Long-Term Outcomes of the Excluded Rectum in Crohn's Disease: A Multicenter International Study.

BACKGROUND: Many patients with Crohn's disease (CD) require fecal diversion. To understand the long-term outcomes, we performed a multicenter review of the experience with retained excluded rectums. METHODS: We reviewed the medical records of all CD patients between 1990 and 2014 who had undergone diversionary surgery with retention of the excluded rectum for at least 6 months and who had at least 2 years of postoperative follow-up. RESULTS: From all the CD patients in the institutions' databases, there were 197 who met all our inclusion criteria. A total of 92 (46.7%) of 197 patients ultimately underwent subsequent proctectomy, while 105 (53.3%) still had retained rectums at time of last follow-up. Among these 105 patients with retained rectums, 50 (47.6%) underwent reanastomosis, while the other 55 (52.4%) retained excluded rectums. Of these 55 patients whose rectums remained excluded, 20 (36.4%) were symptom-free, but the other 35 (63.6%) were symptomatic. Among the 50 patients who had been reconnected, 28 (56%) were symptom-free, while 22(44%) were symptomatic. From our entire cohort of 197 cases, 149 (75.6%) either ultimately lost their rectums or remained symptomatic with retained rectums, while only 28 (14.2%) of 197, and only 4 (5.9%) of 66 with initial perianal disease, were able to achieve reanastomosis without further problems. Four patients developed anorectal dysplasia or cancer. CONCLUSIONS: In this multicenter cohort of patients with CD who had fecal diversion, fewer than 15%, and only 6% with perianal disease, achieved reanastomosis without experiencing disease persistence.

Patients with distal Crohn's disease often undergo colon resection with a stoma to divert the intestinal stream from the rectum in hopes of achieving sufficient healing to allow ultimate re-establishment of intestinal continuity. Patients and practitioners alike should be aware of the long-term success rates of this procedure. Our retrospective study of 197 patients found that half required later proctectomy and an additional one-quarter remained symptomatic with excluded rectums. Only 14% remained symptom-free after reanastomosis, and only 6% if perianal disease was the initial surgical indication. These data provide estimation of long-term surgical outcomes.

Routine placement of abdominal drainage in pouch surgery does not impact on surgical outcomes.

The evidence does not support the routine use of abdominal drainage (AD) in colorectal surgery. However, there is no data on the usefulness of AD, specifically, after ileal pouch-anal anastomosis (IPAA). The aim of this study is to assess post-operative outcomes of patients undergoing IPAA with or without AD at a high volume referral center. A retrospective analysis of prospectively collected data of consecutive patients undergoing IPAA with AD (AD group) or without AD (NAD group) was performed. Baseline characteristics, operative, and postoperative data were analyzed and compared between the two groups. A total of 97 patients were included in the analysis, 46 were in AD group and 51 in NAD group. AD group had a higher BMI (23.9 ± 3.9 kg/m2 vs 21.9 ± 3.0 kg/m2; p = 0.007) and more commonly underwent two-stage proctocolectomy with IPAA compared to the NAD group (50.0% vs 3.9%; p < 0.001). There was no difference in anastomotic leak rate (6.5% AD vs 5.9% NAD group; p = 1.000), major post-operative complication (8.6% vs 7.9%; p = 0.893); median length of stay [IQR] (5 [5-7] days vs 5 [4-7] days; p = 0.305) and readmission < 90 days (8.7% vs 3.9%; p = 0.418). The use of AD does not impact on surgical outcome after IPAA and question the actual benefit of its routine placement.

Different Oncologic Outcomes in Early-Onset and Late-Onset Sporadic Colorectal Cancer: A Regression Analysis on 2073 Patients.

