3.1 days. Of the 216 fiducial markers used for the SBRT delivery, 202 fiducial markers were visible on both the simulation CT and the cone beam CT scan. A median dose of 40cGY was given to all the patients in five fractions. Of these, 41% of the patients reported no SBRT-related toxicities during the follow-up. Fatigue and nausea were the most reported SBRT-related toxicities, which were seen in 35% of the patients post-SBRT. Our results demonstrate that EUS-guided fiducial placement is safe and effective in target volume delineation, facilitating SBRT delivery in PC patients. Further clinical trials are needed to determine the SBRT-related survival benefits in patients with pancreatic cancer.

Endoscopic Intrapyloric Botulinum Toxin Injection with Pyloric Balloon Dilation for Symptoms of Delayed Gastric Emptying after Distal Esophagectomy for Esophageal Cancer: A 10-Year Experience.

Patients with esophageal cancer undergoing esophagectomy have an improved survival over time, however adverse events associated with the use of a gastric conduit are increasingly being reported. Delayed gastric emptying (DGE) is an esophagectomy-related complication which can decreased quality of life by causing debilitating gastrointestinal symptoms and malnutrition. The aim of our study was to evaluate the effect of endoscopic intrapyloric botulinum (BT) injection in combination with pyloric balloon dilation in patients with DGE following distal esophagectomy at our tertiary cancer center. Patients with a prior history of distal esophagectomy who had also undergone endoscopic BT injection with pyloric balloon dilation by a single endoscopist between 2007 and 2017 were included in the study. One hundred units of BT were injected endoscopically into the pylorus in four quadrants using an injection needle. Following BT injection, a standard through-the-scope balloon was passed to the pylorus and inflated to a maximum diameter of 12−20 mm. For patients who underwent repeat procedures, the symptomatic outcomes were assessed and documented by the endoscopist; for the other patients, the electronic medical records were reviewed. A total of 21 patients undergoing 44 endoscopic intrapyloric botox injections combined with balloon dilatations were identified. The patients underwent the procedures at a median of 22 months (range, 1−108 months) after esophagectomy. The procedures were performed only once in 43% of the patients; 43% patients underwent the procedure twice, while 14% had it multiple times (>2). Overall, intrapyloric BT injection coupled with balloon dilation was a safe procedure, without any major immediate or delayed (1 month) procedure-related adverse events. Eighteen patients (85%) reported a significant overall improvement in symptoms from the initial presentation. One patient (5%) showed no improvement, whereas in two (10%) patients responses were not available. In our particular cohort of patients, the interventions of endoscopic intrapyloric BT injection with pyloric balloon dilation proved to be very beneficial, leading to significant symptomatic improvement. The balloon dilation after BT injection might have resulted in better diffusion of the BT into the pyloric sphincter complex, possibly increasing its therapeutic effects. Further prospective studies are needed to validate these results.

Image Fusion Involving Real-Time Transabdominal or Endoscopic Ultrasound for Gastrointestinal Malignancies: Review of Current and Future Applications.

Image fusion of CT, MRI, and PET with endoscopic ultrasound and transabdominal ultrasound can be promising for GI malignancies as it has the potential to allow for a more precise lesion characterization with higher accuracy in tumor detection, staging, and interventional/image guidance. We conducted a literature review to identify the current possibilities of real-time image fusion involving US with a focus on clinical applications in the management of GI malignancies. Liver applications have been the most extensively investigated, either in experimental or commercially available systems. Real-time US fusion imaging of the liver is gaining more acceptance as it enables further diagnosis and interventional therapy of focal liver lesions that are difficult to visualize using conventional B-mode ultrasound. Clinical studies on EUS guided image fusion, to date, are limited. EUS-CT image fusion allowed for easier navigation and profiling of the target tumor and/or surrounding anatomical structure. Image fusion techniques encompassing multiple imaging modalities appear to be feasible and have been observed to increase visualization accuracy during interventional and diagnostic applications.

