Amivantamab plus lazertinib versus osimertinib in first-line EGFR-mutant advanced non-small-cell lung cancer with biomarkers of high-risk disease: a secondary analysis from MARIPOSA.

BACKGROUND: Amivantamab-lazertinib significantly prolonged progression-free survival (PFS) versus osimertinib in patients with epidermal growth factor receptor (EGFR)-mutant advanced non-small-cell lung cancer [NSCLC; hazard ratio (HR) 0.70; P < 0.001], including those with a history of brain metastases (HR 0.69). Patients with TP53 co-mutations, detectable circulating tumor DNA (ctDNA), baseline liver metastases, and those without ctDNA clearance on treatment have poor prognoses. We evaluated outcomes in these high-risk subgroups. PATIENTS AND METHODS: This analysis included patients with treatment-naive, EGFR-mutant advanced NSCLC randomized to amivantamab-lazertinib (n = 429) or osimertinib (n = 429) in MARIPOSA. Pathogenic alterations were identified by next-generation sequencing (NGS) of baseline blood ctDNA with Guardant360 CDx. Ex19del and L858R ctDNA in blood was analyzed at baseline and cycle 3 day 1 (C3D1) with Biodesix droplet digital polymerase chain reaction (ddPCR). RESULTS: Baseline ctDNA for NGS of pathogenic alterations was available for 636 patients (amivantamab-lazertinib, n = 320; osimertinib, n = 316). Amivantamab-lazertinib improved median PFS (mPFS) versus osimertinib for patients with TP53 co-mutations {18.2 versus 12.9 months; HR 0.65 [95% confidence interval (CI) 0.48-0.87]; P = 0.003} and for patients with wild-type TP53 [22.1 versus 19.9 months; HR 0.75 (95% CI 0.52-1.07)]. In patients with EGFR-mutant, ddPCR-detectable baseline ctDNA, amivantamab-lazertinib significantly prolonged mPFS versus osimertinib [20.3 versus 14.8 months; HR 0.68 (95% CI 0.53-0.86); P = 0.002]. Amivantamab-lazertinib significantly improved mPFS versus osimertinib in patients without ctDNA clearance at C3D1 [16.5 versus 9.1 months; HR 0.49 (95% CI 0.27-0.87); P = 0.015] and with clearance [24.0 versus 16.5 months; HR 0.64 (95% CI 0.48-0.87); P = 0.004]. Amivantamab-lazertinib significantly prolonged mPFS versus osimertinib among randomized patients with [18.2 versus 11.0 months; HR 0.58 (95% CI 0.37-0.91); P = 0.017] and without baseline liver metastases [24.0 versus 18.3 months; HR 0.74 (95% CI 0.60-0.91); P = 0.004]. CONCLUSIONS: Amivantamab-lazertinib effectively overcomes the effect of high-risk features and represents a promising new standard of care for patients with EGFR-mutant advanced NSCLC.

Simultaneous immunostaining with anti-S100P and anti-SV40 antibodies revealed the origin of BK virus-infected decoy cells in voided urine samples.

BACKGROUND: Methods for determining the origin of BK virus (BKV)-infected cells (decoy cells) in clinical urine samples have not been established although they could enhance the diagnosis of BKV infection in immunocompromised patients. METHODS: We performed simultaneous immunostaining with anti-S100P (a urothelial marker) and anti-SV40 antibodies in 66 clinical urine samples exhibiting SV40 positivity and a decoy-cell appearance on Papanicolaou staining. The clinical voided urine samples included seven cases of renal transplantation, 47 cases of cancer therapy and 12 cases of non-neoplastic disease. SurePath(™) liquid-based cytology was used for the urine samples. RESULTS: BKV-infected cells were categorized as SV40(+)/S100P(+) and SV40 (+)/S100p(-). SV40(+)/S100P(-) cells were found in 55 cases (83.4%); nine cases (13.6%) carried both SV40(+)/S100P(-) and SV40(+)/S100P(+) cells. The former were identified as BKV infection in renal tubules and the latter in both the renal tubules and urothelial epithelia. The remaining two cases (3.0%) had only SV40(+)/S100P(+) cells of urothelial origin. CONCLUSION: Simultaneous immunostaining with anti-S100P and anti-SV40 is a useful method for determining the origin of BKV-infected cells in clinical urine samples from immunocompromised patients such as renal transplantation recipients.

