Presentation, Diagnosis, and Treatment of a Sporadic Gastrinoma With Liver Metastases.

A gastrinoma is a rare and potentially deadly tumor. Gastrinomas can be difficult to detect at first, given that affected patients can present with nonspecific symptoms, such as anemia, weight loss, and diarrhea, leading to a large list of differentials. The symptoms can be hard to manage, and the treatment almost always includes surgical intervention. Gastrinomas often metastasize to the liver, in which case, the only curative treatment option is surgical resection of the primary tumor along with as many metastatic lesions as possible. This report reviews the case of a 59-year-old female who presented with symptoms of anemia and an upper gastrointestinal bleed, who was discovered to have a pancreatic gastrinoma with more than 12 liver metastases. It also describes the management of her critical condition, which was used to give her the best chance of survival.

Sporadic Zollinger-Ellison syndrome in a patient with isolated mesenteric gastrinoma.

INTRODUCTION: Zollinger-Ellison syndrome (ZES) is due to a gastrin-producing neuroendocrine tumor (gastrinoma) with subsequent gastric acid hypersecretion, gastroesophageal reflux disease (GERD), peptic ulcers, and chronic diarrhea. CASE PRESENTATION: A 40-year old patient presented with epigastric pain associated with diarrhea evolving for 10 years, he has been treated by acid-suppressive medications without substantial clinical improvement. Gastro-duodenal endoscopy was performed with gastric biopsies that showed peptic ulcerations, a serum gastrin assay that showed high levels exceeding 10 times the upper limit of the normal range. The abdominal contrast-enhanced computed tomography scan (CT-Scan) showed a solid-cystic mass with contrast enhancement in the right colon mesentery. The histopathological analysis of the resected mass showed a well-differentiated neuroendocrine tumor, and the diagnosis of a sporadic Zollinger-Ellison syndrome (ZES) was disclosed. Eighteen months after the surgical treatment the patient has no symptoms of the disease. CLINICAL DISCUSSION: Patients with ZES present often with long-standing clinical symptoms with delayed diagnosis. The surgical resection of the causative gastrinoma remains the most effective therapeutic treatment. CONCLUSION: Patients with refractory chronic diarrhea and epigastric pain should be suspected of having ZES in order to benefit from adequate clinical management.

Sporadic gastrinoma with refractory benign esophageal stricture: A case report.

BACKGROUND: Gastrinoma is characterized by an excessive release of gastrin, leading to hypersecretion of gastric acid, subsequently resulting in recurrent peptic ulcers, chronic diarrhea, and even esophageal strictures. This case report aims to improve awareness and facilitate early diagnosis and treatment of gastrinoma by presenting a rare case of gastrinoma with refractory benign esophageal stricture (RBES). Additionally, it highlights the persistent challenges that gastroenterologists encounter in managing RBES. CASE SUMMARY: This case demonstrates a patient with gastrinoma who developed RBES and complete esophageal obstruction despite management with maximal acid suppressive therapy, multiple endoscopic bougie dilations and endoscopic incisional therapy (EIT). CONCLUSION: It is essential to diagnose gastrinoma as early as possible, as inadequately controlled acid secretion over an extended period increases the risk of developing severe esophageal strictures. In patients with esophageal strictures causing complete luminal obstruction, blind reopening EIT presents challenges and carries a high risk of perforation.

The cckOMA syndrome and its relation to the Zollinger-Ellison syndrome: a diagnostic challenge.

OBJECTIVE: Among patients with enteropancreatic neuroendocrine tumor syndromes only one case with a cholecystokinin (CCK) secreting tumor has been reported. She had significant hyperCCKemia leading to a specific syndrome of severe diarrheas, weight loss, repeated duodenal ulcers and a permanently contracted gallbladder with gallstones. There are, however, reasons to believe that further CCKomas exist, for instance among Zollinger-Ellison patients with normal plasma gastrin concentrations. The present review is a call to gastroenterologists for awareness of such CCKoma patients. METHOD: After a short case report, the normal endocrine and oncological biology of CCK is described. Subsequently, the CCKoma symptoms are discussed with particular reference to the partly overlapping symptoms of the Zollinger-Ellison syndrome. In this context, the diagnostic use of truly specific CCK and gastrin assays are emphasized. The discussion also entails the problem of access to accurate CCK measurements. CONCLUSION: Obviously, the clinical awareness about the CCKoma syndrome is limited. Moreover, it is also likely that the knowledge about the necessary specificity demands of diagnostic gastrin and CCK assays have obscured proper diagnosis of the CCKoma syndromes in man.