Diagnostic Value of Artificial Intelligence-Assisted Endoscopic Ultrasound for Pancreatic Cancer: A Systematic Review and Meta-Analysis.

We performed a meta-analysis of published data to investigate the diagnostic value of artificial intelligence for pancreatic cancer. Systematic research was conducted in the following databases: PubMed, Embase, and Web of Science to identify relevant studies up to October 2021. We extracted or calculated the number of true positives, false positives true negatives, and false negatives from the selected publications. In total, 10 studies, featuring 1871 patients, met our inclusion criteria. The risk of bias in the included studies was assessed using the QUADAS-2 tool. R and RevMan 5.4.1 software were used for calculations and statistical analysis. The studies included in the meta-analysis did not show an overall heterogeneity (I2 = 0%), and no significant differences were found from the subgroup analysis. The pooled diagnostic sensitivity and specificity were 0.92 (95% CI, 0.89-0.95) and 0.9 (95% CI, 0.83-0.94), respectively. The area under the summary receiver operating characteristics curve was 0.95, and the diagnostic odds ratio was 128.9 (95% CI, 71.2-233.8), indicating very good diagnostic accuracy for the detection of pancreatic cancer. Based on these promising preliminary results and further testing on a larger dataset, artificial intelligence-assisted endoscopic ultrasound could become an important tool for the computer-aided diagnosis of pancreatic cancer.

Development of an Objective Scoring System for Endoscopic Assessment of Radiation-Induced Upper Gastrointestinal Toxicity.

We developed and implemented an objective toxicity scoring system to be used during endoscopic evaluation of the upper gastrointestinal (GI) tract in order to directly assess changes in toxicity during the radiation treatment of pancreatic cancer. We assessed and validated the upper GI toxicity of 19 locally advanced pancreatic cancer trial patients undergoing stereotactic body radiation therapy (SBRT). Wilcoxon-signed rank tests were used to compare pre- and post-SBRT scores. Comparison of the toxicity scores measured before and after SBRT revealed a mild increase in toxicity in the stomach and duodenum (p < 0.005), with no cases of severe toxicity observed. Kappa and AC1 statistics analysis were used to evaluate interobserver agreement. Our toxicity scoring system was reliable in determining GI toxicity with a good overall interobserver agreement for pre-treatment scores (stomach, κ = 0.71, p < 0.005; duodenum, κ = 0.88, p < 0.005) and post-treatment scores (stomach, κ = 0.71, p < 0.005; duodenum, κ = 0.76, p < 0.005). The AC1 statistics yielded similar results. With future usage, we hope this scoring system will be a useful tool for objectively and reliably assessing changes in GI toxicity during the treatment of pancreatic cancer and for GI toxicity assessments and comparisons during radiation therapy research trials.

Impact of Fiducial Marker Placement Before Stereotactic Body Radiation Therapy on Clinical Outcomes in Patients With Pancreatic Cancer.

PURPOSE: Localized pancreatic cancer is commonly treated with stereotactic body radiation therapy (SBRT), which often requires the placement of fiducial markers. We compared the clinical outcomes of patients with and without fiducial markers. METHODS AND MATERIALS: We retrospectively collected data on patients with pancreatic cancer treated with neoadjuvant SBRT at a single institution. Patients were divided into 2 groups based on the placement of a fiducial marker. Local recurrence was the primary outcome. Time to event endpoints were analyzed using COX regression. RESULTS: We included 96 patients with unresectable pancreatic cancer: 46 patients (47.9%) did not have a fiducial marker, and 50 patients (52.1%) had a fiducial placed. Patients in the fiducial group were older and had more locally advanced pancreatic cancer compared with those who did not have a fiducial placed. Most patients in both groups (92.7%) received chemotherapy before SBRT treatment. SBRT was delivered to a median of 36 Gy over 5 fractions in the no-fiducial group, and 38 Gy over 5 fractions in the fiducial group. At a median follow-up of 20 months, local recurrence was similar irrespective of fiducial placement (adjusted hazard ratio [aHR] 0.6, 95% CI 0.3-1.3, P = .59). Furthermore, no difference in overall survival was noted between the 2 groups (aHR 0.8, 95% CI 0.3-1.9, P = .65). In patients who eventually underwent surgery post-SBRT, no difference in surgical margins (P = .40) or lymphovascular invasion (P = .76) was noted between the 2 groups. No patient developed acute pancreatitis after fiducial placement. CONCLUSIONS: Our data suggest that the use of fiducial markers does not negatively affect clinical outcomes in patients with localized pancreatic cancer. Prospective confirmation of our results is still needed.