The incidence of colorectal cancer (CRC) is increasing in the population aged ≤ 49 (early-onset CRC-EOCRC). Recent studies highlighted the biological and clinical differences between EOCRC and late-onset CRC (LOCRC-age ≥ 50), while comparative results about long-term survival are still debated. This study aimed to investigate whether age of onset may impact on oncologic outcomes in a surgical population of sporadic CRC patients. Patients operated on for sporadic CRC from January 2010 to January 2022 were allocated to the EOCRC and LOCRC groups. The primary endpoint was the recurrence/progression-free survival (R/PFS). A total of 423 EOCRC and 1650 LOCRC was included. EOCRC had a worse R/PFS (p < 0.0001) and cancer specific survival (p < 0.0001) compared with LOCRC. At Cox regression analysis, age of onset, tumoral stage, signet ring cells, extramural/lymphovascular/perineural veins invasion, and neoadjuvant therapy were independent risk factors for R/P. The analysis by tumoral stage showed an increased incidence of recurrence in stage I EOCRC (p = 0.014), and early age of onset was an independent predictor for recurrence (p = 0.035). Early age of onset was an independent predictor for worse prognosis, this effect was stronger in stage I patients suggesting a potentially­and still unknown­more aggressive tumoral phenotype in EOCRC.

Negative-pressure wound therapy after stoma reversal in colorectal surgery: a randomized controlled trial.

BACKGROUND: Stoma-reversal surgery is associated with high postoperative morbidity, including wound complications and surgical-site infections (SSIs). This study aims to assess whether the application of negative-pressure wound therapy (NPWT) can improve wound healing compared with conventional wound dressing. METHODS: This was a single-centre, superiority, open-label, parallel, individually randomized controlled trial. Patients undergoing stoma reversal were randomized (1 : 1) to receive NPWT or conventional wound dressing. The primary endpoint of the study was the rate of wound complications and SSIs after stoma closure. The secondary endpoints were postoperative wound pain, rate of wound healing after 30 days from stoma closure, and wound aesthetic satisfaction. RESULTS: Between June 2019 and January 2021, 50 patients were allocated to the NPWT group (all received NPWT, 49 were analysed); 50 patients were allocated to the conventional wound dressing group (48 received the treatment, 45 were analysed). No significant difference was found in wound-complication rate (10 per cent NPWT versus 16 per cent controls; odds ratio 0.61 (95 per cent c.i. 0.18 to 2.10), P = 0.542) and incisional SSI rate (8 per cent NPWT versus 7 per cent controls; odds ratio 1.24 (95 per cent c.i. 0.26 to 5.99), P = 1.000). The NPWT group showed less pain, higher aesthetic satisfaction (P < 0.0001), and a higher proportion of wound healing (92 versus 78 per cent; P = 0.081) compared with the control group. CONCLUSION: NPWT does not reduce the incidence of SSI after stoma-reversal surgery compared with conventional wound dressing. However, NPWT improved the healing of uninfected wounds, reduced wound pain and led to better aesthetic outcomes.Registration number: NCT037812016 (clinicaltrials.gov).

Transanal Transection and Single-Stapled Anastomosis (TTSS): A comparison of anastomotic leak rates with the double-stapled technique and with transanal total mesorectal excision (TaTME) for rectal cancer.

BACKGROUND: in the literature on rectal cancer (RC) surgery many studies have focused on the quality of total mesorectal excision (TME) dissection, while there is a scarcity of comparative data on transection and anastomosis. No anastomosis has so far proved to be superior to any other. The aim of this study was to compare anastomotic leak (AL) rates between conventional laparoscopic double-stapled (DS), transanal total mesorectal excision (TaTME) and Transanal Transection and Single-Stapled anastomosis (TTSS) techniques. METHODS: consecutive mid-low RC patients undergoing elective laparoscopic TME with stapled anastomosis and protective stoma, by either DS, TaTME or TTSS techniques were retrieved from a prospectively collected database. RESULTS: 127 DS; 100 TaTME and 50 TTSS were included. Demographics, distance of the tumor from anal verge and neoadjuvant therapy were comparable. Operative time was longer in TaTME over DS and TTSS (p < 0.0001). More 90-days complications occurred in DS group vs TTSS (p = 0.029). The AL rate was 17.5% in DS, 6% in TaTME and 2% in TTSS group (p = 0.005). AL grade was: one B (2%) in TTSS; 2 grade B (2%) and 4 grade C (4%) in TaTME; 6 grade A (4.7%), 7 grade B (5.5%) and 9 grade C (7.1%) in DS group. Reintervention rate after AL was higher in DS group over TTSS (12.6% vs 2%; p = 0.003). The rate of stoma closure, pathology data and margin positivity did not differ. CONCLUSIONS: TTSS strategy is feasible, safe and leads to very low AL rates after TME for RC.

Tips to facilitate a preoperative diagnosis of adrenal ganglioneuroma. Report of a challenging experience and review of the literature.

