Short course radiotherapy and delayed surgery for locally advanced rectal cancer in frail patients: is it a valid option?

OBJECTIVE: The endpoint of the present study was to evaluate the outcomes of short-course radiotherapy (SCRT) and SCRT with delayed surgery (SCRT-DS) on a selected subgroup of frail patients with locally advanced middle/low rectal adenocarcinoma. METHODS: From January 2008 to December 2018, a total of 128 frail patients with locally advanced middle-low rectal adenocarcinoma underwent SCRT and subsequent restaging for eventual delayed surgery. Rates of complete pathological response, down-staging, disease free survival (DFS) and overall survival (OS) were analyzed. RESULTS: 128 patients completed 5 × 5 Gy pelvic radiotherapy. 69 of these were unfit for surgery; 59 underwent surgery 8 weeks (average time: 61 days) after radiotherapy. Downstaging of T occurred in 64% and down-staging of N in 50%. The median overall survival (OS) of SCRT alone was 19.5 months. The 1-year, 2-year, 3-year and 5-year OS was 48%, 22%, 14% and 0% respectively. In the surgical group, the median disease-free survival (DFS) and median OS were, respectively, 67 months (95% CI 49.8-83.1 months) and 72.1 months (95% CI 57.5-86.7 months). The 1, 2, 3, 5-year OS was 88%, 75%, 51%, 46%, respectively. Post-operative morbidity was 22%, mortality was 3.4%. CONCLUSIONS: Frail patients with advanced rectal cancer are often "unfit" for long-term neoadjuvant chemoradiation. A SCRT may be considered a valid option for this group of patients. Once radiotherapy is completed, patients can be re-evaluated for surgery. If feasible, SCRT and delayed surgery is the best option for frail patients.

[Short-term efficacy of totally laparoscopic left colon cancer radical resection with overlapped delta-shaped anastomosis technique].

Objective: To evaluate the safety, feasibility and short-term efficacy of totally laparoscopic left colectomy for left colon cancer by using overlapped delta-shaped anastomosis technique for digestive tract reconstruction. Methods: A retrospective cohort study was conducted to collect the clinical data of 86 patients with left colon cancer who underwent laparoscopic surgery in Cancer Hospital of Chinese Academy of Medical Sciences from October, 2017 to February, 2019. The patients were divided into totally laparoscopic left-sided colectomy (TLLC) (treatment group, n=25 cases) and laparoscopic-assisted left-sided colectomy (LALC) (control group, n=61 cases). The intraoperative and postoperative data were compared between the two groups. Results: There were no surgical-related deaths in both groups. All the patients in the TLLC group underwent laparoscopic resection, while one patient in the LALC group transfer to open surgery. The operation time in TLLC group and LALC group were (164.5±42.3) min and (171.0±43.1) min, respectively, without statistically significant difference (P=0.516). However, the intraoperative blood loss of patients in the TLLC group was (36.4±22.7) ml, which was significantly less than (52.9±32.2) ml in the LALC group (P=0.026). The anastomosis time in the TLLC group was (39.1±6.5) min, which was significantly longer than (24.9±5.4) min in the LALC group (P<0.001). Postoperative exhaust time in the TLLC group was (2.6±0.5) days, which was significantly shorter than (3.3±0.8) days in the LALC group (P<0.001). The incision length in the TLLC group was (4.2±2.2) cm, significantly shorter than (7.0±2.5) cm in the LALC group (P<0.001). The length of the resected bowel was (21.0±7.3) cm in the TLLC group, which was significantly longer than (17.5±5.4) cm in the LALC group (P=0.037). The length of hospital stay in the TLLC group was (6.2±1.9) days, which was significantly shorter than (7.9±1.5) days in the LALC group (P<0.001). The incidences of postoperative complications in the TLLC group and LALC group were 0 and 4.9% (3/61), respectively, without statistically significant (P=0.553). No anastomotic complications occurred in both groups. During the follow-up period, neither group of patients was hospitalized again, and no tumor metastasis or recurrence occurred. Conclusions: It is safe and feasible to apply the TLLC with overlapped delta-shaped anastomosis in patients with left colon cancer. It has better short-term effects such as shorter incisions, faster recovery, and shorter postoperative hospital stays, and is worthy of further promotion.

