Occurrence of uroepithelial tumors of the upper urinary tract after the initial diagnosis of bladder cancer

We treated 519 patients with primary bladder cancer, of whom 12 had upper urothelial tumor during followup. Almost all patients had superficial bladder cancer at diagnosis. All but 1 of 12 patients who underwent total cystectomy with ileal conduit diversion also underwent various transurethral procedures for treatment of the primary bladder lesions. The over-all incidence of bladder cancer patients who subsequently had upper urinary tract tumors was 2.3 per cent. Among the patients with treated bladder tumors a higher incidence (13.2 per cent) was observed in dye workers than in the general population (1.1 per cent). The interval between initial treatment of the bladder cancer and diagnosis of the upper urinary tract tumor ranged from 7 to 170 months (mean 70 months). The frequency of upper urinary tract tumors increased with time. We conclude that the appearance of upper urinary tract tumor after diagnosis of primary bladder cancer may be promoted by nonspecific irritation of the urothelium, which previously was made unstable by urinary chemical carcinogens.     

Upper urinary tract transitional cell carcinoma in patients with bladder carcinoma and associated vesicoureteral reflux

Of 269 patients with bladder neoplasms treated during a 20-year period 47 had associated vesicoureteral reflux. All 47 patients were followed for 3 years or more, or until death. Upper urinary tract transitional cell cancer developed in 3, each of whom had recurrent bladder cancer. Among the 222 patients who had vesical cancer without reflux transitional cell carcinoma of the ureter developed in only 1, 11 years after transurethral resection for a bladder tumor. The incidences of upper tract transitional cell cancer in patients with and without vesicoureteral reflux were 6.4 and 0.44 per cent, respectively, which support the suggested role of reflux in disseminating or seeding of cancer cells from the bladder into the upper urinary tract. Patients with bladder cancer and associated vesicoureteral reflux have an approximately 15-fold greater risk of upper tract cancer developing compared with those without reflux. We recommend vigilant scrutiny of patients with recurrent bladder cancer and associated vesicoureteral reflux for early detection of upper urinary tract transitional cell carcinoma.     

The influence of lower urinary tract infection on the recurrence rate of superficial transitional cell carcinoma of the bladder

We studied retrospectively 78 patients with recurrent superficial bladder tumors in an effort to determine whether transitional tumor cells implant and grow preferentially in patients who have undergone endoscopic resection of stage T1 bladder tumors in the presence of an inflamed urothelium. Of the patients 32 (group 1) had an undetected lower urinary tract infection at the time transurethral resection was performed and 46 (group 2) were free of infection. All patients had intravesical chemotherapy by thiotepa (triethylenethiophosphoramide) and were treated with appropriate antibiotics as soon as the urinary tract infection was recognized from 24 to 48 hours postoperatively. Of the patients in group 1, 37.5 per cent had tumor recurrence in less than 6 months and 15.6 per cent in less than 3 months, compared to 30.4 and 6.5 per cent, respectively, in group 2. Although the tumor recurrence rates 3 and 6 months postoperatively were higher among the group 1 patients (with urinary tract infection) the difference between the 2 groups was not significant. Because the patients were treated by intravesical chemotherapy, and antibiotics in those with urinary tract infection, our study does not allow a definite conclusion regarding the contribution of urinary tract infection on the recurrence rate of superficial bladder tumors.     

Uroepithelial tumors of the upper urinary tract following bladder cancer

Five hundred and nineteen patients with primary bladder cancer were treated between January, 1969 and December, 1984, 12 of whom had developed upper urothelial tumors. These patients had received various transurethral treatment for the primary bladder lesions, except for one patient who had undergone total cystectomy and ileal conduit diversion. Overall incidence of patients with upper urinary tract tumors following bladder cancer was 2.3%. The incidence of patients with treated bladder tumors (13.2%) for dye workers was higher than that for the general population (1.1%). The interval between initial treatment of the bladder tumor and diagnosis of the upper tract tumor ranged from 7 to 170 months (mean 70 months). The incidence of upper tract tumors increased with the passage of time. We conclude that the occurrence of upper urinary tract tumors following primary bladder cancers is promoted by nonspecific chemical irritants against the urothelium already made unstable by certain urinary chemical carcinogens.     