Clonal Hematopoiesis and Liquid Biopsy in Gastrointestinal Cancers.

The use of blood liquid biopsy is increasingly being incorporated into the clinical setting of gastrointestinal cancers care. Clonal hematopoiesis (CH) occurs naturally as a result of the accumulation of somatic mutations and the clonal proliferation of hematopoietic stem cells with normal aging. The identification of CH-mutations has been described as a source of biological noise in blood liquid biopsy. Incorrect interpretation of CH events as cancer related can have a direct impact on cancer diagnosis and treatment. This review summarizes the current understanding of CH as a form of biological noise in blood liquid biopsy and the reported clinical significance of CH in patients with GI cancers.

Diagnostic value of digital droplet polymerase chain reaction and digital multiplexed detection of single-nucleotide variants in pancreatic cytology specimens collected by EUS-guided FNA.

BACKGROUND AND AIMS: EUS-guided FNA is recommended as a first-line procedure for the histopathologic diagnosis of pancreatic cancer. Molecular analysis of EUS-FNA samples might be used as an auxiliary tool to strengthen the diagnosis. The current study aimed to evaluate the diagnostic performances of K-ras testing using droplet digital polymerase chain reaction (ddPCR) and a novel single-nucleotide variant (SNV) assay performed on pancreatic EUS-FNA samples. METHODS: EUS-FNA specimens from 31 patients with pancreatic masses (22 pancreatic ductal adenocarcinomas, 7 chronic pancreatitis, and 2 pancreatic neuroendocrine tumors) were included in the study. K-ras testing was initially performed by ddPCR. In addition, mutational status was evaluated using an SNV assay by NanoString technology, using digital enumeration of unique barcoded probes to detect 97 SNVs from 24 genes of clinical significance. RESULTS: The overall specificity and sensitivity of cytologic examination were 100% and 63%, respectively. K-ras mutation testing was performed using ddPCR, and the sensitivity increased to 87% with specificity 90%. The SNV assay detected at least 1 variant in 90% of pancreatic ductal adenocarcinoma samples; the test was able to detect 2 K-ras codon 61 mutations in 2 cases of pancreatic ductal adenocarcinoma, which were missed by ddPCR. The overall diagnostic accuracy of the cytologic examination alone was 74%, and it increased to 91% when the results of both molecular tests were considered for the cases with negative and inconclusive results. CONCLUSIONS: The current study illustrated that integration of K-ras analysis with cytologic evaluation, especially in inconclusive cases, can enhance the diagnostic accuracy of EUS-FNA for pancreatic lesions.

EUS-through-the-needle microbiopsy forceps in pancreatic cystic lesions: A systematic review.