Complicated Disease Course in Initially Computed Tomography-Proven Uncomplicated Acute Diverticulitis.

Background: Although uncomplicated acute diverticulitis has a benign disease course, some patients are at increased risk for complications. Identification of these patients may aid the selection of treatment strategies such as outpatient treatment. This study aimed to assess the rate and timing of a complicated disease course in initially computed tomography (CT)-proven uncomplicated diverticulitis, and to identify risk factors for the development of these diverticular complications. Patients and Methods: Computed tomography-proven, left-sided uncomplicated diverticulitis patients from two cohorts were included. Main outcome measure was complicated diverticulitis (perforation, abscess, obstruction, or fistula) within three months after presentation. Risk factors for diverticular complications were identified using multivariable logistic regression. Results: Of the 1,087 patients with initially CT-proven uncomplicated diverticulitis, 4.9% (53/1,087) developed complicated diverticulitis. Most perforations and abscesses (16/21) occurred during the first 10 days, whereas colonic obstruction and fistula occurred during three months of follow-up. Independent risk factors for the transition from uncomplicated to complicated diverticulitis were American Society of Anesthesiologists (ASA) classification 3/4 (odds ratio [OR] 4.43, 95% confidence interval [CI] 1.57-12.48), duration of symptoms before presentation longer than five days (OR 3.25, 95% CI 1.72-6.13), vomiting (OR 3.94, 95% CI 1.96-7.92), and C-reactive protein (CRP) above 140 mg/L (OR 2.86, 95% CI 1.51-5.43). Conclusion: Approximately one in 20 patients with CT-proven uncomplicated diverticulitis develops a complicated disease course within three months; perforation and abscess occur predominantly within 10 days after presentation. Patients with systemic comorbidity, symptoms for more than five days, those who vomit, or have high CRP levels at presentation are at risk for diverticular complications after an uncomplicated initial presentation and may warrant closer observation.

Manejo nutricional en la rehabilitación multimodal precoz en cirugía pancreática / Nutrition management in enhanced recovery after abdominal pancreatic surgery

Los programas de rehabilitación multimodal precoz son estrategias estandarizadas perioperatorias con el objetivo de mejorar la recuperación del paciente, disminuir las complicaciones, la estancia hospitalaria y el coste sanitario. El aspecto nutricional es un componente esencial de la rehabilitación multimodal precoz, recomendándose realizar un cribado nutricional previo al ingreso hospitalario, evitar el ayuno prequirúrgico mediante una sobrecarga oral de hidratos de carbono, e iniciar de manera precoz la ingesta oral posquirúrgica. Sin embargo, no existen protocolos estandarizados de progresión de dieta en cirugía pancreática. Se realiza una revisión de las diferentes estrategias nutricionales publicadas desde 2006 hasta 2016 en la rehabilitación multimodal precoz de este tipo de cirugía y sus posibles implicaciones en la evolución postoperatoria. Los estudios evaluados son muy heterogéneos por lo que no se pueden extraer resultados concluyentes sobre el protocolo de dieta a implementar, su influencia en variables clínicas ni la necesidad o no de nutrición artificial concomitante (AU)

Multimodal rehabilitation programs are perioperative standardized strategies with the objective of improving patient recovery, and decreasing morbidity, hospital stay and health cost. The nutritional aspect is an essential component of multimodal rehabilitation programs and therefore nutritional screening is recommended prior to hospital admission, avoiding pre-surgical fasting, with oral carbohydrate overload and early initiation of oral intake after surgery. However, there are no standardized protocols of diet progression after pancreatic surgery. A systematic review was been performed of papers published between 2006 and 2016, describing different nutritional strategies after pancreatic surgery and its possible implications in postoperative outcome. The studies evaluated are very heterogeneous, so conclusive results could not be drawn on the diet protocol to be implemented, its influence on clinical variables, or the need for concomitant artificial nutrition (AU)

Increased genitourinary fistula rate after bevacizumab in recurrent cervical cancer patients initially treated with definitive radiochemotherapy and image-guided adaptive brachytherapy.