AIM: Ganglioneuroma (GN) is the most uncommon and the most benign tumor among neuroblastic neoplasms, and in 29.7% of cases it finds in an adrenal gland. Usually asymptomatic, this tumor is detected incidentally in the majority of cases. It is generally challenging to obtain a precise diagnosis of adrenal ganglioneuroma (AGN) before surgery. Misdiagnosis rate of AGN on CT and MRI is 64.7% and clinicians and surgeons are often lacking in knowledge of this rare disease. For this reason, we pointed out the clinical, biochemical, radiologic and pathologic features of AGN in an our experience, with the aim to find out if there are some features able to facilitate a preoperative diagnosis. The present article also includes a review of the relevant literature in order to compare laparoscopic versus open adrenalectomy. CASE REPORT: Right AGN in a 42-year-old woman, in whom preoperative diagnosis was very difficult and only histopathological studies of the surgical specimen established the exact diagnosis. The patient underwent bilateral subcostal laparotomy for a large mass (sized measuring 14.5 x 11.6 x 6.5 cm.) and a right adrenalectomy was performed. Postoperative recovery was uneventful and the patient, at 12-months follow-up, is disease-free and in good health. DISCUSSION / CONCLUSIONS: Authors stress the importance of interdisciplinary collaboration between surgeons, radiologists and endocrinologists to optimize clinical management and surgical indications. Careful evaluation by endocrine examinations and multiple imaging procedures are necessary to provide a differential diagnosis. Surgeons should consider a diagnosis of AGN in case of: 1) an adrenal incidentaloma; 2) a nonfunctioning tumor with no elevated hormonal secretions, in which compressive symptoms may occur; 3) a homogeneous, encapsulated mass, with well-defined edges, without invasion of nearby structures (no vascular involvement), with presence of calcifications and nonenhanced attenuation of <40 HU on CT; 4) a homogeneous hypointense adrenal mass on T1-weighted MRI, a heterogeneous hyperintense mass on T2-weighted MRI and a poor delayed enhancement on dynamic MRI; a SUV level on PET less than 3.0. Nevertheless, diagnosis of AGN can be extremely challenging and can only be achieved by means of histology. Treatment is complete surgical resection without the need for chemotherapy or radiotherapy. Laparoscopic adrenalectomy is contraindicated in the presence of local infiltration or tumor greater than 12 cm. Even if AGN has an excellent prognosis and recurrences are rare after surgical resections, long-term follow-up is recommended. KEY WORDS: Adrenal gland, Adrenal ganglioneuroma, Laparoscopic adrenalectomy, Open adrenalectomy.

Food labels use is associated with higher adherence to Mediterranean diet: results from the Moli-sani study.

Mediterranean diet (MD) has been associated with lower risk of ischemic cerebro- and cardio-vascular disease, neurological degenerative disease, and breast and colonrectal cancers. Nevertheless, adherence to this pattern has decreased. Food labels are a potentially valid means to encourage towards healthier dietary behavior. This study, conducted on a subsample of 883 subjects enrolled in the Moli-sani Project, evaluated whether food labels reading (LR) is associated with MD adherence. Participants completed a questionnaire on nutrition knowledge, information, and attitudes, with a specific question on food labels reading. Biometric measurements, socio-economic status, education, physical activity, and smoking habits were collected. The European Prospective Investigation into Cancer and Nutrition (EPIC) food frequency questionnaire was used to collect dietary habits, and subsequently evaluated by both the Mediterranean diet score (MDS) and Italian Mediterranean index (IMI), a priori dietary patterns. Food consumption patterns were generated by Principal Components Analysis (PCA), an a posteriori approach. Multivariable odds ratios were calculated to quantify the association of LR categories with dietary habits. LR was significantly associated with greater adherence to both MDS (p = 0.0004) and IMI (p = 0.0019) in a multivariable model. LR participants had 74% (MDS) or 68% (IMI) higher probability to be in the highest level of adherence to Mediterranean diet-like patterns. Moreover, they showed greater adherence to Mediterranean-like food consumption patterns (0.1 vs. -0.2, p < 0.0001) and lower adherence to two Western-like patterns (0.01 vs. 0.2, p = 0.009 and 0.1 vs. 0.2, p = 0.02). These findings support an association between food label use and consuming a Mediterranean-type diet.