Upper urinary tract transitional cell cancer after radical cystectomy for bladder cancer

We studied 425 patients who had undergone radical cystectomy for transitional cell cancer of the bladder and were followed for 5 years or more, or until death. Upper urinary tract urothelial cancer developed in 14 patients (3.3 per cent), 3 of whom had bilateral disease: 2 synchronous and 1 asynchronous. The interval between cystectomy and emergence of the upper tract tumor ranged from 8 to 100 months (mean 40 months). There was a declining incidence of upper tract cancer relative to cystectomy P stage for carcinoma in situ (9.1 per cent), papillary stages O and A (3.6 per cent), stages B1, C and D1 (2.6 per cent) and no residual cancer (0 per cent). Of the 14 patients 8 (57 per cent) had features of multifocal carcinoma in situ in the cystectomy specimens. In 4 of the 14 patients (29 per cent) ipsilateral disease developed when the distal ureteral margins were involved with cancer at cystectomy. Only 3 of the 14 patients (21.4 per cent), all with stage I disease, were alive at the time of this report.     

Carcinoma of the renal pelvis and ureter following bladder carcinoma: frequency, risk factors and clinicopathological findings

We followed 657 primary bladder carcinoma patients for at least 10 years or until death. Subsequent carcinomas of the renal pelvis or ureter were found in 11 patients (1.7 per cent) 10 months to 13 years after the primary bladder tumor. In 3 patients the tumors were diagnosed or suspected by excretory urography, while in 5 the tumors were not found until autopsy. Four patients had undergone cystectomy and 9 had multiple bladder tumors at the initial assessment or during followup. The initial or recurrent bladder tumor involved the ipsilateral ureteral orifice in 6 patients. We conclude that in bladder cancer patients routine excretory urography is not indicated in the absence of upper urinary tract symptoms but it should be performed in selected patients, that is those with multiple and recurrent bladder tumors or tumors involving the ureteral orifices, or those with a previous cystectomy.     

Subsequent upper urothelial cancer following bladder tumor

A total of 110 patients were treated with primary transitional cell carcinoma (TCC) of the urinary bladder from 1990 to 2000. During the follow-up period, which was for at least two years, four patients (3.6 percent) had subsequent upper urothelial cancer at an average of 61.5 months after initial treatment of the bladder tumor. Two of the four patients received transurethral resection several times, and the remaining two patients underwent radical cystectomy for the initial bladder tumor. The histopathological findings of subsequent upper urothelial cancer were almost the same as those for the initial bladder tumor. One patient had accompanying carcinoma in situ (CIS) and the other had adenocarcinoma with TCC. Since 1) high grade, 2) multiple, 3) recurrent and 4) occupational bladder tumors, 5) concomitant CIS, 6) vesicoureteral reflux and 7) tumor invasion of the intravesical ureters have been reported to be risk factors for developing subsequent upper urothelial cancer, patients with bladder tumors who have these risk factors should be followed-up closely.     

Treatment of superficial bladder cancer with intravesical mitomycin C: analysis of immediate and long-term response in 70 patients

A total of 70 patients received intravesical mitomycin C for treatment of superficial bladder cancer. The drug was instilled weekly for 8 weeks. Thirty-nine patients (56 per cent) had failed thiotepa therapy and 25 had high grade tumors. Of the patients 27 (39 per cent) had complete eradication of tumor at the initial 3-month evaluation and an additional 27 had a partial response. The response did not vary with initial tumor grade or stage. Followup averaged 28 months for the 70 patients. A muscle invasive tumor developed during followup in 7 per cent of the patients with an initial complete response, 15 per cent with a partial response and 25 per cent of the initial failures. To date 5 patients (7 per cent) have died of bladder cancer. Intravesical mitomycin C is an effective modality for treatment of superficial bladder cancer. Patients achieving a complete response are at little risk for progressive disease.     

Vesicorenal reflux and upper urinary tract transitional cell carcinoma after transurethral resection of recurrent superficial bladder carcinoma

Of 288 patients with superficial transitional cell carcinoma of the bladder vesicorenal reflux developed after transurethral resection in 26 per cent. This proportion was higher (77 per cent) when we considered only those tumors located near the ureteral orifices. There was a statistically significant relationship (p less than 0.001) between the development of upper urinary tract tumors and vesicorenal reflux (20 per cent of the patients with reflux and 0.9 per cent without reflux had a tumor), which corresponds to a 22-fold greater risk in the former group. Close followup is advised, since 1 of 5 patients with reflux after transurethral resection may have upper urinary tract transitional cell carcinoma.     