BACKGROUND AND PURPOSE: Patients with recurrent cervical cancer (RecCC) who received definitive radiochemotherapy including image-guided adaptive brachytherapy (IGABT) as primary treatment are currently treated in our institution with palliative intent by chemotherapy (CHT) combined with bevacizumab (BEV). We aim to evaluate the risk of gastrointestinal (GI)/genitourinary (GU) fistula formation in these patients. MATERIALS AND METHODS: Data of 35 consecutive patients with RecCC treated initially with radiochemotherapy and IGABT were collected. Known and presumed risk factors associated with fistula formation were evaluated. Fistula rate was compared between patients receiving CHT or CHT+BEV. RESULTS: Of the 35 patients, 25 received CHT and 10 patients received CHT+BEV. Clinical characteristics were comparable. Fistulae were reported in 6 patients: two fistulae (8%) in the CHT group, four (40%) in the CHT+BEV group. GU fistula occurred in the CHT+BEV group only (3/4). Of these 6 patients with fistulae, 5 (83%) had undergone previous invasive procedures after the diagnosis of RecCC and 1 patient had undergone pelvic re-irradiation; 3/6 patients had developed a local recurrence. No other risk factors for fistula formation were identified. CONCLUSION: In patients with RecCC after definitive radiochemotherapy including IGABT, the addition of BEV to CHT may increase the risk for GU fistula formation, particularly after invasive pelvic procedures. Future clinical studies are required to identify predictors for fistula formation to subsequently improve patient selection for the addition of BEV in the RecCC setting.

[Clinical research of delta-shaped anastomosis technology in laparoscopic distal gastrectomy and digestive tract reconstruction].

OBJECTIVE: To evaluate the feasibility and safety of the delta-shaped anastomosis in laparoscopic distal gastrectomy and digestive tract reconstruction. METHODS: Clinical data of 34 gastric cancer patients undergoing laparoscopic distal gastrectomy with the delta-shaped anastomosis for digestive tract reconstruction (delta-shaped group) and 83 gastric cancer patients undergoing laparoscopic distal gastrectomy with Billroth I( for digestive tract reconstruction (Billroth group) by same surgeon team from July 2013 to July 2015 at the Department of Digestive Surgery, Affiliated Tumor Hospital of Shanxi Medical University were retrospectively analyzed. Data of two groups were compared. RESULT: Age, gender, tumor stage were not significantly different between the two groups(all P>0.05). Operation time of the first 15 cases in delta-shaped group was longer than that in Billroth group [(254.7±35.4) min vs. (177.8±33.0) min, t=11.190, P=0.000], while after above 15 cases, the operation time of delta-shaped group was significantly shorter than that of Billroth group [(142.1±14.6) min vs. (177.8±33.0) min, t=-4.109, P=0.001]. Delta-shaped group had less blood loss during operation [(87.1±36.7) ml vs. (194.0±55.1) ml, t=-10.268, P=0.000], and shorter length of incision [(4.1±0.4) cm vs. (6.1±1.0) cm, t=-10.331, P=0.000] than Billroth group. Compared with Billroth group, delta-shaped group presented faster postoperative bowel function return [(2.8±0.6) d vs. (3.3±0.5) d, t=-3.755, P=0.000], earlier liquid food intake [(7.4±1.5) d vs. (8.1±1.7) d, t=-4.135, P=0.000], earlier ambulation [(4.0±1.6) d vs. (6.8±1.4) d, t=-7.197, P=0.000] and shorter postoperative hospital stay [(12.6±1.9) d vs.(13.6±2.0) d, t=-20.149, P=0.000]. Morbidity of postoperative complication was 5.9%(2/34) in delta-shaped group, including anastomotic fistula in 1 case and incision infection in 1 case, and 6.0%(5/83) in Billroth group, including anastomotic fistula, incision infection, anastomotic stricture and dumping syndrome, without significant difference(P>0.05). Difference value of total protein and albumin between pre-operation and post-operation, and average decreased value of total protein, albumin, body weight between pre-operation and postoperative 6-month were not significantly different between two groups(all P>0.05). As for patients with BMI > 25 kg/m2, compared to Billroth group, delta-shaped group presented less blood loss during operation [(94.1±36.7) ml vs. (203.0±55.1) ml, t=-10.268, P=0.000], lower injective dosage of postoperative analgesics [(1.9±1.1) ampule vs.(3.3±2.0) ampule, t=-2.188, P=0.032], faster intestinal recovery [(2.9±0.7) d vs. (3.2±0.9) d, t=-3.755, P=0.009], shorter hospital stay [(10.5±1.2) d vs. (11.7±1.5) d, t=-2.026, P=0.004], and lower morbidity of postoperative complication [7.1%(1/14) vs. 13.6%(3/22), χ2=4.066, P=0.031]. CONCLUSION: In laparoscopic distal gastrectomy and digestive tract reconstruction, the delta-shaped anastomosis is safe and feasible, especially suitable for obese patients.

