{'fraction_non_alphanumeric': 0.02748385323622372, 'fraction_numerical': 0.044019971600018325, 'mean_word_length': 4.846813069094805, 'pattern_counts': {'":': 0, '<': 3, '<?xml version=': 0, '>': 0, 'https://': 0, 'lorem ipsum': 0, 'www.': 0, 'xml': 0}, 'pii_count': 0, 'substrings_counts': 0, 'word_list_counts': {'cursed_substrings.json': 0, 'profanity_word_list.json': 0, 'sexual_word_list.json': 3, 'zh_pornsignals.json': 0}}
Efficacy and long-term prognosis of nerve-sparing radical hysterectomy for cervical cancer.

BackgroundRadical hysterectomy (RH) is a type of radical surgery performed for cervical cancer. Urinary dysfunction due to RH exacerbates the postoperative quality of life of cervical cancer patients. The nerve-sparing RH (NSRH) technique has been used as an effective measure to conserve urinary function. However, few reports have been published on the long-term prognosis. This study described performance of our nerve-sparing technique and the long-term prognosis of patients.MethodsSixty-one patients underwent radical hysterectomy in a 5-year period during which the nerve-sparing technique was introduced; of these, 31 patients underwent NSRH and 30 underwent conventional RH. We retrospectively examined the medical records and compared postoperative urinary function and treatment outcome between the two groups.ResultsThe median time required for urinary residual volume to fall to ≤50 ml after removal of the urinary catheter was 6 days (range, 2-20 days) in the NSRH group and 13.5 days (range, 3-46 days) in the RH group. The results were significantly better in the NSRH group (p < 0.05). The mean follow-up period was 2,456.3 days (range, 48-4,213 days). Investigations on curability revealed no significant difference between the two groups in local recurrence and long-term survival rates. The 5-year survival rate was 0.861 in the NSRH group and 0.782 in the RH group; the 10-year survival rate was 0.861 in the NSRH group and 0.679 in the RH group.ConclusionsSurgical procedures for NSRH significantly improved postoperative urinary function without deteriorating local recurrence rates and long-term prognosis.


Introduction 49
Radical hysterectomy (RH), a surgical treatment for cervical cancer, includes removal of 50 the uterus as well as the parametrium and upper vagina and also includes bilateral pelvic 51 lymphadenectomy. This surgical approach, which can cure cervical cancer, was first 52 described by Wertheim more than 100 years ago, was subsequently modified by Okabayashi 53 in 1921, and was made popular again by Meigs in the 1950s and by Piver in the 1970s 1-4 . In 54 Japan, Okabayashi-style RH has a history of use as an optimal therapy for International 55 Federation of Gynecology and Obstetrics (FIGO) stage Ib-IIb cervical cancer. RH, although 56 useful with good therapeutic efficacy, is associated with bladder dysfunction as a long-term 57 postoperative complication due to damage to the pelvic autonomic nervous system 5-8 . The 58 incidence of postoperative bladder dysfunction has been reported to occur in 70%-85% of 59 cases 9 . The pelvic splanchnic nerve is the pathway for neural control of the rectum, bladder, 60 and sexual function. The hypogastric nerve is a sympathetic nerve fiber that is involved in 61 relaxation of the bladder detrusor and contraction of the urethral sphincter. To maintain 62 postoperative bladder function, these neural networks should be preserved as intact as 63 that meet from the anterior had already been cut, the deep uterine vein could be easily 157 lifted to a shallow position. The pelvic nerve plexus was located inside and dorsal to the 158 venous plexus (Fig. 3). 159 7. The nerve plexus was formed where the autonomic nerves exit S2-S4 and the 160 hypogastric nerve exits the cranial side and were joined at the site of the cardinal ligament. 161 Branches of the nerve then advanced in the direction of the uterus and bladder from the 162 plexus. A procedure was performed to protect this bladder branch passing through the 163 lateral portion of the paracolpium that was exposed in the previous step. The outer 164 portion of the paracolpium was detached from the vagina toward the paravesical space, 165 taking care not to damage the vascular plexus inside the paracolpium. This was marked 166 and protected using tape and by moving it outward. 167 8. The hypogastric nerve and the pelvic splanchnic nerve were crossed; these nerves, 168 which are located around the pelvic plexus, and the branching nerves (i.e., the uterine 169 branch and the bladder branch), could be confirmed. Only the uterine branch was cut 170 from this cross, and the pelvic plexus was peeled outward with the cut site as a starting 171 point (Fig. 4). After careful dissection of the pelvic plexus toward the dorsal side, the 172 paravesical space and pararectal space were continuous as the lateral vaginal space, 173 and the pelvic plexus was laterally displaced in a plate-like form (Fig. 5). The plate-like tissue, including nerve fibers completely separated from the uterus and parametrium, 175 became a T-shape without the uterine branch from the cross (Fig. 6). 