Severe esophageal stricture after perforation and necrotizing esophagitis: unusual presentation of a duodenal gastrinoma.

Gastrinomas are pancreatic or duodenal endocrine tumors that secrete excess gastrin, which causes gastroesophageal reflux disease, peptic ulcers, and chronic diarrhea. Due to the rarity of the disease, nonspecific symptoms, and the outstanding effect of proton pump inhibitors, diagnosing gastrinomas is difficult. Here, we present the case of a 58-year-old woman who had a duodenal gastrinoma that caused rare but critical events, including esophageal perforation, necrotizing esophagitis, and severe esophageal stricture. She presented with a non-malignant severe lower esophageal stricture, which was resistant to endoscopic dilatation. During esophagectomy, a duodenal mass was excised and diagnosed as gastrinoma. This was considered the main cause of all events. Gastrinomas are rarely encountered in clinical practice, but early diagnosis is necessary to avoid serious conditions. Therefore, whenever we encounter a patient with gastroesophageal reflux disease requiring long-term treatment or is refractory, we must not forget to screen for gastrinomas.

Complete Esophageal Obstruction: A Rare Complication of Zollinger-Ellison Syndrome.

Complete esophageal obstruction (CEO) is a rare phenomenon usually observed after receiving head and neck radiation. Zollinger-Ellison syndrome (ZES) is typically associated with minimal esophageal morbidity because of advancements in antisecretory medications. There are currently no documented reports of CEO in patients with ZES. Although surgeries are available for the treatment of CEO, there is no established method for endoscopic lumen restoration, given its rarity. This case documents potential sequala of modern-day patients with ZES.

Multiple endocrine neoplasia type 1 with Zollinger-Ellison syndrome: clinicopathological analysis of a Japanese family with focus on menin immunohistochemistry.

Background: Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant disorder characterized by the occurrence of multiple epithelial neuroendocrine tumors (NETs) and non-NETs in various organs. MEN1 encodes a 610-amino acid-long tumor suppressor protein, menin. The optimal treatment for multiple tumors, identification of the most critical tumors for patient prognosis, and menin immunohistochemistry findings remain controversial. Therefore, we aimed to elucidate these issues through a histological analysis of tumors and tumor-like lesions in a Japanese family, comprising a father and his two sons, who had MEN1 with Zollinger-Ellison syndrome (ZES). Patients and methods: All family members had a germline alteration in exon 10, c.1714-1715 del TC of MEN1, and exhibited multiple synchronous and metachronous tumors. The patients had pulmonary NETs, hyperparathyroidism, hypergastrinemia, pituitary adenomas, pancreaticoduodenal NETs, adrenocortical adenoma with myelolipoma, nodular goiter of the thyroid, lipomas, and angiofibroma. Most tumors were resected and histologically examined. We compared their clinical courses and tumor histology, and conducted menin immunohistochemistry (IHC). Results: Two patients died of pulmonary NET G2. One patient who underwent pancreaticoduodenectomy was cured of ZES; however, the two other patients who did not undergo pancreaticoduodenectomy suffered persistent ZES despite treatment with octreotide. Menin IHC revealed varying NET intensities, ranging from positive to negative stains. Conclusion: Pancreaticoduodenectomy is the most effective treatment for ZES. Long-term follow-up is essential for pulmonary NET G2 owing to the risk of distant metastasis and/or multiplicity. Moreover, the variability of menin IHC in MEN1-related tumors may indicate the pattern of tumor formation rather than the diagnostic utility of menin in MEN1.

Esophageal Perforation Unveiling the Diagnosis of Zollinger-Ellison Syndrome.

