Interleukin 10 (IL-10) is an important anti-inflammatory cytokine. To examine its role in virus-induced encephalomyelitis, IL-10-deficient (IL-10 −/−) mice were infected with a neurotropic strain of mouse hepatitis virus (JHMV). JHMV-infected IL-10 −/− mice, compared to IL-4 −/− and syngeneic C57BL/6 mice, exhibited increased morbidity and mortality. Virus was cleared from the CNS of all groups of mice with equal kinetics by day 9 postinfection and the lack of either IL-4 or IL-10 did not alter the distribution of viral antigen, suggesting a lack of correlation between viral replication and the increased clinical disease in IL-10 −/− mice. In moribund IL-10 −/− mice, a moderate increase in mononuclear cell infiltration was correlated with increased expression of tumor necrosis factor-α, interferon-γ, and inducible nitric oxide synthase mRNAs. In the small percentage of IL-10 −/− mice that survived, no differences in either demyelination or inflammation were observed. Together, these results suggest that IL-10 is not required for viral clearance, and although it appears to be one of the mechanisms responsible for inhibiting the extent of inflammation in the CNS during acute JHMV infection, it has little role in the eventual resolution of CNS inflammatory responses.

Background: Identifying patients at risk for early recurrence (ER) following resection for pancreatic neuroendocrine tumors (pNETs) might help to tailor adjuvant therapies and surveillance intensity in the post-operative setting. Methods: Patients undergoing surgical resection for pNETs between 1998–2018 were identified using a multi-institutional database. Using a minimum p-value approach, optimal cut-off value of recurrence-free survival (RFS) was determined based on the difference in post-recurrence survival (PRS). Risk factors for early recurrence were identified. Results: Among 807 patients who underwent curative-intent resection for pNETs, the optimal length of RFS to define ER was identified at 18 months (lowest p-value of 0.019). Median RFS was 11.0 months (95% 8.5–12.60) among ER patients (n = 49) versus 41.0 months (95% CI: 35.0–45.9) among non-ER patients (n = 77). Median PRS was worse among ER patients compared with non-ER patients (42.6 months vs. 81.5 months, p = 0.04). On multivariable analysis, tumor size (OR: 1.20, 95% CI: 1.05–1.37, p = 0.007) and positive lymph nodes (OR: 4.69, 95% CI: 1.41–15.58, p = 0.01) were independently associated with ER. Conclusion: An evidence-based cut-off value for ER after surgery for pNET was defined at 18 months. These data emphasized the importance of close follow-up in the first two years after surgery.

Background: The adoption of spleen-preserving distal pancreatectomy (SPDP) for malignant disease such as pancreatic neuroendocrine tumors (pNETs) has been controversial. The objective of the current study was to assess the impact of SPDP on outcomes of patients with pNETs. Methods: Patients undergoing a distal pancreatectomy for pNET between 2002 and 2016 were identified in the US Neuroendocrine Tumor Study Group database. Propensity score matching (PSM) was used to compare short- and long-term outcomes of patients undergoing SPDP versus distal pancreatectomy with splenectomy (DPS). Results: Among 621 patients, 103 patients (16.6%) underwent an SPDP. Patients who underwent SPDP were more likely to have lower BMI (median, 27.5 [IQR 24.0–31.2] vs. 28.7 [IQR 25.7–33.6]; p = 0.005) and have undergone minimally invasive surgery (n = 56, 54.4% vs. n = 185, 35.7%; p < 0.001). After PSM, while the median total number of lymph nodes examined among patients who underwent an SPDP was lower compared with DPS (3 [IQR 1–8] vs. 9 [5–13]; p < 0.001), 5-year overall survival (OS) and recurrence-free survival (RFS) were comparable (OS: 96.8 vs. 92.0%, log-rank p = 0.21, RFS: 91.1 vs. 84.7%, log-rank p = 0.93). In addition, patients undergoing SPDP had less intraoperative blood loss (median, 100 mL [IQR 10–250] vs. 150 mL [IQR 100–400]; p = 0.001), lower incidence of serious complications (n = 13, 12.8% vs. n = 28, 27.5%; p = 0.014), and shorter length of stay (median: 5 days [IQR 4–7] vs. 6 days [IQR 5–13]; p = 0.049) compared with patients undergoing DPS. Conclusion: SPDP for pNET was associated with acceptable perioperative and long-term outcomes that were comparable to DPS. SPDP should be considered for patients with pNET.