176 9. The rectovaginal septum was developed, and the rectum was detached from the 177 posterior wall of the vagina. After resection of the uterosacral ligament and the rest of 178 paracolpium, the uterus was connected only to the vagina. The vagina was cut to the 179 required length depending on the degree of tumor invasion. According to the previous 180 step, the pelvic plexus and its branches were completely outside the surgical field, and 181 thus, they were not damaged. 182 The difference between our improved surgical technique and the conventional method is 183 that the pelvic plexus and bladder branch are completely outwardly separated. A crucial goal 184 of the procedure is to maximize the protection of the nerves by ensuring nerve plexus 185 detachment, which has been unpopular because of major bleeding due to venous plexus 186 damage. Therefore, the procedure as it relates to hysterectomy was revised. The procedure 187 that was historically performed from the cranial side to the caudal side (in the order of cardinal The indwelling bladder catheter was placed at the time of surgery and removed after 197 7 days. After removal of the catheter, the patients were free to urinate, and the urination 198 volume and residual urine volume were recorded at the prescribed six times a day. On-time 199 measurement of residual urine volume was performed at 3:00, 7:00, 11:00, 15:00, 19:00, and 200 23:00. The residual urine volume was measured by a nurse immediately after urination and 201 was accurately performed by inserting a catheter into the bladder cavity of the patient. When 202 the residual urine volume was less than or equal to 50 ml for two consecutive days at the 203 same time of day, the residual urine measurement was terminated only at that time. When 204 all measurement times were cleared, it was determined that urination ability was completely 205 established. In addition to the measurement of residual urine volume, micturition desire was 206 also recorded. If no improvement in urinary function was observed even after more than 3 207 weeks from the start of residual urine measurement, the patient was instructed on the method 208 of self-catheterization and discontinued residual urine measurement. If urinary function improved over time even after more than 3 weeks, measurement of residual urine was 210 continued until urination was established. The results are expressed as the mean ± standard deviation (SD) or median as 228 appropriate. The normality of the distribution was examined for all variables that were 229 continuous data. The t-test was used for comparisons of age and BMI between the two 230 groups, where the data showed a normal distribution. For comparisons between the two 231 groups with respect to the operative time, the amount of blood loss, and the number of days 232 until establishment of urination, where the data did not show a normal distribution, the 233 difference between the medians was evaluated using the Mann-Whitney U 234 test. Fisher's exact test was used to compare the nominal variables between the two 235 groups. The log-rank test was used for prognostic comparison between the two groups. All 236 tests were two-sided, and p < 0.05 was considered statistically significant. All statistical 237 analyses were performed with EZR (Saitama Medical Center, Jichi Medical University, 238 Saitama, Japan), which is a graphical user interface for R (The R Foundation for Statistical 239 Computing, Vienna, Austria). More precisely, it is a modified version of R commander 240 designed to add statistical functions frequently used in biostatistics 23 . cancer underwent RH. Patients were divided into two groups according to the type of 245 treatment received: 31 patients were in the NSRH group and 30 were in the RH group. No 246 significant differences in the measured parameters, including staging and histology, were 247 observed between the two groups (Table 1). In the NSRH group, one patient had diabetes, 248 two had depression, one had panic disorder, and one had Hashimoto's disease. In the RH 249 group, two patients had diabetes, one had schizophrenia, and four had hypertension. All In order to evaluate the invasiveness of the surgical procedure, operative time, 263 intraoperative blood loss, and intraoperative complications were compared in both groups. In 264 the NSRH group, the median operative time was 390.0 minutes (range, 253-580 minutes) 265 and the median blood loss was 1,212.0 g (range, 500-3,195 g). In the RH group, the median 266 operative time was 361.5 minutes (range, 255-555 minutes) and the median blood loss was 267 1,562.5 g (range, 500-4,780 g). No significant difference was observed between the two 268 groups (Table 2), and no intraoperative complications occurred in either the NSRH or the RH 269

group. 270