Adherence to a Mediterranean diet is associated with a better health-related quality of life: a possible role of high dietary antioxidant content.

OBJECTIVES: Mediterranean diet (MD) is associated with a reduced risk of major chronic disease. Health-related quality of life (HRQL) is a valid predictor of mortality. The aim of this study is to investigate the association between MD and HRQL and to examine the possible role of dietary antioxidants, fibre content and/or fatty acid components. DESIGN: Cross-sectional study on a sample of Italian participants enrolled in the Moli-sani Project, a population-based cohort study. Food intake was recorded by the Italian European prospective investigation into cancer and nutrition study food frequency questionnaire. Adherence to MD was appraised by a Greek Mediterranean diet score (MDS), an Italian Mediterranean diet index (IMI) and by principal component analysis (PCA). HRQL was assessed by the 36-Item Short Form Health Survey. SETTING: Molise region, Italy. PARTICIPANTS: 16 937 participants of 24 325 Italian citizens (age≥35). MAIN OUTCOMES: Dietary patterns and HRQL. RESULTS: Mental health was associated consistently and positively with MDS, IMI and an 'Olive oil and vegetable' pattern (PCA1), but negatively with an 'Eggs and sweets' pattern (PCA3). Physical health was associated positively with MDS and PCA1, but negatively with a 'Meat and pasta' pattern. Subjects with the highest MD adherence had 42% (MDS), 34% (IMI) or 59% (PCA1) statistically significant multivariable odds of being in the uppermost level of mental health, as compared with subjects in the lowest category. The associations disappeared after further adjustment for either total food antioxidant content or dietary fibre, while they were not modified by the inclusion of either monounsaturated or polyunsaturated fatty acids. Individuals in the highest PCA1 or PCA3 had significantly higher odds of being in the top level of physical health. CONCLUSIONS: Adherence to an MD pattern is associated with better HRQL. The association is stronger with mental health than with physical health. Dietary total antioxidant and fibre content independently explain this relationship.

Nutrition knowledge is associated with higher adherence to Mediterranean diet and lower prevalence of obesity. Results from the Moli-sani study.

A Mediterranean dietary pattern has been associated with reducing the risk of cardiovascular and chronic disease. The aim of this study was to evaluate the role of nutrition knowledge in determining possible differences among dietary patterns in a general population from a Mediterranean region. We conducted a cross-sectional study on a subsample of 744 subjects enrolled in the population-based cohort of the Moli-sani Project. A 92-item questionnaire on nutrition knowledge was elaborated, validated and administered. Dietary information were obtained from the EPIC food frequency questionnaire and adherence to a Mediterranean dietary pattern was evaluated both by the a priori Greek Mediterranean diet score and the a posteriori approach obtained by principal component analysis. Nutrition knowledge was significantly associated with higher adherence to a Mediterranean dietary pattern. The odds of having higher adherence to a Mediterranean dietary pattern increased with greater nutrition knowledge. The odds ratio of being obese significantly decreased with increasing nutrition knowledge levels. The results showed that nutrition knowledge was significantly associated with higher adherence to a Mediterranean dietary pattern and with lower prevalence of obesity in a Southern Italian region with Mediterranean diet tradition independently from education and other socioeconomic factors.

Low income is associated with poor adherence to a Mediterranean diet and a higher prevalence of obesity: cross-sectional results from the Moli-sani study.

OBJECTIVES: To examine cross-sectional associations of socioeconomic status (ie, income and education) with an adherence to a Mediterranean dietary pattern and obesity prevalence. DESIGN: Cross-sectional study on a sample of Italian subjects enrolled in the Moli-sani Project, a population-based cohort study. The Italian EPIC food frequency questionnaire was used to determine food intake. Adherence to a Mediterranean diet (MD) was appraised according to both the Mediterranean score elaborated by Trichopoulou (MDS) and the novel Italian Mediterranean Index (IMI) and to the a posteriori scores derived from principal component analysis. Four income categories were identified. SETTING: Molise region, Italy. PARTICIPANTS: 13 262 subjects (mean age 53±11, 50% men) out of 24 318 citizens (age ≥35) randomly enrolled in the Moli-sani Project. MAIN OUTCOMES: Dietary patterns and risk factors for cardiovascular disease. RESULTS: Household higher income were significantly associated with greater adherence to an MD (p<0.0001) and to Olive oil and Vegetables dietary pattern in a multivariable model including age, sex, daily energy intake, body mass index, physical activity, smoking, alcohol consumption, education and marital status. The odds of having the highest adherence to an MD clearly increased according to income levels. People having the highest income had 54% (95% CI 21% to 97%, MDS) or 72% (95% CI 34% to 121%, IMI) higher probability to stick to an MD-like eating pattern than those in the lowest-income group. Obesity prevalence was higher in the lowest-income group (36%) in comparison with the highest-income category (20%, p<0.0001). Income was associated with dietary patterns in all categories of education. CONCLUSIONS: A higher income and education are independently associated with a greater adherence to MD-like eating patterns and a lower prevalence of obesity.