Pancreatic cystic lesions (PCLs) are being increasingly encountered in clinical practice, and sometimes, they can represent a diagnostic challenge. Recently, a through-the-needle micro forceps biopsy (MFB) device was introduced in the endosonography practice to facilitate EUS-guided sampling of PCLs. The aim was to perform a systematic review of studies evaluating the technical aspects, safety, and efficacy of the EUS-guided MFB for PCLs. A literature search was performed in three major databases, PubMed, Embase, and Web of Science in September 2019 using the search terms: "through-the-needle," "biopsy forceps," "microforceps," "endoscopic ultrasound," and "endosonography." Case reports and case series with <10 patients were excluded from the analysis. Altogether nine studies reporting on 463 patients were included in our systematic review. The mean age of the patients was 68.3 years, with a slight female predominance (60.9%). Most of the cysts were located in the body/tail of the pancreas (61.2%), with an overall mean size of 33 mm. The technical success of EUS-guided MFB was reported in 98.5%. The tissue acquisition yield reported was 88.2%, and the diagnostic accuracy was 68.6%. Adverse events were reported in 9.7%. EUS-guided MFB is technically feasible, safe, and has a high diagnostic accuracy for PCLs.

EUS and EUS-guided FNA/core biopsies in the evaluation of subepithelial lesions of the lower gastrointestinal tract: 10-year experience.

BACKGROUND AND OBJECTIVE: The widespread use of colonoscopy has led to an increasing number of subepithelial lesions (SELs) being detected in the lower gastrointestinal (GI) tract. This study aimed to analyze the utility of EUS and its role in the management of lower GI SELs. PATIENTS AND METHODS: Records of all patients who were referred for lower EUS evaluation of a SEL at a tertiary center between 2007 and 2018 were retrospectively reviewed after IRB approval. Data collection included patient/lesion characteristics, technical details of procedure, and pathology results. RESULTS: A total of 47 patients underwent EUS examinations for the evaluation of 49 suspected SEL in the lower GI tract (2 patients had 2 SELs each). Out of the 49 suspected lesions, the most frequent location was in the rectum (30/49, 61.2%). EUS showed extraluminal compression in 2 cases (2/49, 4.1%) and intraluminal lesions were identified in 40 cases (40/49, 81.6%). In 7 patients (7/49, 14.3%), no lesion could be identified by EUS. Twenty (20/49, 40.8%) SELs were malignant or had malignant potential. Twenty-six EUS-guided fine-needle aspirations (FNAs) and 14 EUS-core biopsies were performed. EUS-FNA alone was able to correctly diagnose 15/26 (57.7%) of the lower SELs. When EUS-guided fine needle biopsies (FNB) were performed during the same procedure, the final diagnosis was confirmed in 21/26 (80.8%) cases. There was only one procedure-related complication caused by use of narcotics. CONCLUSION: EUS-guided FNA/FNB are feasible and safe techniques for assessing lower GI SELs and provide valuable information regarding lesion characteristics and their malignant potential with high diagnostic accuracy.

Endoscopic Ultrasound-Guided Treatment of Pancreatic Cancer.

PURPOSE OF REVIEW: The aim of this review is to evaluate the emerging role of endoscopic ultrasound (EUS) in the guidance of tumor-targeted therapies for patients with pancreatic cancer (PC). RECENT FINDINGS: EUS-guided ablation, brachytherapy, fiducial marker placement, and antitumor agent injection have been described to date. EUS-guided fiducial placement for SBRT in pancreatic cancer has entered the clinical practice and is performed at many centers clinically without a research protocol. EUS-guided brachytherapy and RFA have been shown to be feasible and safe procedures, and potentially offer local disease control. Other potential techniques of EUS-guided treatment of pancreatic cancer are still considered experimental, with many of them appearing to be safe and reasonably well tolerated. However, their effectiveness and exact role in oncological treatment have yet to be established. Clinical trials with many of the techniques/agents described are underway and multicentric randomized trials with prospective design are eagerly awaited.

Clinical impact of strain histogram EUS elastography and contrast-enhanced EUS for the differential diagnosis of focal pancreatic masses: A prospective multicentric study.