Superficial bladder tumors (stage pTa, grades 1 and 2): the importance of recurrence pattern following initial resection

We treated 414 new patients with stage pTa, grades 1 and 2 bladder tumors by transurethral resection between 1970 and 1982. All of the patients with grade 3 or previous upper tract tumors, or who had been treated at some stage with intravesical chemotherapy were excluded. Followup for 5 or more years was available in 188 of the patients. There was a low increase in T stage (6 per cent). Of the patients followed for 5 or more years 46 per cent remained free of tumor. Only 16 per cent of the patients had multiple tumors at presentation and 20 per cent had tumors of 10 gm. or more. These factors were associated with a worse prognosis. Patients free of tumor at 3 months had an 80 per cent chance of having no further recurrences and this rate remained the same up to 2 years from the start of the disease. Patients with a recurrence at 3 months were much less likely to remain free of tumor, and had a higher chance of recurrence at every future visit.     

Present status and background of occupational uroepithelial tumors

The incidence of urothelial cancers in a group of 231 dyestuff plant workers who had been exposed to benzidine (BZ) or to beta-naphthylamine (BNA) was surveyed from 1962 to 1988. Fifteen out of 231 patients (6.5%) were found to have bladder cancer with the mean age at onset of 57.1 +/- 8.7 years. The estimated average period of engaging in this dyestuff exposure for these 15 patients was 92.4 +/- 47.3 months. The mean latent periods from the initial and last exposure until tumor development were 28.8 +/- 5.7 years and 16.6 +/- 7.0 years, respectively. Good negative correlation was observed between exposure periods and latent periods from the last exposure to onset (R = -0.06814). All 15 patients demonstrated tumors in the bladder, and one patient had a metachronous upper urinary tract cancer after treatment for bladder cancer. All tumors were histologically transitional cell carcinomas except for one adenocarcinoma. For initial treatment, five underwent total cystectomy, eight had transurethral resection (TUR) of the tumor, and one had partial cystectomy. Five out of 8 patients who had TUR have developed recurrent bladder tumors, and two of those patients underwent total cystectomy for second treatments. The mean follow-up period was 8.6 +/- 5.2 years, with two dying of cancer. For detection and monitoring, flow cytometric (FCM) analyses were available in five cases with bladder tumor and in two follow-up cases after bladder preserving treatments.(ABSTRACT TRUNCATED AT 250 WORDS)     

Patients with clinically unconfirmed positive urinary cytology --retrospective analysis of clinical courses

We retrospectively analyzed the clinical courses of 7 patients with clinically unconfirmed positive urine cytology characterized by persistent positive urine cytology but without any evidence of tumor by endoscopy or image diagnosis during the time from January 1999 to June 2004. A past history of urothelial cancer was found in 5 patients. In 2 of these 5 patients, transurethral resection of the bladder mucosa and ureteroscopy done as the initial examination identified bladder cancer and ureteral cancer, respectively. Urothelial cancer was found in the remaining 3 patients by subsequent endoscopy, image diagnosis and surgical resection that were done in the follow-up period of 8 months. Two patients who did not have a history of urothelial cancer were diagnosed as having bladder cancer and ureteral cancer in the initial or subsequent examination. Patients with clinically unconfirmed positive urine cytology should be carefully followed up with endoscopy and image diagnosis since the subsequent examinations tend to identify urothelial cancer in the upper urinary tract or bladder.     

The value of urodynamic testing in the management of neonates with myelodysplasia: a prospective study