Gastrinomas are the most common neuroendocrine tumors worldwide and cause a clinical syndrome known as Zollinger-Ellison Syndrome (ZES). Increased acid production resulting from elevated gastrin levels contributes to symptoms such as abdominal pain, heartburn, and diarrhea. However, the non-specificity and overlap in the symptoms with idiopathic peptic ulcer disease and gastroesophageal reflux disease (GERD) can lead to delayed diagnosis. In this case, we describe a patient with a past medical history of GERD and a perforated gastric ulcer who continued to experience symptoms of dyspepsia and had a subsequent esophageal perforation, despite H. pylori eradication and high-dose proton pump inhibitor (PPI) therapy. Multiple ulcers were visualized in the first portion of the duodenum, and metastatic lesions were demonstrable in the liver. Serum gastrin level was elevated to 433 pg/mL. Histology of liver biopsy showed a well-differentiated neuroendocrine tumor, supporting the diagnosis of ZES. This article underscores the significance of considering ZES in the differential in cases of refractory gastric hyperacidity and the importance of early diagnosis with serum gastrin testing to prevent complications such as gastric obstruction, perforation, hemorrhage, esophageal strictures, or rupture and to minimize the risk of metastasis. It is noteworthy that while perforations in cases of ZES typically occur in the duodenum, this particular case is atypical as it had involved the stomach. Furthermore, it was associated with esophageal perforation, likely resulting from forceful and prolonged vomiting caused by persistent dyspepsia.

A Rare Case of Hepatic Gastrinoma.

Zollinger-Ellison syndrome (ZES) is a rare condition caused by gastrin-secreting neuroendocrine tumors known as gastrinomas. We present a case of hepatic ZES presenting as upper gastrointestinal (GI) bleeding in a 70-year-old female. Initial evaluation revealed the patient to be in severe sepsis with septic shock secondary to a urinary tract infection, and her hospitalization was complicated by hematemesis and melena in the setting of multiple duodenal ulcers. Subsequent investigations, including elevated gastrin levels and a somatostatin receptor scan, confirmed the diagnosis of gastrinoma.

Typical Zollinger-Ellison syndrome-atypical location of gastrinoma and absence of hypergastrinemia: A case report and review of literature.

BACKGROUND: Zollinger-Ellison syndrome (ZES) results from hypersecretion of gastrin from pancreatic or duodenal neuroendocrine tumors, commonly referred to as gastrinomas. The high levels of gastrin lead to a typical presentation involving watery diarrhea and multiple ulcers in the duodenum. Here, we have presented the rare case of a patient with ZES and absence of hypergastrinemia as well as an atypical location of gastrinoma. CASE SUMMARY: A 72-year-old woman presented with the typical clinical manifestations of ZES, including upper abdominal pain, significant watery diarrhea, and acidic liquid vomitus. Surprisingly, however, she did not have an increased level of serum gastrin. In addition, there was no evidence of gastrinoma or any other ulcerogenic tumor. Esophagogastroduodenoscopy was conducted to examine the upper digestive tract. Revised diagnoses were considered, and an individualized treatment plan was developed. The patient responded to antacid medication while experiencing intermittent, recurring bouts of ZES. 18F-AlF-NOTA-octreotide positron emission tomography (18F-OC PET)/computed tomography (CT) helped locate the tumor. Postoperative pathology and immunohistochemistry results suggested that the tumor was a gastrinoma located at an unconventional site. CONCLUSION: This present case study demonstrates the possibility of ZES-like manifestation in patients with absence of hypergastrinemia. 18F-OC PET/CT is a relatively new imaging technique that can be applied for diagnosing even tiny gastrinomas that are atypical in terms of location.

Closed-Loop Gastric Outlet Obstruction Secondary to Duodenal Ulcer in a Patient With Esophageal Stricture.

Closed-loop gastric outlet obstruction (GOO) is a rare complication that results from a mechanical obstruction in the pylorus or duodenum. In the early 1990s, the common cause of GOO was peptic ulcer disease, accounting for 5% to 10% of hospital admissions. Peptic ulcer disease is the disruption of the mucosal integrity in the stomach and duodenum and can be categorized into gastric ulcers and duodenal ulcers. With the treatment for Helicobacter  pylori and the increased use of proton pump inhibitors (PPI), GOO now occurs in fewer than 5% of patients with duodenal ulcer disease and even less in those with gastric ulcer disease. Although the morbidity of duodenal ulcers has been declining in recent years, the incidence of post-bulbar duodenal ulcer (PBDU) remains at a constant 9.33%, primarily due to diagnostic and therapeutic difficulties. Additionally, fewer than 5% of obstructing duodenal ulcers are caused by PBDU, and even fewer are located in the second or third portions of the duodenum. Ulcers located in the distal part of the duodenum raise concern for syndromes associated with hypersecretion of acid, including Zollinger-Ellison syndrome (ZES). The ZES is rare, accounting only for 0.1% of all duodenal ulcers. Here, we present a case where a patient with esophageal stricture developed a rare case of closed-loop GOO secondary to a duodenal ulcer. The patient, initially treated for esophageal perforation, developed an esophageal stricture. The patient was being worked up for ZES and multiple endocrine neoplasia link type 1 (MEN1) syndrome due to his concerning laboratory findings and rare clinical presentation.