Epidemiology and outcome of patients with postoperative abdominal fistula.

OBJECTIVE: to present the epidemiological profile, incidence and outcome of patients who developing postoperative abdominal fistula. METHODS: This observational, cross-sectional, prospective study evaluated patients undergoing abdominal surgery. We studied the epidemiological profile, the incidence of postoperative fistulas and their characteristics, the outcome of this complication and the predictors of mortality. RESULTS: The sample consisted of 1,148 patients. The incidence of fistula was 5.5%. There was predominance of biliary fistula (26%), followed by colonic fistulas (22%) and stomach (15%). The average time to onset of fistula was 6.3 days. For closure, the average was 25.6 days. The mortality rate of patients with fistula was 25.4%. Predictors of mortality in patients who developed fistula were age over 60 years, presence of comorbidities, fistula closure time more than 19 days, no spontaneous closure of the fistula, malnutrition, sepsis and need for admission to the Intensive Care Unit. CONCLUSION: abdominal postoperative fistulas are still relatively frequent and associated with significant morbidity and mortality. OBJETIVO: apresentar o perfil epidemiológico, incidência e desfecho em pacientes que evoluíram com fístula abdominal pós-operatória. MÉTODOS: trata-se de um estudo prospectivo transversal observacional que avaliou pacientes submetidos à cirurgia abdominal. Foram estudados o perfil epidemiológico, a incidência das fístulas pós-operatórias e suas características, desfecho desta complicaçãoe fatores preditivos de mortalidade. RESULTADOS: a amostra constou de 1148 pacientes. A incidência de fístula foi 5,5%. Houve predominância de fístulas biliares (26%), seguidas de fístulas colônicas (22%) e gástricas (15%). O tempo médio para o surgimento da fístula foi 6,3 dias. Para o fechamento, a média foi 25,6 dias. A taxa de mortalidade dos pacientes com fístula foi 25,4%. Os fatores preditivos de mortalidade nos casos que desenvolveram fístula foram idade maior do que 60 anos, presença de comorbidades, tempo de fechamento da fístula superior a 19 dias, não fechamento espontâneo da fístula, desnutrição, sepse e necessidade de admissão em Unidade de Terapia Intensiva. CONCLUSÃO: as fístulas pós-operatórias abdominais ainda são relativamente frequentes e associadas à morbidade e mortalidade significativas.

Epidemiology and outcome of patients with postoperative abdominal fistula / Perfil epidemiológico, incidência e desfecho dos pacientes com fístula abdominal pós-operatória

ABSTRACT Objective: to present the epidemiological profile, incidence and outcome of patients who developing postoperative abdominal fistula. Methods: This observational, cross-sectional, prospective study evaluated patients undergoing abdominal surgery. We studied the epidemiological profile, the incidence of postoperative fistulas and their characteristics, the outcome of this complication and the predictors of mortality. Results: The sample consisted of 1,148 patients. The incidence of fistula was 5.5%. There was predominance of biliary fistula (26%), followed by colonic fistulas (22%) and stomach (15%). The average time to onset of fistula was 6.3 days. For closure, the average was 25.6 days. The mortality rate of patients with fistula was 25.4%. Predictors of mortality in patients who developed fistula were age over 60 years, presence of comorbidities, fistula closure time more than 19 days, no spontaneous closure of the fistula, malnutrition, sepsis and need for admission to the Intensive Care Unit Conclusion: abdominal postoperative fistulas are still relatively frequent and associated with significant morbidity and mortality.