We report the results of a prospective study conducted to identify neonates with myelomeningocele at risk for changes in the upper urinary tract. Thirty newborns underwent full urological evaluation and were followed for a mean period of 18.2 months. The initial studies included voiding cystourethrography, excretory urography and urodynamic tests. Followup consisted of periodic radiographic studies and repeat urodynamic testing if any changes were observed. According to urodynamic findings the patients were divided into 2 groups: group 1 consisted of 9 neonates (30 per cent) with detrusor-sphincter dyssynergia and high pressure, decreased-compliance bladders, and group 2 consisted of 21 children (70 per cent) with atonic bladders and low pressure, reduced-compliance bladders without dyssynergia. In group 1, 55 per cent of the patients had initially abnormal radiographic findings in contrast with 28.5 per cent in group 2. Anticholinergic drugs and clean intermittent catheterization or vesicostomy reversed the changes in 40 per cent of the children in group 1, 40 per cent remained stable and 20 per cent showed signs of deterioration. Four children in group 1 with normal neonatal radiographs were treated expectantly and at followup they all showed signs of deterioration. The neonates in group 2 with normal radiographic findings remained normal at followup. Of those who initially had changes 67 per cent reversed to normal without treatment, 17 per cent remained stable and 17 per cent had deterioration. Newborns with detrusor-sphincter dyssynergia or high pressure, reduced-compliance bladders are at high risk of having upper urinary tract changes and require preventive decompressive treatment. Children with atonic or low pressure, reduced-compliance bladders and those with a coordinated bladder and sphincter are at low risk and need only close followup.     

The outcome of patients on dialysis with upper urinary tract transitional cell carcinoma

PURPOSE: Transitional cell carcinoma is the most common upper urinary tract cancer in Taiwanese patients on dialysis. It is a unique finding compared with Western countries. Unfortunately, the long-term outcomes of patients with upper urinary tract transitional cell carcinoma on dialysis are largely unknown. This study presents clinical outcome of patients on dialysis with upper urinary tract transitional cell carcinoma. MATERIALS AND METHODS: We retrospectively reviewed the medical records of all patients with upper urinary tract transitional cell carcinoma who had end stage renal disease and underwent dialysis. Traditional prognostic factors including age, sex, tumor grade, stage and tumor location were analyzed with respect to disease recurrence and survival. RESULTS: A total of 73 patients were included in this study. The major complaints were painless gross hematuria and urethral bloody discharge. Disease relapsed in 40 (54.8%) patients at average time of 15 months (2 to 92). Univariate analysis failed to identify significant prognostic factors for recurrence. The average duration between primary and contralateral metachronous upper urinary tract transitional cell carcinoma recurrence was 36 months (range 5 to 96). Patients on dialysis with upper urinary tract transitional cell carcinoma who had previous or concurrent bladder tumor, or who had a history of recurrent bladder tumor, had high contralateral upper urinary tract transitional cell carcinoma recurrence. (p = 0.038) The statistically significant prognostic factor for disease-free survival was pT stage (p = 0.041). CONCLUSIONS: Patients on dialysis with painless gross hematuria or bloody urethral discharge must undergo detail urinary system evaluation. Since patients with upper urinary tract transitional cell carcinoma on dialysis have a high recurrence rate and metachronous or even multiple, early synchronous tumor characteristics that may be missed by imaging, total urinary tract exenteration is a recommended therapeutic option.     

Superficial transitional cell carcinoma of the ureteral orifice: Higher risk of developing subsequent upper urinary tract tumors

AIM: Reports specifically addressing transitional cell carcinoma (TCC) of the ureteral orifice are scarce. This paper presents our experiences of such tumors, including the characteristics of the disease and the incidence of subsequent upper urinary tract recurrence. METHODS: This study included 572 new cases of TCC of the urinary bladder diagnosed in our institute during a period of 5 years. Thirty-one (5.4%) patients had superficial tumors involving ureteral orifices. All 31 patients underwent transurethral resection of the bladder tumors, including the involved ureteral orifices. After the surgery, patients received regular follow up with cystourethroscopy, urine cytology and periodic intravenous pyelography (IVP). Ureterorenoscopy was performed in cases of suspicious IVP or urine cytology findings. RESULTS: Thirty-one patients with superficial tumors involving the ureteral orifice were followed up for 5-8 years or until death. The pathological stage was Ta in 16 cases and T1 in 15 cases. Bladder tumor recurrence was noted in three (18.8%) of the pTa patients and in seven (46.7%) of the pT1 patients. Subsequent upper urinary tract tumors developed in four (12.9%) patients between 33 and 67 months (mean: 33.5) after the first transurethral resection. All four cases of upper tract recurrence had pT1 primary bladder tumor, which recurred for 1-3 times (mean 1.8) before upper tract recurrence. None of these patients had ureteral stenting after bladder tumor resection. Three of four patients with upper tract recurrence had single lower ureteral tumor, while the remaining one patient had multiple tumors. Patients with subsequent upper urinary tract tumors underwent nephroureterectomy and bladder cuff excision. One died of the disease; the other three cases were free of the disease after the therapy. CONCLUSIONS: Patients with primary superficial bladder transitional cell carcinoma involving the ureteral orifice have a higher risk of developing subsequent upper urinary tract tumors, particularly for pT1 primary bladder tumors. Frequent and close follow up is recommended.     