All you need to know about gastrinoma today | Gastrinoma and Zollinger-Ellison syndrome: A thorough update.

Zollinger-Ellison syndrome (ZES) is a distinct syndrome characterized by hyperchlorhydria-induced peptic ulcer disease and chronic diarrhea. It is the result of a gastrin-excess state caused by a duodenal or pancreatic neuroendocrine tumor referred to as gastrinoma. This gastrin-secreting neuroendocrine tumor is usually sporadic in nature, or part of multiple endocrine neoplasia type 1 syndrome. The high rate of malignancy associated with gastrinomas substantiates the need for early diagnosis. In order to diagnose ZES with laboratory tests, patients under antacid medication are required to stay off proton pump inhibitors for at least one week and H2 receptor antagonists for 48 h. Fasting serum gastrin level measurement serves as an initial and fundamental diagnostic test, boasting a sensitivity of 99%. Gastrinoma patients will present with a gastrin level greater than 100 pg/mL, while a serum gastrin level higher than 1000 pg/mL, in the presence of gastric pH <2, is considered diagnostic. Since more common causes of hypergastrinemia exist in the setting of hypochlorhydria, ruling those out should precede ZES consideration. Such causes include atrophic gastritis, Helicobacter pylori (H. pylori)-associated pangastritis, renal failure, vagotomy, gastric outlet obstruction and retained antrum syndrome. The secretin stimulation test and the calcium gluconate injection test represent classic adjuvant diagnostic techniques, while alternative approaches are currently being introduced and evaluated. Specifically, the secretin stimulation test aids in differentiating ZES cases from other hypergastrinemic states. Its principle is based on secretin stimulation of gastrinoma cells to secrete gastrin, while inhibiting normal G cells. The rapid intravenous infusion of 4 µg/kg secretin over 1 min is followed by gastrin level evaluation at specific intervals post-infusion. Localization of the primary tumor and its metastases is the next diagnostic step when gastrinoma-associated ZES is either suspected or biochemically confirmed. Endoscopic ultrasound has showcased sensitivity as high as 83% for pancreatic gastrinomas and is considered the primary modality in such cases, although its tumor detection rates are substantially lower in duodenal lesions. Gallium-68 radiotracers, especially DOTATOC with positron emission tomography, are currently setting the standard in tumor localization, enhancing traditional imaging techniques and showcasing high sensitivity and specificity. Although gastrinomas have been reported in various anatomic locations, the vast majority arise in a specific site named the "gastrinoma triangle", involving parts of the duodenum, pancreas and extra-hepatic biliary system. Proton pump inhibitors serve as the cornerstone of symptomatic ZES treatment. Surgery is routinely performed in localized sporadic ZES, irrespective of imaging results. ZES in multiple endocrine neoplasia type 1 requires work-up for evaluation and treatment of hyperparathyroidism, while surgery might be an option for selected cases. In cases of advanced and metastatic disease, there is a variety of potential treatments, ranging for somatostatin analogs to chemotherapeutic drugs, liver-directed therapies and liver transplantation, while neither hepatic metastases, nor locally invasive disease necessarily preclude surgical management. This article thoroughly and critically reviews available literature and provides an extensive and multidimensional overview of ZES, along with current controversies regarding management of this disease.

Successful Lifetime/Long-Term Medical Treatment of Acid Hypersecretion in Zollinger-Ellison Syndrome (ZES): Myth or Fact? Insights from an Analysis of Results of NIH Long-Term Prospective Studies of ZES.