RESUMO Objetivo: apresentar o perfil epidemiológico, incidência e desfecho em pacientes que evoluíram com fístula abdominal pós-operatória. Métodos: trata-se de um estudo prospectivo transversal observacional que avaliou pacientes submetidos à cirurgia abdominal. Foram estudados o perfil epidemiológico, a incidência das fístulas pós-operatórias e suas características, desfecho desta complicaçãoe fatores preditivos de mortalidade. Resultados: a amostra constou de 1148 pacientes. A incidência de fístula foi 5,5%. Houve predominância de fístulas biliares (26%), seguidas de fístulas colônicas (22%) e gástricas (15%). O tempo médio para o surgimento da fístula foi 6,3 dias. Para o fechamento, a média foi 25,6 dias. A taxa de mortalidade dos pacientes com fístula foi 25,4%. Os fatores preditivos de mortalidade nos casos que desenvolveram fístula foram idade maior do que 60 anos, presença de comorbidades, tempo de fechamento da fístula superior a 19 dias, não fechamento espontâneo da fístula, desnutrição, sepse e necessidade de admissão em Unidade de Terapia Intensiva. Conclusão: as fístulas pós-operatórias abdominais ainda são relativamente frequentes e associadas à morbidade e mortalidade significativas.

Clinical Factors Associated with the Development of Crohn's Disease in Inflammatory Bowel Disease-unclassified Patients Undergoing Ileal Pouch-anal Anastomosis.

BACKGROUND: Patients with inflammatory bowel disease-unclassified (IBDU) undergoing ileal pouch-anal anastomosis (IPAA) are at the risk of developing Crohn's disease (CD) after surgical procedure. In these patients, a clinically centered set of preoperative risk factors has not been prospectively defined. We report a single-center analysis of clinical factors associated with the development of CD after IPAA. METHODS: Consecutive IBDU patients undergoing IPAA were identified. The diagnosis of IBDU was based on the presence of atypical disease distribution, presence of granulomas on endoscopic biopsy, and/or perianal disease. The diagnosis of CD after IPAA included the presence of afferent limb inflammation on pouchoscopy in the absence of nonsteroidal anti-inflammatory drug use and/or the development of pouch fistulizing disease more than 3 months after ileostomy closure. RESULTS: Of the 149 study patients, 33 (22%) were diagnosed with CD after IPAA at a median of 37 months (interquartile range, 11-83 mo) after ileostomy closure. CD was diagnosed by mucosal inflammation above the pouch (n = 23; 70%), pouch fistulizing disease (n = 4; 12%), anorectal septic complications (n = 2; 6%), or the presence of ≥2 of the above complications (n = 4; 12%). The sole clinical predictor for the development of CD after IPAA was younger age at disease onset even after controlling for relevant clinical factors in a multivariate analysis. The odds of developing CD increased by 4% for each year that IBDU was diagnosed at a younger age. CONCLUSIONS: Younger age at disease onset is the only clinical factor associated with the development of CD after IPAA for IBDU. Patients with IBDU undergoing IPAA with young age at disease onset should be counseled about the potentially higher risk of developing CD.

Stapler suture of the pharynx after total laryngectomy.

The use of a stapler for pharyngeal closure during total laryngectomy was first described in 1971. It provides rapid watertight closure without surgical field contamination. The objective of our study was to compare the incidence of pharyngocutaneous fistula after total laryngectomy with manual and mechanical closures of the pharynx. This was a non-randomised, prospective clinical study conducted at two tertiary medical centres from 1996 to 2011 including consecutive patients with laryngeal tumours who underwent total laryngectomy. We compared the incidence of pharyngocutaneous fistula between two groups of patients: in 20 patients, 75 mm linear stapler closure was applied, whereas in 67 patients a manual suture was used. Clinical data were compared between groups. The groups were statistically similar in terms of gender, age, diabetes mellitus, smoking and alcohol consumption and tumour site. The group of patients who underwent stapler-assisted pharyngeal closure had a higher number of patients with previous tracheotomy (p < 0.001) and previous chemoradiation (p < 0.001). The incidence of pharyngocutaneous fistula was 30% in the mechanical closure group and 20.9% in the manual suture group (p = 0.42). In conclusion the use of the stapler does not increase the rate of fistulae.

Repeat sleeve gastrectomy compared with primary sleeve gastrectomy: a single-center, matched case study.