Different treatment strategies for end stage renal disease in patients with transitional cell carcinoma

PURPOSE: Transitional cell carcinoma is the most common urinary tract cancer in Taiwanese patients on dialysis. It is a unique finding compared within Western countries. Due to this geographic difference and a higher recurrence rate a more extensive operation and aggressive followup protocols should be refined for these patients on dialysis. MATERIALS AND METHODS: We retrospectively reviewed the medical records of all patients with transitional cell carcinoma who had end stage renal disease and underwent hemodialysis. Records were reviewed for hemodialysis duration, initial tumor location, tumor grade, stage, operative method, operative complication and final surgical status. Tumor grade and stage was determined by the WHO and proposed Jewett systems. Six patient groups were classified according to final surgical status for comparative analysis. RESULTS: A total of 30 patients were included in this study. Painless gross hematuria and urethral bloody discharge were the most common complaints. Tumor in 25 of the 30 cases was high grade and all were early stage. Of the patients 11 (36.7%) had undergone bilateral nephroureterectomy and radical cystectomy in as a 1 or multiple step procedure. Six patients (20%) had undergone bilateral nephroureterectomy at 1 or 2 sequential operations. Seven of the 13 patients (53.8%) in whom low urinary tract transitional cell carcinoma was initially treated with transurethral resection unfortunately had recurrent transitional cell carcinoma of the upper urinary tract. Ten of the 14 patients (71.4%) with upper urinary tract transitional cell carcinoma who underwent nephroureterectomy and bladder cuff excision had subsequent transitional cell carcinoma within the bladder. CONCLUSIONS: Patients with transitional cell carcinoma on dialysis had a higher recurrence rate in the upper urinary tract than patients not on dialysis. Most cases were at an early stage but with high grade tumor behavior. In 11 patients (36.7%) total exenteration of the urinary tract except the urethra was eventually done. The final bilateral nephroureterectomy rate was 56.7%. Since the rate of total exenteration and bilateral nephrectomy was abnormally high at such a short followup, 1-step bilateral nephroureterectomy and radical cystectomy are a recommended treatment for patients with transitional cell carcinoma on dialysis.     

Acute urinary retention associated with prostatic carcinoma

We describe the prospective evaluation of 90 patients seen at 2 medical centers who presented with acute urinary retention. All patients had a pre-retention history obtained, as well as careful prostate examination, perineal prostate biopsy and followup treatment or monitoring. Prostate cancer was found in 12 of the 90 patients (13.3 per cent), while 1 had metastatic leukemia to the prostate. Of the 90 patients 69 (76.7 per cent) had a palpably benign prostate and 2 malignancies (2.9 per cent) were diagnosed, while 11 malignancies occurred in 21 patients (52.4 per cent) with a suspicious examination. A total of 46 patients (51.1 per cent) underwent further prostate resection and no malignancy was found in any of these specimens: 43 underwent transurethral resection (24.9 gm. average), while 3 underwent open prostatectomy (97 gm. average). Other etiologies of acute retention included benign hyperplasia, other underlying illness, medical procedures, medications, prostatitis and prostatic infarction. Among the 44 patients who did not undergo prostatectomy 13 had treatment of the diagnosed cancer, 9 had resolution of retention and symptoms without intervention, 9 remained catheterized due to severe medical problems, 8 were treated for prostatitis, 2 had discontinuation of sympathomimetic drugs and 1 each underwent urethrotomy, bladder neck incision and resolution of prostatic infarction. In contrast to the older literature in which approximately 25 per cent of the patients presenting with acute urinary retention had prostate cancer, our data suggest a lower incidence. Prostatic biopsy for patients who present with acute urinary retention and a benign examination does not appear to be justified.     