Analysis of the efficacy/pharmacology of long-term/lifetime medical treatment of acid hypersecretion in a large cohort of ZES patients in a prospective study. This study includes the results from all 303 patients with established ZES who were prospectively followed and received acid antisecretory treatment with either H2Rs or PPIs, with antisecretory doses individually titrated by the results of regular gastric acid testing. The study includes patients treated for short-term periods (<5 yrs), patients treated long-term (>5 yrs), and patients with lifetime treatment (30%) followed for up to 48 years (mean 14 yrs). Long-term/lifelong acid antisecretory treatment with H2Rs/PPIs can be successfully carried out in all patients with both uncomplicated and complicated ZES (i.e., with MEN1/ZES, previous Billroth 2, severe GERD). This is only possible if drug doses are individually set by assessing acid secretory control to establish proven criteria, with regular reassessments and readjustments. Frequent dose changes both upward and downward are needed, as well as regulation of the dosing frequency, and there is a primary reliance on the use of PPIs. Prognostic factors predicting patients with PPI dose changes are identified, which need to be studied prospectively to develop a useful predictive algorithm that could be clinically useful for tailored long-term/lifetime therapy in these patients.

Ga-68 DOTATATE PET/CT in a patient with Zollinger-Ellison syndrome.

This case report follows a 70-year-old male patient with Zollinger-Ellison syndrome undergoing computed tomography (CT) for weight loss and surveillance of bilateral adrenal nodules. Incidentally, diffuse gastric and duodenal wall thickening was noted on CT. The patient underwent esophagogastroduodenoscopy with biopsy results showing well-differentiated neuroendocrine tumors (NET) in the stomach and duodenum. Subsequent imaging with gallium-68 DOTATATE PET/CT showed intense tracer uptake in the stomach and proximal duodenum with liver and regional nodal metastases around the superior mesenteric artery. This case outlines the utility of Ga-68 DOTATATE PET/CT in diagnosing, localizing, and staging NET such as gastrinomas.

[Gastroenteropancreatic neuroendocrine tumors : (GEP-NENs)]. / Neuroendokrine Neoplasien des Gastrointestinaltrakts : (GEP-NENs).

The entity of NENs represent a highly heterogenous group of malignancies that require a multidisciplinary approach during the treatment of patients. The following article aims to provide a concise overview of the current state of the art in diagnostics and therapy. One specific feature of G1/G2 NENs is that the indication for surgery is given even in metastatic settings. Specific details regarding the treatment of its various different subgroups need to be gathered from available guidelines or current clinical studies. The field of nuclear medicine offers promising options for diagnostics and therapy which needs further investigation.

Sporadic and MEN1-related gastrinoma and Zollinger-Ellison syndrome: differences in clinical characteristics and survival outcomes.

PURPOSE: Gastrinoma with Zollinger-Ellison syndrome (ZES) may occur sporadically (Sp) or as part of the inherited syndrome of multiple endocrine neoplasia 1 (MEN-1). Data comparing Sp and MEN-1/ZES are scanty. We aimed to identify and compare their clinical features. METHODS: Consecutive patients with ZES were evaluated between 1992 and 2020 among a monocentric Italian patient cohort. RESULTS: Of 76 MEN-1 patients, 41 had gastroenteropancreatic neuroendocrine neoplasm (GEP-NEN), 18 of whom had ZES; of 320 Sp-GEP-NEN, 19 had Sp-ZES. MEN-1/ZES patients were younger (p = 0.035) and the primary MEN-1/ZES gastrinoma was smaller than Sp-ZES (p = 0.030). Liver metastases occurred in both groups, but only Sp-ZES developed extrahepatic metastases. 13 Sp-ZES and 8 MEN-1/ZES underwent surgery. 8 Sp-ZES and 7 MEN-1/ZES received somatostatin analogs (SSAs). Median overall survival (OS) was higher in MEN-1/ZES than in Sp-ZES (310 vs 168 months, p = 0.034). At univariate-logistic regression, age at diagnosis (p = 0.01, OR = 1.1), G3 grading (p = 0.003, OR = 21.3), Sp-ZES (p = 0.02, OR = 0.3) and presence of extrahepatic metastases (p = 0.001, OR = 7.2) showed a significant association with OS. At multivariate-COX-analysis, none of the variables resulted significantly related to OS. At univariate-logistic regression, age (p = 0.04, OR = 1.0), size (p = 0.039, OR = 1.0), G3 grade (p = 0.008, OR = 14.6) and extrahepatic metastases (p = 0.005, OR = 4.6) were independently associated with progression-free survival (PFS). In multivariate-COX-analysis, only extrahepatic metastases (p = 0.05, OR = 3.4) showed a significant association with PFS. Among SSAs-treated patients, MEN-1/ZES showed better PFS (p = 0.0227). After surgery, the median PFS was 126 and 96 months in MEN-1 and Sp, respectively. CONCLUSION: MEN-1/ZES patients generally show better OS and PFS than Sp-ZES as well as better SSAs response.