Pandemic and seasonal vaccine coverage and effectiveness during the 2009-2010 pandemic influenza in an Italian adult population.

OBJECTIVES: To evaluate the response to pandemic vaccination and seasonal and pandemic vaccine effectiveness (VE) in an Italian adult population, during the 2009-2010 influenza season. METHODS: Data were recorded by interviewing 19,275 subjects (≥35 years), randomly recruited from the general population of the Moli-sani project. Events [influenza-like illness (ILI), hospitalization and death], which had occurred between 1 November 2009 and 31 January 2010 were considered. VE was analyzed by multivariable Poisson regression analysis. RESULTS: Pandemic vaccine coverage was very low (2.4%) in subjects at high-flu risk, aged 35-65 years (N = 8,048); there was no significant preventive effect of vaccine against ILI. Seasonal vaccine coverage was 26.6% in the whole population (63% in elderly and 21.9% in middle-aged subjects at high-flu risk). There was a higher risk to develop ILI in middle-age [VE: -17% (95% CI: -35,-1)] or at high flu-risk [VE: -17% (95% CI: -39, 2)] vaccinated groups. CONCLUSIONS: Coverage of pandemic vaccine was very low in a Southern Italy population, with no protective effect against ILI.

Mass media information and adherence to Mediterranean diet: results from the Moli-sani study.

OBJECTIVE: To investigate the association between mass media information, dietary habits and risk factors for cardiovascular disease in an Italian adult population. METHODS: Subsample of 1,132 subjects (mean age 53 ± 10, 50% men) enrolled in the Moli-sani Project, a population-based cohort study. A specific questionnaire on exposure to information from various media sources was elaborated, validated, and administered. A mass media exposure score was obtained from principal component analysis of ten items of media exposure. Dietary habits were assessed based on eating patterns obtained from principal component analysis of 45 food groups derived from the EPIC food frequency questionnaire and by the Mediterranean score. RESULTS: In a multivariable general linear regression analysis including age, sex, social status, physical activity, C-reactive protein, total calories intake, three dietary patterns or Mediterranean score, higher media exposure was positively associated with adherence to a Mediterranean-like eating pattern (P = 0.0018) as well as to the Mediterranean score (P = 0.0005). CONCLUSIONS: Exposure to mass media information is significantly associated with greater adherence to both Mediterranean diet and Mediterranean-like eating pattern, an association that public health strategies should take into account.

[The surgical tratment of the subperitoneal rectal cancer]. / Trattamento chirurgico del carcinoma del retto sottoperitoneale.