BACKGROUND: Recent advances in EUS techniques (real-time EUS elastography and contrast-enhanced EUS) have allowed a better characterization of focal pancreatic masses. Mean strain histograms (SHs) are considered a good parameter for the semi-quantitative evaluation of focal pancreatic masses, alongside complementary contrast-enhanced EUS parameters which can be quantified during both the early arterial and late venous phase. MATERIALS AND METHODS: The study design was prospective, blinded, and multicentric, assessing real-time EUS elastography and contrast-enhanced EUS results for the characterization of focal pancreatic masses using parametric measurements, in comparison with pathology which is the gold standard. SHs were performed based on the embedded software of the ultrasound system, with the values being reversed as opposed to our initially published data on hue histograms. Consequently, a cutoff of 80 was derived from previous multicentric trials. Contrast-enhanced EUS also allowed the focal masses to be classified as hyper-, iso-, or hypoenhanced in comparison with the normal pancreatic parenchyma. EUS-FNA was then performed for all patients, with a positive cytological diagnosis taken as a final proof of malignancy for the pancreatic masses. The diagnoses obtained by EUS-FNA were verified further either by surgery or during a clinical follow-up of at least 6 months. RESULTS: A total number of 97 consecutive patients with focal pancreatic masses were included in the study. Based on previously defined cutoffs of 80, the values of sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of the mean SHs for the diagnosis of pancreatic cancer were 100%, 29.63%, 78.65%, 100%, and 80.41%, respectively. Corresponding values for contrast-enhanced EUS (taking into consideration hypoenhencement as a predictive factor of malignancy) were 98.57%, 77.78%, 92%, 95.45%, and 92.78%, respectively. Combining contrast enhancement-EUS (hypoenhencement) and semi-quantitative EUS elastography (SH cutoffs <80), the resulting values corresponding for sensitivity, specificity, and accuracy were 98.57%, 81.48%, and 93.81%, respectively. CONCLUSION: The current study using objective parametric tools for both EUS elastography and contrast-enhanced EUS confirmed the results of previous studies and meta-analyses that indicated a complementary role for the differential diagnosis of focal pancreatic masses. Moreover, the best values for the receiver operating curves were obtained using a sequential clinical algorithm based on the initial use of elastography, followed by contrast enhancement.

Upfront molecular profiling of pancreatic cancer patients - An idea whose time has come.

Pancreatic cancer patients have not benefited from survival improvements brought about by personalized medicine in other malignancies. Even though this is the era of precision medicine, unfortunately most clinicians in practice either do not embrace or are unaware of the concept of molecular profiling for pancreatic cancer patients. Improving the grim prognosis of this challenging disease requires a paradigm shift. To exploit all potential therapeutic options in this lethal disease, molecular profiling should be performed ideally at the moment of diagnosis to identify potentially trial-eligible tumoral mutations or support off label use of an agent approved for another indication. This perspective article aims to increase awareness of the importance of upfront molecular profiling for pancreatic cancer patients.

Role of gastrointestinal endoscopy in the screening of digestive tract cancers in Europe: European Society of Gastrointestinal Endoscopy (ESGE) Position Statement.

In Europe at present, but also in 2040, 1 in 3 cancer-related deaths are expected to be caused by digestive cancers. Endoscopic technologies enable diagnosis, with relatively low invasiveness, of precancerous conditions and early cancers, thereby improving patient survival. Overall, endoscopy capacity must be adjusted to facilitate both effective screening programs and rigorous control of the quality assurance and surveillance systems required. 1 : For average-risk populations, ESGE recommends the implementation of organized population-based screening programs FOR COLORECTAL CANCER: , based on fecal immunochemical testing (FIT), targeting individuals, irrespective of gender, aged between 50 and 75 years. Depending on local factors, namely the adherence of the target population and availability of endoscopy services, primary screening by colonoscopy or sigmoidoscopy may also be recommendable. 2 : In high-risk populations, endoscopic screening FOR GASTRIC CANCER: should be considered for individuals aged more than 40 years. Its use in countries/regions with intermediate risk may be considered on the basis of local settings and availability of endoscopic resources. 3 : For esophageal and pancreatic cancer, endoscopic screening may be considered only in high-risk individuals:- FOR SQUAMOUS CELL CARCINOMA: , in those with a personal history of head/neck cancer, achalasia, or previous caustic injury; - FOR BARRETT'S ESOPHAGUS (BE)-ASSOCIATED ADENOCARCINOMA: , in those with long-standing gastroesophageal reflux disease symptoms (i. e., > 5 years) and multiple risk factors (age ≥ 50 years, white race, male sex, obesity, first-degree relative with BE or esophageal adenocarcinoma [EAC]). - FOR PANCREATIC CANCER SCREENING: , endoscopic ultrasound may be used in selected high-risk patients such as those with a strong family history and/or genetic susceptibility.