Comparison of clinical outcomes of osimertinib and first-generation EGFR-tyrosine kinase inhibitors (TKIs) in TKI-untreated EGFR-mutated non-small-cell lung cancer with leptomeningeal metastases.

BACKGROUND: Leptomeningeal metastases (LM) are devastating complications of epidermal growth factor receptor (EGFR)-mutated non-small-cell lung cancer (NSCLC). Although osimertinib, a third-generation EGFR-tyrosine kinase inhibitor (TKI), has better penetration into the central nervous system than first-generation EGFR-TKIs, data on the distinct activity of EGFR-TKIs in untreated advanced EGFR-mutated NSCLC with LM are lacking. PATIENTS AND METHODS: We retrospectively reviewed patients treated with EGFR-TKIs for TKI-untreated common EGFR-mutated NSCLC with LM between July 2002 and July 2021 at the National Cancer Center Hospital. The patients were divided into two groups: patients treated with osimertinib (Osi group) and those treated with gefitinib or erlotinib [first-generation (1G)-TKI group]. RESULTS: Of the 967 patients, 71 were eligible, including 29 in the Osi group and 42 in the 1G-TKI group. The median progression-free survival (PFS) and overall survival (OS) in the Osi group were better than those in the 1G-TKI group (PFS: 16.9 months versus 8.6 months, P = 0.007, and OS: 26.6 months versus 20.0 months, P = 0.158). The LM-overall response rate (ORR) and LM-PFS were significantly better in the Osi group than in the 1G-TKI group (LM-ORR: 62.5% versus 25.7%, P = 0.007; LM-PFS: 23.4 months versus 12.1 months, P = 0.021). In the subgroup analysis of EGFR mutation status, LM-PFS for patients with exon 19 deletion was significantly longer in the Osi group than in the 1G-TKI group (32.7 months versus 13.4 months, P = 0.013), whereas those with L858R mutation in exon 21 did not differ between the two groups. In the multivariate analysis, osimertinib and exon 19 deletion were significant factors for better LM-PFS and OS. CONCLUSION: Osimertinib can be more effective for untreated common EGFR-mutated NSCLC patients with LM, especially those with exon 19 deletion, compared to first-generation TKIs.

Crossed renal ectopia and asymmetric fused kidney, with special reference to associated vertebral anomalies.

Crossed renal ectopia and/or asymmetric fused kidney are unusual congenital anomalies. The deformity itself usually produces no symptoms and the clinical presentation generally suggests obstruction and infection. In our series, 10 of 11 patients presented with various vertebral anomalies. A theory of embryogenesis was reviewed to explain asymmetric patterns of renal fusion with special reference to vertebral anomalies.

[7 cases of congenital multicystic kidney with special reference to its embryogenesis].