Pancreatic neuroendocrine tumors (PNETs) are often indolent; however, identifying patients at risk for rapidly progressing variants is critical, particularly for those with small tumors who may be candidates for expectant management. Specific growth rate (SGR) has been predictive of survival in other malignancies but has not been examined in PNETs. A retrospective cohort study of adult patients who underwent PNET resection from 2000 to 2016 was performed utilizing the multi-institutional United States Neuroendocrine Study Group database. Patients with ≥ 2 preoperative cross-sectional imaging studies at least 30 days apart were included in our analysis (N = 288). Patients were grouped as “high SGR” or “low SGR.” Demographic and clinical factors were compared between the groups. Kaplan–Meier and log-rank analysis were used for survival analysis. Cox proportional hazard analysis was used to assess the impact of various clinical factors on overall survival (OS). High SGR was associated with higher T stage at resection, shorter doubling time, and elevated HbA1c (all P ≤ 0.01). Patients with high SGR had significantly decreased 5-year OS (63 vs 80%, P = 0.01) and disease-specific survival (72 vs 91%, P = 0.03) compared to those with low SGR. In patients with small (≤ 2 cm) tumors (N = 106), high SGR predicted lower 5-year OS (79 vs 96%, P = 0.01). On multivariate analysis, high SGR was independently associated with worse OS (hazard ratio 2.67, 95% confidence interval 1.05–6.84, P = 0.04). High SGR is associated with worse survival in PNET patients. Evaluating PNET SGR may enhance clinical decision-making, particularly when weighing expectant management versus surgery in patients with small tumors.

Objective: To improve the prognostic accuracy of the eighth edition of AJCC staging system for pNETs with establishment and validation of a new staging system. Background: Validation of the updated eighth AJCC staging system for pNETs has been limited and controversial. Methods: Data from the SEER registry (1975–2016) (n = 3303) and a multi-institutional database (2000–2016) (n = 825) was used as development and validation cohorts, respectively. A mTNM was proposed by maintaining the eighth AJCC T and M definitions, and the recently proposed N status as N0 (no LNM), N1 (1–3 LNM), and N2 (≥4 LNM), but adopting a new stage classification. Results: The eighth TNM staging system failed to stratify patients with stage I versus IIA, stage IIB versus IIIA, and overall stage I versus II relative to long-term OS in both database. There was a monotonic decrement in survival based on the proposed mTNM staging classification among patients derived from both the SEER (5-year OS, stage I 87.0% vs stage II 80.3% vs stage III 72.9% vs stage IV 57.2%, all P < 0.001), and multi-institutional (5-year OS, stage I 97.6% vs stage II 82.7% vs stage III 78.4% vs stage IV 50.0%, all P < 0.05) datasets. On multivariable analysis, mTNM staging remained strongly associated with prognosis, as the hazard of death incrementally increased with each stage among patients in the 2 cohorts. Conclusion: A mTNM pNETs clinical staging system using N0, N1, N2 nodal categories was better at stratifying patients relative to long-term OS than the eighth AJCC staging.

Background: Pancreatoduodenectomy (PD) or distal pancreatectomy (DP) are common procedures for patients with a pancreatic neuroendocrine tumor (pNET). Nevertheless, certain patients may benefit from a pancreas-preserving resection such as enucleation (EN). The aim of this study was to define the indications and differences in long-term outcomes among patients undergoing EN and PD/DP. Methods: Patients undergoing resection of a pNET between 1992 and 2016 were identified. Indications and outcomes were evaluated, and propensity score matching (PSM) analysis was performed to compare long-term outcomes between patients who underwent EN versus PD/DP. Results: Among 1034 patients, 143 (13.8%) underwent EN, 304 (29.4%) PD, and 587 (56.8%) DP. Indications for EN were small size (1.5 cm, IQR:1.0-1.9), functional tumors (58.0%) that were mainly insulinomas (51.7%). After PSM (n = 109 per group), incidence of postoperative pancreatic fistula (POPF) grade B/C was higher after EN (24.5%) compared with PD/DP (14.0%) (p = 0.049). Median recurrence free survival (RFS) was comparable among patients who underwent EN (47 months, 95% CI:23-71) versus PD/DP (37 months, 95% CI: 33-47, p = 0.480). Conclusion: Comparable long-term outcomes were noted among patients who underwent EN versus PD/DP for pNET. The incidence of clinically significant POPF was higher after EN.