Evaluation of the Visibility and Artifacts of 11 Common Fiducial Markers for Image Guided Stereotactic Body Radiation Therapy in the Abdomen.

PURPOSE: The purpose of this study was to quantitatively evaluate the visibility and artifacts of commercially available fiducial markers to optimize their selection for image guided stereotactic body radiation therapy. METHODS AND MATERIALS: From 6 different vendors, we selected 11 fiducials commonly used in image guided radiation therapy. The fiducials varied in material composition (e.g., gold, platinum, carbon), shape (e.g., cylindrical, notched/linear, coiled, ball-like, step), and size measured in terms of diameter (0.28-1.0 mm) and length (3.0-20.0 mm). Each fiducial was centered in 4-mm bolus within a 13-cm-thick water-equivalent phantom. Fiducials were imaged with the use of a simulation computed tomography (CT) scanner, a CT-on-rails system, and an onboard cone beam CT system. Acquisition parameters were set according to clinical protocols. Visibility was assessed in terms of contrast (Δ Hounsfield unit [HU]) and the Michelson visibility metric. Artifacts were quantified in terms of relative standard deviation and relative streak artifacts level (rSAL). Twelve radiation oncologists ranked each fiducial in terms of clinical usefulness. RESULTS: Contrast and artifacts increased with fiducial size. For CT imaging, maximum contrast (2722 HU) and artifacts (rSAL = 2.69) occurred for the largest-diameter (0.75 mm) platinum fiducial. Minimum contrast (551 HU) and reduced artifacts (rSAL = 0.65) were observed for the smallest-diameter (0.28 mm) gold fiducial. Carbon produced the least severe artifacts (rSAL = 0.29). The survey indicated that physicians preferred gold fiducials with a 0.35- to 0.43-mm diameter, 5- to 10-mm length, and coiled or cylindrical shape that balanced contrast and artifacts. CONCLUSIONS: We evaluated 11 different fiducials in terms of visibility and artifacts. The results of this study may assist radiation oncologists who seek to maximize contrast, minimize artifacts, or balance contrast versus artifacts by fiducial selection.

Quality of life impact of EUS in patients at risk for developing pancreatic cancer.

BACKGROUND AND OBJECTIVES: The current knowledge about the psychological impact of pancreatic cancer (PC) screening is limited. We aimed to assess the changes in quality of life (QOL) and level of distress after undergoing EUS in individuals with pancreatic cystic lesions (PCLs) and in patients at high risk for PC based on genetic and familial factors. METHODS: Eighty patients with PCL and/or increased genetic or familial risk for PC who had undergone EUS were contacted. Fifty percent of those patients successfully completed the brief profile of mood states (POMS) and the linear analog scale assessment (LASA) QOL questionnaires to evaluate their pre/post-EUS overall QOL. The effect size (ES) method was used to assess clinically meaningful changes in the scores. RESULTS: There was a significant difference in patients' overall QOL scores before and after the EUS procedure (LASA, mean difference 0.73, standard deviation (SD) 1.76, ES 0.58, P < 0.01; brief POMS, mean difference -5.46, SD -6.72, ES 0.81, P < 0.01). CONCLUSIONS: QOL of patients with PCL or increased risk factors for PC is significantly improved after a EUS/EUS-guided fine-needle aspiration (FNA) negative for malignancy.