We have experienced 7 cases of multicystic kidney. The latest two cases, etiologically of interest, are reported herein with special reference to its embryogenesis. Case 6: A 4-year-old girl was referred to our clinic for further evaluation of mild azotemia and nonvisualization of left kidney. Left kidney was strongly thought to be multicystic kidney from abdominal CT, whereas her contralateral kidney exhibited hydrocalycosis resembling infundibular stenosis with diminished calyceal numbers. Nephrectomy of her left kidney was performed and histological studies confirmed renal dysplasia (primitive duct, metaplastic cartilage, etc.). Case 7: A 7-year-old girl was referred to Hakodate Kyokai Hospital for the evaluation of azotemia and low stature. Her right kidney was not visualized on IVP and her left kidney exhibited hydronephrosis with diminished calyceal numbers. Her right kidney was diagnosed as multicystic kidney on CT-scan. Pyeloplasty of her left kidney was performed. Multicystic kidney is a rather rare congenital disease. Association of various anomalies in contralateral kidney has been emphasized as well as the notion that infundibulopelvic stenosis is a linked in the clinical spectrum extending from cystic dysplasia of the kidney to hydronephrosis. Our last two cases seem to be included in this category of obstruction theory. As shown by microdissection technique (Potter), however, severe ampullary inhibition early in fetal life is also an attractive hypothesis. Diminished calyceal number of contralateral kidneys seen in our recent two cases is compatible with possibility of ampullary damage. Recent experimental study also showed that renal dysplasia is not solely caused by simply mechanical obstruction to urinary drainage, even when the obstruction is imposed at an early stage of renal development.

[Clinical evaluation of combination therapy with cefoxitin and amikacin in complicated urinary tract infections].

The clinical efficacy of combination therapy using Cefoxitin (CFX) and Amikacin (AMK) was studied in 19 patients with complicated urinary tract infections. Patients received 2 g of CFX i.v. and 100 mg of AMK i.m. twice a day. The overall clinical efficacy of treatment was evaluated by the criteria proposed by the UTI Committee, Japan, as excellent, moderate or poor. The overall clinical efficacy was excellent in 89%, moderate in 5% and poor in 5% of the patients. Of the 21 strains isolated from the patients, 20 strains (95%) were eradicated. No subjective side effects were observed. Drug-related aggravation in laboratory tests were observed slight elevations of glutomic-oxalacefic transaminase, glutamic-pyruvic transaminase and alkaliphosphatase in 2 cases, but all of them were minimal and reversible. Underlying condition-related aggravation was observed a slight elevation of BUN and creatinine clearance in 1 case. These results suggest that the combination therapy with CFX and AMK might be useful in the treatment of complicated urinary tract infections.

[Effective administration of recombinant granulocyte colony-stimulating factor to prevent granulocytopenia due to combination chemotherapy for testicular germ cell tumors].

A prospective randomized study on the administration of recombinant granulocyte colony stimulating factor (rG-CSF) was conducted on 15 patients with testicular germ cell tumors. The clinical stagings of all patients except one were minimal to moderate extent according to the Indiana University staging system. Combination chemotherapy using bleomycin, etoposide and cisplatinum (BEP) was performed as the initial treatment on the eligible patients. rG-CSF was administered by two different methods; 1) routine administration on the 6th day after BEP chemotherapy (group A), and 2) the same method, but after granulocytopenia of 1,500/mm3 had developed (group B). The administration of rG-CSF in group A significantly reduced the severity of leucocytopenia and also the incidence of stomatitis compared with group B. Although rG-CSF produced no significant side effects, the thrombocytopenia was prominent in the group A patients (not significant). BEP chemotherapy itself is an easily-tolerable and well established method for treating young adult patients. The method used in group B seems to be suitable in situations where thrombocytopenia and cost effectiveness.

[An electromyographic study of detrusor sphincter dyssynergia in neurogenic vesical dysfunction. Part 2. Changes after radical transurethral resection of prostate and response to alpha-adrenergic stimulation].