BackgroundDeveloping the ability to use tumor-directed therapies to trigger potentially therapeutic immune responses against cancer antigens remains a high priority for cancer immunotherapy. We hypothesized that histotripsy, a novel non-invasive, non-thermal ablation modality that uses ultrasound-generated acoustic cavitation to disrupt tissues, could engender adaptive immune responses to tumor antigens.MethodsImmunocompetent C57BL/6 mice inoculated with flank melanoma or hepatocellular carcinoma tumors were treated with histotripsy, thermal ablation, radiation therapy, or cytotoxic T lymphocyte-associated protein-4 (CTLA-4) blockade checkpoint inhibition. Lymphocyte responses were measured using flow cytometric and immunohistochemical analyses. The impact of histotripsy on abscopal immune responses was assessed in mice bearing bilateral tumors, or unilateral tumors with pulmonary tumors established via tail vein injection.ResultsHistotripsy ablation of subcutaneous murine melanoma tumors stimulated potent local intratumoral infiltration of innate and adaptive immune cell populations. The magnitude of this immunostimulation was stronger than that seen with tumor irradiation or thermal ablation. Histotripsy also promoted abscopal immune responses at untreated tumor sites and inhibited growth of pulmonary metastases. Histotripsy was capable of releasing tumor antigens with retained immunogenicity, and this immunostimulatory effect was associated with calreticulin translocation to the cellular membrane and local and systemic release of high mobility group box protein 1. Histotripsy ablation potentiated the efficacy of checkpoint inhibition immunotherapy in murine models of melanoma and hepatocellular carcinoma.ConclusionsThese preclinical observations suggest that non-invasive histotripsy ablation can be used to stimulate tumor-specific immune responses capable of magnifying the impact of checkpoint inhibition immunotherapy.

Insurance status predicts access to medical care in the USA. Previous studies have shown uninsured patients with some malignancies have worse outcomes than insured patients. The impact of insurance status on patients with gastroenteropancreatic neuroendocrine tumors (GEP-NETs) is unclear. A retrospective cohort study of adult patients with resected GEP-NETs was performed using the US Neuroendocrine Tumor Study Group (USNETSG) database (2000–2016). Demographic and clinical factors were compared by insurance status. Patients ≥ 65 years were excluded, as these patients are almost universally covered by Medicare. Kaplan–Meier and log-rank analyses were used for survival analysis. Logistic regression was used to assess factors associated with overall survival (OS). The USNETSG database included 2022 patients. Of those, 1425 were aged 18–64 years at index operation and were included in our analysis. Uninsured patients were more likely to have an emergent operation (7.9% versus 2.5%, p = 0.01) and less likely to receive postoperative somatostatin analog therapy (1.6% versus 9.9%, p = 0.03). OS at 1, 5, and 10 years was significantly higher for insured patients (96.3%, 88.2%, and 73.8%, respectively) than uninsured patients (87.7%, 71.9%, and 44.0%, respectively) (p < 0.01). On Cox multivariate regression analysis controlling for T/M stage, tumor grade, ASA class, and income level, being uninsured was independently associated with worse OS [hazard ratio (HR) 2.69, 95% confidence interval (CI) 1.32–5.48, p = 0.006]. Insurance status is an independent predictor of survival in patients with GEP-NETs. Our study highlights the importance of access to medical care, disparities related to insurance status, and the need to mitigate these disparities.

Background and Objectives Lack of high-level evidence supporting adjuvant therapy for patients with resected gastroenteropancreatic neuroendocrine tumors (GEP NETs) warrants an evaluation of its non-standard of care use. Methods Patients with primary GEP NETs who underwent curative-intent resection at eight institutions between 2000 and 2016 were identified; 91 patients received adjuvant therapy. Recurrence-free survival (RFS) and overall survival (OS) were compared between adjuvant cytotoxic chemotherapy and somatostatin analog cohorts. Results In resected patients, 33 received cytotoxic chemotherapy, and 58 received somatostatin analogs. Five-year RFS/OS was 49% and 83%, respectively. Cytotoxic chemotherapy RFS/OS was 36% and 61%, respectively, lower than the no therapy cohort (P < .01). RFS with somatostatin analog therapy (compared to none) was lower (P < .01), as was OS (P = .01). On multivariable analysis, adjuvant cytotoxic therapy was negatively associated with RFS but not OS controlling for patient/tumor-specific characteristics (RFS P < .01). Conclusions Our data, reflecting the largest reported experience to date, demonstrate that adjuvant therapy for resected GEP NETs is negatively associated with RFS and confers no OS benefit. Selection bias enriching our treatment cohort for individuals with unmeasured high-risk characteristics likely explains some of these results; future studies should focus on patient subsets who may benefit from adjuvant therapy.