Upper urinary tract recurrence following radical cystectomy for bladder cancer

AIM: The objective of this study was to analyze the clinicopathological features of upper urinary tract recurrence following radical cystectomy for bladder cancer. METHODS: Between 1995 and 2003, 583 patients underwent radical cystectomy and urinary diversion for bladder cancer at the authors' institution and the related hospitals. A retrospective review of patient records was carried out to evaluate characteristics of patients who underwent upper urinary tract recurrence after radical cystectomy. RESULTS: During the observation period (median, 41.5 months), 12 (2.1%) of the 583 patients had upper urinary tract recurrence. Of the 12 patients with upper urinary tract recurrence, there were multiple tumors in eight at the initial diagnosis of bladder cancer, and eight received transurethral resections two or more times before radical cystectomy. The median time to diagnosis of an upper urinary tract cancer after radical cystectomy was 29.5 months. When upper urinary tract recurrence was detected, five patients had metastatic diseases simultaneously, and two had bilateral upper urinary tract cancers. The cancer-specific survival in patients with upper urinary tract recurrence was significantly poorer than that in those without upper urinary tract recurrence. In addition, eight of the 12 patients (66.7%) died of disease progression within 3 years after the diagnosis of upper urinary tract cancer. CONCLUSIONS: These findings suggest that despite the low incidence of upper urinary tract recurrence following radical cystectomy, the prognosis of such patients was markedly poorer compared with that of those without upper urinary tract recurrence. Accordingly, intensive therapies should be considered when upper urinary tract recurrence is detected after radical cystectomy.     

Relationship of leukoplakia to urothelial malignancy

The records of 108 patients presenting with leukoplakia of the urinary tract during the last 35 years were reviewed to define the natural history of this disease, with emphasis upon its association with urothelial cancer. Of the 108 patients 24 had upper urinary tract, 78 bladder and 10 urethral leukoplakia (1 with renal and bladder involvement, 3 with bladder and urethral involvement, and 1 with ureteral and renal involvement). Presenting complaints were primarily irritative. To date, 41 patients (37 per cent) have had associated carcinoma of the urothelium: 23 (21 per cent) presented with a concomitant or previous carcinoma and 18 of 85 (21 per cent) presenting without a concomitant or previous neoplasm have had documented progression to cancer. These figures support the concept that leukoplakia is a premalignant disease and that patients with this diagnosis deserve careful and frequent followup.     

Conservative elective treatment of upper urinary tract tumors: a multivariate analysis of prognostic factors for recurrence and progression

PURPOSE: We evaluate the safety and efficacy of conservative elective treatment of upper urinary tract tumors, and determine predictive factors for recurrence and progression to optimize indications of this type of treatment. MATERIALS AND METHODS: Since 1984 we have performed a prospective study of conservative treatment of single, low grade and stage, less than 3 cm. upper tract tumors. The study includes 54 patients with a normal contralateral kidney who had been followed for more than 36 months. Open conservative surgery was performed in 31 cases and endourological surgery in 23. Minimum followup was 36 months, maximum 210 and mean 84.8. Univariate and multivariate analyses of recurrence and progression were performed in relation to age, sex, association with a bladder tumor, bladder tumor stage and grade, sequence of bladder tumor in relation to upper urinary tract tumor, number of previous bladder tumor recurrences, association with bladder carcinoma in situ, upper urinary tract tumor grade, stage, location, size and therapy, and upper urinary tract cytology. RESULTS: Of the 54 patients 19 (35%) had recurrence, which was bilateral recurrence in 4, and progression occurred in 9 (16%). At the end of analysis 44 (62.9%) patients were disease-free and alive at a mean time of 92.88 months, 13 (24%) died disease-free at a mean of 72.7 months and 7 (12.9%) died of disease at a mean of 97.85 months. Cause specific mortality occurred in 7 (12.9% cases). Among the 54 initially conservatively treated units 42 (77.7%) kidneys were ultimately preserved. On univariate and multivariate analysis tumor location in the renal pelvis and association with a previous multi-recurrent bladder tumor were variables significantly related to recurrence and progression, as well as bilateral recurrence. CONCLUSIONS: Conservative treatment is an optional approach for select upper urinary tract tumors. The strongest risk factors for recurrence and progression were association with a previous multi-recurrent bladder tumor and tumor location in the renal pelvis but these conditions were also the strongest risk factors for bilateral recurrence. Conservative treatment can also be recommended in these cases but only with compliant patients and close followup.