The relevance of the type of detrusor sphincter dyssynergia (DSD) and motor unit analysis as examined by simultaneous recordings of electromyography (EMG) of the external urethral sphincter (EUS) and bladder pressure was discussed in the first report. In this report, they were analysed similarly before and after radical transurethral resection of the prostate (TUR-P) to see how it was effective in relieving DSD. Furthermore, the response of the EUS to alpha-adrenergic stimulation was examined by analyzing its motor unit activity. Radical TUR-P was performed in 18 cases. After radical TUR-P, there was an improvement in the type of DSD (3 cases) or in its sub-types (8 cases), associated with decrease in residual urine rate in 16 cases. EUS responded to alpha-adrenergic stimulation with an increase in the frequency of pre-existing motor units and recruitment of new motor units. After radical TUR-P,EUS was similarly activated when stimulated with alpha-adrenergics. These data indicated that radical TUR-P was effective in relieving DSD by suppressing or abolishing abnormal continence reflex. Moreover, alpha-adrenergic activation of EUS also seemed to suggest a possible sympathetic role in the genesis of DSD, although exact mode of its involvement in the somatomotor innervation of the EUS remains to be settled.

[An electromyographic study of detrusor sphincter dyssynergia in the neurogenic vesical dysfunction. Part 1. Its type and further sub-typing based on the analysis of motor units].

Simultaneous recordings of electromyography of the external urethral sphincter (EUS) and bladder pressure were performed in 73 patients. The majority (69 cases) were afflicted with neurogenic vesical dysfunction, while four with benign prostatic hypertrophy (BPH) were also examined as control. Detrusor sphincter dyssynergia (DSD), whereby EUS failed to relax on voiding attempt, was noted in 64 patients. By examining the patterns of DSD throughout the voiding, it was possible to classify them into three distinct types as done by Blaivas. Type 1 was found in 7 patients, Type 2 in 10 patients, and Type 3 in 47 patients. Synergic urethral sphincter activity (Type 0) was found in other 9 patients including all four with BPH. Voiding dysfunction as evaluable by residual urine rate tended to increase as the type deteriorated from 1 to 3. Analysis of motor units revealed that the units noted during continent phase of the bladder disappeared (A0), decreased (A1), and retained or rather increased their activity (A2) during voiding attempt with (B1) or without (B0) recruitment of new units. A0B1 was found in 3 patients, A1B1 in 7, A2B1 in 32, A2B0 in 4, and A1B0 in 2. Again there was a tendency for voiding function to deteriorate as motor units sub-type changed from A0 to A1 and A2. The analysis of these motor units activities suggested that abnormal continence reflex (i.e. failure of vesicourethral and urethrourethral relaxation reflex and exaggeration of urethrourethral contraction reflex) might be contributing to the genesis of DSD.

[Long-term follow up of transurethral resection of the prostate--a review of 137 patients].

For assessing the long-term outcome of patients after transurethral prostatic resection (TUR-P), telephone interview in terms of the urinary symptom and the sexual function was conducted on 191 cases who underwent TUR-P in Hokkaido University Hospital from 1982 to 1988. Adequate replies were obtained from 137 patients (71.7%), whose mean age was 70.2 years old and mean follow up period was 4.8 years. Subjective urinary symptoms, which are mainly classified as dysuria, frequency and incontinence, were improved in 114/120 (95.0%), 99/108 (91.7%), and 20/21 (95.2%) respectively. Overall symptom-free rates of dysuria, frequency, and incontinence were 85.1% (114/134), 86.6% (116/134), and 90.3% (121/134). Morbidity of incontinence following TUR-P was only 6/134 (4.5%). There was one deaths (0.7%) at 2 weeks after TUR-P, but was not attributable to the operative procedure itself. Although 82 cases (59.9%) had risk factors such as the cardiovascular disease, malignancy or other systemic disorders, they did not jeopardize the postoperative course nor were attributed to the mortality. Uninhibited contraction and/or vesical denervation supersensitivity on perioperative cystometrogram were found in 53/84 (63%). These urodynamic abnormalities were not considered to be postoperative urinary symptoms. Postoperatively, the decrease in libido was noted in 12/63 (19%), but its causal relation to the procedure was obscure in most of the patients. We believe TUR-P can offer a satisfactory outcome in the majority of the patients with minimum risk.

[The natural history of renal angiomyolipoma].