The ACS established an online risk calculator to help surgeons make patient-specific estimates of postoperative morbidity and mortality. Our objective was to assess the accuracy of the ACS-NSQIP calculator for estimating risk after curative intent resection for primary GI neuroendocrine tumors (GI-NETs). Adult patients with GI-NET who underwent complete resection from 2000 to 2017 were identified using a multi-institutional database, including data from eight academic medical centers. The ability of the NSQIP calculator to accurately predict a particular outcome was assessed using receiver operating characteristic curves and the area under the curve (AUC). Seven hundred three patients were identified who met inclusion criteria. The most commonly performed procedures were resection of the small intestine with anastomosis (N = 193, 26%) and partial colectomy with anastomosis (N = 136, 18%). The majority of patients were younger than 65 years (N = 482, 37%) and ASA Class III (N = 337, 48%). The most common comorbidities were diabetes (N = 128, 18%) and hypertension (N = 395, 56%). Complications among these patients based on ACS NSQIP definitions included any complication (N = 132, 19%), serious complication (N = 118, 17%), pneumonia (N = 7, 1.0%), cardiac complication (N = 1, 0.01%), SSI (N = 80, 11.4%), UTI (N = 17, 2.4%), venous thromboembolism (N = 18, 2.5%), renal failure (N = 16, 2.3%), return to the operating room (N = 27, 3.8%), discharge to nursing/rehabilitation (N = 22, 3.1%), and 30-day mortality (N = 9, 1.3%). The calculator provided reasonable estimates of risk for pneumonia (AUC = 0.721), cardiac complication (AUC = 0.773), UTI (AUC = 0.716), and discharge to nursing/rehabilitation (AUC = 0.779) and performed poorly (AUC < 0.7) for all other complications Fig. 1). The ACS-NSQIP risk calculator estimates a similar proportion of risk to actual events in patients with GI-NET but has low specificity for identifying the correct patients for many types of complications. The risk calculator may require modification for some patient populations.

Background The benefit derived from lymph node dissection (LND) in patients with pancreatic neuroendocrine tumors (pNETs) based on clinicopathological characteristics remains unclear. Methods Patients undergoing surgery for pNET between 1997 and 2016 were identified using a multi-institutional dataset. The therapeutic index of LND relative to patient characteristics was calculated. Results Among 647 patients, the median number of lymph nodes (LNs) evaluated was 10 (interquartile range: 4-16) and approximately one quarter of patients had lymph node metastasis (LNM) (N = 159, 24.6%). Among patients with LNM, 5-year recurrence-free survival was 56.0%, reflecting a therapeutic index value of 13.8. The therapeutic index was highest among patients with a moderately/poorly-differentiated pNET (21.5), Ki-67 >= 3% (20.1), tumor size >= 2.0 cm (20.0), and tumor location at the head of the pancreas (20.0). Patients with >= 8 LNs evaluated had a higher therapeutic index than patients who had 1 to 7 LNs evaluated (>= 8: 17.9 vs 1-7: 7.5; difference of index: 11.4). Conclusion LND was mostly beneficial among patients with pNETs >2 cm, Ki-67 >= 3%, and lesions located at the pancreatic head as identification of LNM was most common among individuals with these tumor characteristics. Evaluation of >= 8 LNs was associated with a higher likelihood of identifying LNM as well as a higher therapeutic index, and therefore this number of LNs should be considered the goal.