Primary gastrinoma of the gallbladder: a case report and review of the literature.

Background: Primary gallbladder gastrinoma is an exceptionally uncommon tumor and is a rare form of neuroendocrine neoplasm. Until now, no cases of primary gallbladder gastrinoma and rare cases of primary gastrinoma from the biliary system have been reported. Case presentation: We report a case of a 50-year-old woman with watery diarrhea who intermittently received proton pump inhibitors (PPIs) as treatment. A serum gastrin level of 711 pg/ml was recorded after the withdrawal of PPI over 1 week. Enhanced computed tomography (CT) imaging and octreotide imaging uncovered a solitary tumor at the hepatic hilar region. During the laparoscopic surgery, it was determined that the tumor had its origin in the wall of the gallbladder neck, prompting the implementation of a laparoscopic cholecystectomy. Histological analysis revealed a primary neuroendocrine tumor from the neck of the gallbladder. The patient's symptoms disappeared after the surgery with a follow-up of 6 months. Conclusions: This case confirmed that primary gallbladder gastrinoma represents a distinct nosological entity. Immunohistochemical analysis plays a pivotal role in the diagnostic process. Given the limited understanding of primary gallbladder gastrinoma, our objective is to offer novel insights into this rare disease by delivering distinctive information and highlighting the therapeutic significance of surgical intervention.

A survey on the incidence of common musculoskeletal side effects among the patients taking long-term anti-ulcerant therapies in Bangladesh.

Background: Proton pump inhibitors (PPIs) and H2 blockers are commonly prescribed medications to treat ulcers in the stomach and the upper part of the small intestine and prescribed for some other common gastrointestinal complications such as gastroesophageal reflux disease, esophagitis, irritable bowel syndrome, and dyspepsia. Previous studies claimed that, apart from other side effects, these anti-ulcerant therapies significantly altered bone mineral density by interfering with intestinal reabsorption of minerals and vitamin B12, and the most widely prescribed PPIs were significantly associated with increased risks of hip and spine fractures. However, the potential skeletal side effects of these antiulcerants are unknown in Bangladesh. Methods: To examine safety concerns of anti-ulcer therapies and their impact on musculoskeletal health among patients in Bangladesh, the present work surveyed 200 patients in five different hospitals from December 2019 to February 2020. Results: The current study revealed that most respondents (95 %) received PPIs for gastrointestinal indications while the rest were taking H2 receptor antagonists for their gastric ailments. Most patients taking PPIs alone (> 3 years; 95 % of respondents) claimed some unusual musculoskeletal side effects, such as weakness, flank pain, spasm of hands and feet, muscle aches, numbness, and tremor. About 61 % of patients taking PPIs experienced low back pain whereas the respondents with neck pain and knee joint pain were 10 % and 7 %, respectively. However, few osteopenia and osteoporotic incidences have been also recorded. Although further studies are required to confirm the impact of these antiulcerants on the bone, these patient responses suggest that these musculoskeletal side effects might have some links with altered bone metabolism. Conclusions: It is possible that anti-ulcerant therapies may worsen the bone metabolism of patients suffering from osteoporosis or other bone disorders, and awareness and precautions should be raised among the patients and clinicians for the careful administration of PPIs to patients suffering from bone disorders.

Radiological Features of Zollinger-Ellison Syndrome: A Report of Two Cases.

Hypersecretion of gastrin from duodenal or pancreatic gastrinomas results in a rare clinical entity called Zollinger-Ellison syndrome (ZES). It mostly presents with abdominal pain and diarrhea. ZES may be sporadic or occur in association with multiple endocrine neoplasia type 1. Usually, ZES manifests between 20 and 50 years. We report two cases of patients who presented with abdominal pain, vomiting, watery diarrhea, and significant weight loss.