PURPOSE: To make the policy of treatment with angiomyolipomas (AML) more clear, we discussed the natural history of angiomyolipomas retrospectively. PATIENTS AND METHODS: Between May 1982 and December 1997, 14 patients with AML in 18 kidneys were followed, who were 2 men in 2 kidneys and 12 women in 16 kidneys, 27 to 80 years old. No patients suffered from tuberous sclerosis. Symptoms, initial sizes and changes of the size were evaluated for these patients. RESULTS: Ten patients with AML in 14 kidneys were asymptomatic and four patients were symptomatic. But one of the 4 patients had symptoms of abdominal pain and palpable mass which were due to contralateral AML that were treated with nephrectomy, so symptoms due to small AML were seen in 3 cases (2.0 cm, 3.5 cm, 3.8 cm). Among 11 patients in 15 kidneys followed radiologically for more than 6 months, the tumors were unchanged in size in 7 kidneys, which were in all of 6 cases with unilateral solitary tumor and in 1 with bilateral multiple tumors. In other 8 kidneys the sizes of the tumors were increased, which were in the cases with multiple tumors in one kidney or in bilateral cases. Compared to the cases of unilateral solitary AML, the size of AML with multiple tumors in one kidney or in bilateral kidneys significantly increased (p < 0.01). Embolization were performed for 4 kidneys, which were in 2 cases with increased tumor in size to more than 4 cm in following period, in 1 with dull flank pain, and in 1 with the tumor more than 4 cm at diagnosis that grew to more than 5 cm. CONCLUSIONS: Unilateral solitary AML was appeared to be hard to increase in size and to have a different natural history from bilateral or multiple tumors.

[Laparoscopic pelvic lymphadenectomy--experimental operation using young pigs and clinical experience in 21 cases with prostate and bladder cancer].

In order to gain the technical skills for performing laparoscopic pelvic lymphadenectomy, we selected the young pigs (12-15 kg) as the experimental model. Five pigs (male 2, female 3) underwent laparoscopic pelvic lymphadenectomy under intravenous anesthesia. Postoperatively, the pigs were euthanized, and laparatomy was performed to demonstrate the area of dissection. Operation time was from 50 to 80 minutes, and no complication occurred in all cases, mastery came rapidly. Following experimental operation, 21 cases with prostate and/or bladder cancer underwent laparoscopic pelvic lymphadenectomy for staging operation from Nov. 1991 to Oct. 1993. Operation time was from 60 to 310 minutes (mean 137). In one of 21 cases, lymph node metastasis was proved. Eighteen of 21 cases underwent radical prostatectomy or cystectomy between 6 to 24 days after laparoscopic pelvic lymphadenectomy. On radical operation, the adhesion of the post-lymphadenectomy was severe in the patients 8 days after laparoscopic pelvic lymphadenectomy, compared with those within 7 days. Radical operation was seemed to be recommended within 7 days after laparoscopic pelvic lymphadenectomy.

[Early experience with an ileocolic bladder substitution (Mainz pouch) in 11 cases].

In the last decade, many continent urinary diversions have been developed for the cystectomy patients. Mainz pouch, which seems to be a sophisticated one without using an alloplastic prosthesis, was adopted in our clinic. We preliminarily report our result in 11 patients who underwent a Mainz pouch procedure in the last 2 years: 1 for bladder augmentation, 5 for total bladder substitution after cystoprostatectomy and 5 (including 2 females) for continent urinary diversion. The mean age of them was 54 years old and the follow up periods ranged from 6 to 24 months. The antimesenteric longitudinal incision of the ileum and cecum and their sutures were performed similarly to the usual detubularized intestinal pouch. The ureteral reimplantation to the colonic segment was accomplished by the submucosal tunnel method. Although the ureteral hiatus was initially positioned at the anal edge of the colon, a new hiatal creation by stabbing the more oral portion of the colon according to the Goodwin's ureterocolic anastomosis was subsequently employed to avoid the trouble of closure of this portion. When the urethral anastomosis was achieved by 4-5 interrupted sutures between the most dependent portion of the cecum and the urethral stump after cystoprostatectomy, the mucosa was everted to the colonic serosa to prevent the stricture. The continent stoma was created by an intussusception of the proximal ileum, which was stabilized by the seromuscular stripping and 2-3 rows of external metal staples. Complication of the alimentary system occurred in 6 of 11 cases (55%), though they were successfully treated by an appropriate conservative management except one who suffered an ileostomy and nephrostomy because of severe panperitonitis.(ABSTRACT TRUNCATED AT 250 WORDS)