Background: Packed red blood cell (PRBC) transfusion has been associated with worse survival in multiple malignancies but its impact on pancreatic neuroendocrine tumors (PNETs) is unknown. The aim of this study was to determine the impact of PRBC transfusion on survival following PNET resection. Methods: A retrospective cohort study of PNET patients was performed using the US Neuroendocrine Tumor Study Group database. Demographic and clinical factors were compared. Kaplan-Meier and log-rank analyses were performed. Factors associated with transfusion, overall (OS), recurrence-free (RFS) and progression-free survival (PFS) were assessed by logistic regression. Results: Of 1129 patients with surgically resected PNETs, 156 (13.8%) received perioperative PRBC transfusion. Transfused patients had higher ASA Class, lower preoperative hemoglobin, larger tumors, more nodal involvement, and increased major complications (all p < 0.010). Transfused patients had worse median OS (116 vs 150 months, p < 0.001), worse RFS (83 vs 128 months, p < 0.01) in curatively resected (n = 1047), and worse PFS (11 vs 24 months, p = 0.110) in non-curatively resected (n = 82) patients. On multivariable analysis, transfusion was associated with worse OS (HR 1.80, p = 0.011) when controlling for TNM stage, tumor grade, final resection status, and pre-operative anemia. Conclusion: PRBC transfusion is associated with worse survival for patients undergoing PNET resection.

methacrylation (5% vs. 28%) and volume of the hydrogel.We experimentally evaluated 5 mg hydrogels loaded with 350 mg sunitinib (Figure 1 A,B) which released around 300,000 ng of sunitinib into cell culture.This dose was approximately 30x higher than the complete kill dose invitro fro QGP-1 and BON 1 (Figure 1C).We also found that the CS hydrogel + sunitinib compound retained maximal cytotoxicity towards the QGP-1 and BON 1 PanNET cell lines for 21 days and remained architecturally intact during this time period (Figure 1 D,E,F).Similar results were found with CS hydrogels loaded with ribociclib.Conclusion: CS hydrogels loaded with sunitinib or ribociclib have sustained long-term cytotoxic effects on two PanNETs cell lines.This novel drug delivery approach could allow physicians to inject hydrogel drug compounds into PanNETs during surgical or endoscopic-procedures or be used for intra-arterial delivery as a liver-directed approach for metastatic PanNETs while limiting systemic toxicity.

The current study sought to investigate the impact of tumor size and total number of LN examined (TNLE) on the incidence of lymph node metastasis (LNM) among patients with duodenal neuroendocrine tumor (dNET).

Appendiceal neuroendocrine tumors (A-NETs) are rare neoplasms of the GI tract. They are typically managed according to tumor size; however, the impact of surgical strategy on the short- and long-term outcomes is unknown. All patients who underwent resection of A-NET at 8 institutions from 2000 to 2016 were analyzed retrospectively. Patient clinicopathologic features and outcomes were stratified according to resection type. Of 61 patients identified with A-NET, mean age of presentation was 44.7 ± 16.0 years and patients were predominantly Caucasian (77%) and female (56%). Mean tumor size was 1.2 ± 1.3 cm with a median of 0.8 cm. Thirty-one patients (51%) underwent appendectomy and 30 (49%) underwent colonic resection. The appendectomy group had more T1 tumors (87% vs 42%, p < 0.01) than the colon resection group. Of patients in the colon resection group, 27% had positive lymph nodes and 3% had M1 disease. R0 resections were achieved in 90% of appendectomy patients and 97% of colon resection patients. Complications occurred with a higher frequency in the colon resection group (30%) compared with those in the appendectomy group (6%, p = 0.02). The colon resection group also had a longer length of stay, higher average blood loss, and longer average OR time. Median RFS and OS were similar between groups. A-NET RFS and OS are equivalent regardless of surgical strategy. Formal colon resection is associated with increased length of stay, OR time, higher blood loss, and more complications. Further study is warranted to identify patients that are likely to benefit from more aggressive surgery.