Longitudinal sleeve gastrectomy (LSG) has been validated for the treatment of morbid obesity. However, treatment failures can appear several months after SG. Additional malabsorptive surgery is generally recommended in such cases. The objective of the present study was to evaluate the outcomes of repeat SG (re-SG) relative to first-line SG. This was a retrospective study included 15 patients underwent re-SG after failure of first-line SG (i.e. University Hospital, France; Public Practice). These patients were matched (for age, gender, body mass index and comorbidities) 1:2 with 30 patients having undergone first-line SG. The efficacy criteria comprised intra-operative data and postoperative data. The overall study population comprised 45 patients. The re-SG and first-line SG groups did not differ significantly in terms of median age (p = NS). The median BMI was similar in the two groups (43 kg/m(2) vs. 42.3 kg/m(2), p = NS). The two groups were similar in terms of the prevalence of comorbidities. The mean operating time was longer in the re-SG group (116 vs. 86 min; p ≤ 0.01). The postoperative complication rate was twice as high in the re-SG group (p = 0.31). Two patients in the re-SG group developed a gastric fistula (p = 0.25) and one of the latter died. At 12 months, the Excess Weight Loss was 66% (re-SG group) and 77% (first-line SG group) (p = 0.05). Re-SG is feasible but appears to be associated with a greater risk of complications. Nevertheless, re-SG can produce results (in terms of weight loss), equivalent to those obtained after first-line SG.

Epidemiology and diagnosis of endograft infection.

Endograft infection is reported to occur in between 0.2 and 0.7 of patients and in general presents either within four months of endograft implantation of after more than 12 months. Review of all cases reported to date reveals three modes of presentation: approximately one third of patients present with evidence of an aorto-enteric fistula (although less than half of these present with gastrointestinal haemorrhage), one third present with non specific signs of low grade sepsis (malaise, weight loss) and the remainder with evidence of severe systemic sepsis. Infection is most commonly attributed to Staphylococcus aureus. Diagnosis relies on a high index of suspicion, imaging of the aorta and periaortic tissues (computed tomography or magnetic resonance imaging) and bacteriological culture. This paper presents a detailed analysis of the features of all cases reported to date and examines the aetiology, pathogenesis and imaging of endograft infection and aorto-enteric fistula.

[Postoperative digestive fistulas. Etiopathogenic considerations]. / Consideratii asupra etiopatogeniei fistulelor digestive externe postoperatorii.

The digestive fistula is one of the most serious complications that might appear following different types of resectional digestive surgery. This condition still carries a considerable morbidity and mortality rate and therefore all surgical and ICU staff pay a great deal of attention and intensify their care to avoid the fatalities. The postoperative digestive fistulas, through their physiopathological and clinical complexity induce the disturbance of the biological equilibrium with vital consequences. The trend of the last decades is the increasing of digestive fistulas incidence with a variable mortality rate after different authors. A therapeutic algorithm is needed. The mortality rate due to digestive fistulas, two decades ago was, around 60%; at the present there is a decrease of the mortality rate, which is around 10%. The explanation is the introduction of the new methods of treatment such as lactic acid lavage aspiration for alkaline fistulas or total parenteral nutrition, continuous enteral nutrition and antiexocrine chemotherapy. A fistula is a communication between two epithelial or endothelial surfaces, lined by granulation tissue. It can be a life-threatening condition.

The natural history of fistulizing Crohn's disease in Olmsted County, Minnesota.

BACKGROUND & AIMS: Little is known about the cumulative incidence and natural history of fistulas in Crohn's disease in the community. METHODS: The medical records of all Olmsted County, Minnesota residents who were diagnosed with Crohn's disease from 1970 to 1993 and who developed a fistula were abstracted for clinical features and outcomes. Six patients denied research authorization. The cumulative incidence of fistula from time of diagnosis was estimated by using the Kaplan-Meier product-limit method. RESULTS: At least 1 fistula occurred in 59 patients (35%), including 33 patients (20%) who developed perianal fistulas. Twenty-six (46%) developed a fistula before or at the time of formal diagnosis. Assuming that the 9 patients with fistula before Crohn's disease diagnosis were instead simultaneous diagnoses, the cumulative risk of any fistula was 33% after 10 years and was 50% after 20 years (perianal, 21% after 10 years and 26% after 20 years). At least 1 recurrent fistula occurred in 20 patients (34%). Most fistulizing episodes (83%) required operations, most of which were minor. However, 11 perianal fistulizing episodes (23%) resulted in bowel resection. CONCLUSIONS: Fistulas in Crohn's disease were common in the community. In contrast to referral-based studies, only 34% of patients developed recurrent fistulas. Surgical treatment was frequently required.