[Endourology update].

In urology, endoscopic surgery and laparoscopic surgery are generally named as endourology. Transurethral endoscopic surgery was originated in mid 19th century, and established by 1950s. At present, transurethral resection of the prostate, transurethral resection of the bladder tumor, transurethral incision of the urethral stricture, transurethral vesicolithotripsy, and transurethral ureterolithotripsy, were commonly performed in many urological clinics. Percutaneous nephrolithotripsy and extracorporeal shock wave lithotripsy were introduced in 1980s, and now, open operation for urolithiasis are rarely performed. In 1990s, as a new endourologic procedure, laparoscopic operations are being increasingly applied to the treatment of urological diseases; for example, laparoscopic pelvic lymphadenectomy, laparoscopic varicocelectomy, laparoscopic exploration of non-palpable testis, laparoscopic nephrectomy, and laparoscopic adrenalectomy etc. Of the variety of treatment modalities available, the most effective and least invasive method should be selected appropriately. So, we anticipate the further advancement in minimally invasive therapy, interdependently with our sufficient experience and skills.

Role of lymph node dissection in the treatment of urothelial carcinoma of the upper urinary tract: multi-institutional relapse analysis and immunohistochemical re-evaluation of negative lymph nodes.

AIM: To determine the role of lymph node dissection (LND) in the treatment of urothelial carcinoma (UC) of the upper urinary tract (UUT). PATIENTS AND METHODS: [Study-1] A retrospective multi-institutional study evaluated 293 patients undergoing predominantly nephroureterectomy for UC of the UUT. Of 293 patients, 267 patients had pure UC and 26 demonstrated other histological components. Regarding the pathological node status, 130 patients had pN0 disease, 141 patients had pNx disease and 22 patients had pN+ disease. The sites of initial recurrence and time to first recurrence were reviewed. The sites of recurrence were classified as locoregional or distant recurrence. The relationship between node status and future recurrence was analyzed. [Study-2] Fifty-one patients treated by nephroureterectomy at Hokkaido University Hospital were included. All had LND and all LNs were negative on hematoxylin and eosin staining. We re-evaluated the presence of micrometastasis in LND specimens by anti-cytokeratin immunohistochemistory. RESULTS: [Study-1] Of 293 patients, 76 developed disease relapse. Regional lymph node recurrence was the most common site (34 patients). On multivariate analyses that adjusted for the effect of tumor stage and tumor grade, pNx (skipping LND) was an adverse factor not only for locoregional recurrence, but also for distant relapse. [Study-2] Immunohistochemistry identified micrometastases in 7 (14%) of 51 patients. Regarding survival, 5 of these 7 patients with micrometastases were alive at last follow-up. CONCLUSIONS: On relapse analysis, skipping LND was an adverse factor not only for locoregional recurrence, but also for distant relapse. Immunohistochemistry detected micrometastases in about 14% of patients previously diagnosed as pN0. These findings further support a potential therapeutic benefit of LND by eliminating micrometastases.

Acute renal failure occurring from urinary retention due to a müllerian duct cyst.

A patient with a müllerian duct cyst, which caused acute renal failure secondary to urinary retention, is reported. The case was treated successfully by transurethral unroofing of the cyst.