Background: To define recurrence patterns and time course, as well as risk factors associated with recurrence following curative resection of pNETs. Method: Patients who underwent curative-intent resection for pNET between 1997 and 2016 were identified from the US Neuroendocrine Tumor Study Group. Data on baseline and tumor-specific characteristics, overall survival (OS), timing and first-site of recurrence, predictors and recurrence management were analyzed. Results: Among 1020 patients, 154 (15.1 %) patients developed recurrence. Among patients who experienced recurrence, 76 (49.4%) had liver-only recurrence, while 35 (22.7%) had pancreas-only recurrence. The proportion of liver-only recurrence increased from 54.3% within one-year after surgery to 61.5% from four-to-six years after surgery; whereas the proportion of pancreas-only recurrence decreased from 26.1 % to 7.7% over these time periods. While liver-only recurrence was associated with tumor characteristics, pancreas-only recurrence was only associated with surgical margin status. Patients undergoing curative resection of recurrence had comparable OS with patients who had no recurrence (median OS, pancreas-only recurrence, 133.9 months; liver-only recurrence, not attained; no recurrence, 143.0 months, p = 0.499) Conclusions: Different recurrence patterns and timing course, as well as risk factors suggest biological heterogeneity of pNET recurrence. A personalized approach to postoperative surveillance and treatment of recurrence disease should be considered.

376 Background: The prognostic value of pathologic variables is not consistent for gastroenteropancreatic neuroendocrine tumors (GEP-NETs). We previously demonstrated a limited prognostic role of lymph node (LN) positivity in small bowel NETs (SBNET) compared to pancreatic NETs (panNET). Although minority race is often associated with worse cancer outcomes, the interaction of race with pathologic and oncologic outcomes of pts with GEP-NETS is not known. Methods: Pts with GEP-NETs who underwent curative intent resection at eight institutions of the US NET Study Group from 2000-16 were included. Given few pts of other races, only Black and White race pts were analyzed. Results: Of 2,182 pts, 1,143 met inclusion criteria. Median age was 58 yrs, median follow up was 3 yrs, 48% were male, 14% (n = 157) were Black, and 86% (n = 986) were White. Black pts were more likely uninsured (7 vs 2%, p = 0.005), had symptomatic bleeding (13 vs 7%, p = 0.006), required emergency surgery (7 vs 3%, p = 0.003), and had LN positive disease (47 vs 36%, p = 0.016). Despite this, Black pts had improved 5 yr recurrence free survival (RFS) compared to White pts (90 vs 80%, p = 0.008). The quality of care received was comparable between both groups, demonstrated by similar LN yield at surgery, neg margin resection rate, post-op complications, and need for reoperation or readmission (all p > 0.05). Black pts were more likely to have SBNET (22 vs 13%) and less likely to have panNET (43 vs 68%) compared to White pts (p < 0.001). Consistent with prior data, pts with LN pos panNET had decreased 5yr RFS (67 vs 83%, p = 0.001); however, for SBNET, LN involvement was not prognostic (77 vs 96%, p = 0.08). The prognostic value of LN pos disease was similar between Black and White pts in both SBNET (p = 0.34) and panNET (p = 0.95). Conclusions: Black pts with GEP-NET present with more advanced disease, including higher LN positivity. Despite this, Black pts have improved RFS compared to White pts. Although there may be delays in seeking or reaching care, Black pts received similar quality of care compared to White pts. The improved RFS seen in Black pts may be attributed to the epidemiologic differences in the site of presentation of GEP-NETs and variable prognostic value of LN pos disease.

INTRO:Chromogranin A (CgA) may be prognostic for patients with neuroendocrine tumors; however, the clinical utility of this test is unclear. METHODS:Patients undergoing resection for pancreatic neuroendocrine tumors (pNET) were selected from the eight institutions of the US Neuroendocrine Tumor Study Group database. Cox regression was used to identify pre-operative variables that predicted recurrence-free survival (RFS), and those with p < 0.1 were included in a risk score. The risk score was tested in a unique subset of the overall cohort. RESULTS:In the entire cohort of 287 patients, median follow-up time was 37 months, and 5-year RFS was 73%. Cox regression analysis identified four variables for inclusion in the risk score: CgA > 5x ULN (HR 4.3, p = 0.01), tumor grade 2/3 (HR 3.7, p = 0.01), resection for recurrent disease (HR 6.2, p < 0.01), and tumor size > 4 cm (HR 4.5, p = 0.1). Each variable was assigned 1 point. Risk-score testing in the unique validation cohort of 63 patients revealed a 95% negative predictive value for recurrence in patients with zero points. DISCUSSION:This simple pre-operative risk scoring system resulted in a high degree of specificity for identifying patients at low-risk for tumor recurrence. This test can be utilized pre-operatively to aid informed decision-making.

In the original article, Ryan C. Fields' middle initial is missing.