AIM: To value the results of "open" surgery with sphincter preservation, TME nerve-sparing, fast-track, without a protective stoma in a consecutive series of patients with subperitoneal rectal cancer (s.p.r.c.). MATERIALS AND METHODS: In January 1989, we started a prospective, non-randomized study designed to assess when a primary derivative stoma was warranted in a series of consecutive patients electively treated with open low and ultralow AR. The inclusion criteria were: all patients with middle and low rectal cancer who underwent elective low and ultralow AR, including those treated with neoadjuvant therapy. The exclusion criteria were: urgent surgery, incomplete rings in the stapler, a positive hydropneumatic test, preoperative involvement of the external sphincter and/or surrounding structures by the tumor as demonstrated by CT-scan and endorectal MR and/or transrectal ultrasound. Anastomoses between 7 cm and 4 cm from the pectinate line were defined as low colo-rectal anastomoses, while anastomoses lower than 4 cm from the pectinate line were defined as ultralow anastomoses. A fistula or anastomotic dehiscence was suspected when pelvic and/or peritoneal pain, fever, leucocytosis, fecaloid liquid in the drainage and/or perianal erythematosus swelling were present. An anastomotic leak was confirmed by means of angio-CT and/or endoscopy and/or contrast enema depending on the procedure available most promptly. Signs of peritoneal reaction were considered to be indicative of a major dehiscence, regardless of the diameter of the fistula; when diagnosed, a transverse colostomy was immediately performed. Clinically less serious cases were defined as minor dehiscences, for which a "wait and see" strategy or a transcutaneous CT or ultrasound guided drainage of an abscess were used. Sixty-five patients were treated according to a fast-track postoperative protocol. RESULTS: Between 1998 and 2007, 89 patients with s.p.r.c. were treated according to a prospective protocol. One hundred and nineteen patients (69.6%) underwent low anastomoses and 52 patients (30.4%) underwent ultra low anastomoses. Forty-two (24.6%) were treated with traditional AR, 129 (75.4%) with AR and nerve-sparing TME. Forty-six (26.9%) patients underwent neoadjuvant therapy. One hundred and two patients underwent a mechanical end-to-end anastomosis, 67 a double stapled anastomosis, and 2 a colo-anal anastomosis at the pectinate line performed according to our technique. All 6 patients with major dehiscences underwent a protective colostomy within hours of the onset of clinical symptoms immediately after the radiologically- or endoscopically-confirmed diagnosis. The 7 minor dehiscences were successfully treated with conservative therapy (antibiotic and enteral feeding) using an out-patient regimen. Two (28.6%) required percutaneous drainage: one pelvic CT-guided drainage and the other (an ultralow dehiscence) perineal drainage. The 72.6% of the patients survived at 5-years follow-up. The incidence of local recurrences in 2-years followup was 3.2% (on 124 patients). We had no deaths in patients treated with fast-track protocol. CONCLUSION: Open, TME nerve-sparing A.R. with selective use of neoadjuvant therapy, can be successfully performed without a protective stoma in more than 80% of the patients. Fast-track protocol seems to increase quality of p.o. period and decrease hospital stay

[Results of a National Questionnaire on "Treatment of the subperitoneal rectal cancer". Comparision among the international guidelines and metaanalysis]. / Risultati del Questionario Nazionale sulla "Terapia del cancro del retto sottoperitoneale". Confronto con le linee guida internazionali e le metanalisi.

A questionnaire including 20 questions about different aspects of subperitoneal rectal cancer was sent to 2200 fellows of Italian Society of Surgery. The answers were compared with International guidelines and with more recent metaanalyses from the literature. On the whole less than half of Italian surgeons fulfil the terms of the guidelines and the prevalent trend of the International literature. This behaviour concerns the choice of surgical procedure and prevention and diagnosis of anastomotic fistulas.

A randomized comparison of sentinel-node biopsy with routine axillary dissection in breast cancer.

BACKGROUND: Although numerous studies have shown that the status of the sentinel node is an accurate predictor of the status of the axillary nodes in breast cancer, the efficacy and safety of sentinel-node biopsy require validation. METHODS: From March 1998 to December 1999, we randomly assigned 516 patients with primary breast cancer in whom the tumor was less than or equal to 2 cm in diameter either to sentinel-node biopsy and total axillary dissection (the axillary-dissection group) or to sentinel-node biopsy followed by axillary dissection only if the sentinel node contained metastases (the sentinel-node group). RESULTS: The number of sentinel nodes found was the same in the two groups. A sentinel node was positive in 83 of the 257 patients in the axillary-dissection group (32.3 percent), and in 92 of the 259 patients in the sentinel-node group (35.5 percent). In the axillary-dissection group, the overall accuracy of the sentinel-node status was 96.9 percent, the sensitivity 91.2 percent, and the specificity 100 percent. There was less pain and better arm mobility in the patients who underwent sentinel-node biopsy only than in those who also underwent axillary dissection. There were 15 events associated with breast cancer in the axillary-dissection group and 10 such events in the sentinel-node group. Among the 167 patients who did not undergo axillary dissection, there were no cases of overt axillary metastasis during follow-up. CONCLUSIONS: Sentinel-node biopsy is a safe and accurate method of screening the axillary nodes for metastasis in women with a small breast cancer.