To evaluate urinary function, the postoperative micturition desire and the number of days 271 required to establish urination without a catheter were compared between the two groups. As 272 a result of a self-reported subjective survey, 80.6% (25/31) in the NSRH group were aware 273 of urination after removal of the indwelling bladder catheter, while 46.7% (14/30) in the RH 274 group were aware. The median time required to establish urination after removal of the 275 indwelling bladder catheter was 6 days (range, 2-20 days) in the NSRH group and 13.5 days 276 (range, 3-46 days) in the RH group. These results were significantly better in the NSRH 277 group (p < 0.05). None of the patients in the NSRH group required self-catheterization at 278 discharge, whereas five patients in the RH group did require it (Table 2). A higher prevalence 279 of dysuria has been observed in patients with diabetes or mental illnesses such as depression [24][25][26][27] . However, in this study, postoperative urinary function did not differ 281 significantly between patients with these complications and those without complications. The 282 results of five cases where the patient underwent a unilateral nerve-sparing procedure in the 283 NSRH group were analyzed. The median time required to establish urination was 7 days 284 (range, 5-15 days) in those patients. This number was slightly inferior compared to that of 285 the patients who underwent the bilateral nerve-sparing procedure but was significantly better 286 when compared to that of the patients in the RH group. This result is consistent with a 287 previous report that the contractile function of the detrusor muscle of the bladder is 288 maintained if the unilateral nerve preservation is successful 22 . 289 To assess curability, the local recurrence-free rate, disease-free survival, and overall 290 survival were compared between the two groups. Local recurrence-free rate was observed 291 in 87.1% (27/31) of patients in the NSRH group and 83.3% (25/30) in the RH group. The 292 disease-free survival rate in the NSRH group was 70.0% at 5 years (70.0% at 10 years), 293 while that in the RH group was 68.3% at 5 years (63.1% at 10 years). The overall survival 294 rate was 86.1% in the NSRH group at 5 years (86.1% at 10 years) and 78.2% at 5 years in 295 the RH group (67.9% at 10 years). No differences were observed between the two groups in 296 terms of the local recurrence-free rate, disease-free survival, or overall survival (Fig. 7). The 297 mean follow-up period after treatment was 2,456.3 days (range, 48-4,213 days).

Discussion 299
RH has been the longstanding standard surgical treatment for cervical cancer 300 worldwide. In Western countries, the resection line of RH is defined according to the 301 classification of Piver, Rutledge, and Smith, while in Japan, it is defined according to 302 Okabayashi 4, 28 . Okabayashi surgery is more radical than Piver type III surgery and usually 303 involves sacrifice of the pelvic plexus. Since the sympathetic and parasympathetic nervous 304 systems throughout the pelvic plexus play a key role in normal urinary function, damage to 305 these autonomic nerves caused by RH is strongly associated with the risk of consequent 306 bladder dysfunction 8, 19-21, 29-32 . The importance of carefully identifying and preserving 307 autonomic nerves to minimize bladder dysfunction has recently been emphasized in the 308 practice of RH. Preserving the pelvic autonomic nerves without sacrificing the radicality of 309 RH has been an important issue for gynecological oncologists. Therefore, many studies have 310 been published that include descriptions of nerve-sparing surgical techniques and patient 311 outcomes 5,6,12,13,15,17,18,20,21,[29][30][31][32][33][34][35][36][37][38] . 312 The results of this study showed that, as reported by the authors, our improved nerve-313 sparing technique resulted in well-preserved bladder function and contributed to maintaining 314 the postoperative quality of life of these patients. However, some patients exhibited 315 insufficient bladder function despite nerve-sparing surgery. Commonly conceivable reasons may be nerve damage due to surgical procedures unnoticed by the surgeon and non-visible 317 thermal damage from powered devices. In addition, occasional cases had unexpectedly poor 318 bladder function outcomes, despite complete intraoperative progress and careful adherence 319 to nerve-sparing techniques. We consider that in some cases, the preservation rate of the 320 pelvic plexus may be low due to large individual differences in how nerve tracts run, which 321 may cause unexpectedly poor results. It is very difficult to focus on the nerves that are not 322 present as single distinct nerve bundles such as the obturator nerve. The hypogastric nerve 323 runs like a membrane, while multiple thin nerve fibers cross each other as in a mesh. Similarly, 324 the bladder branch diverging from the pelvic plexus also spreads to the bladder as narrow 325 nerve fibers. Most of the bladder branches pass through the posterior layer of the 326 vesicouterine ligament and reach the area in the back of the bladder mainly from the 327 vesicoureteral junction to the bladder neck. However, these nerve tracts show atypical 328 differences in terms of location, e.g., some fibers run along the ureter, some fibers pass 329 through the anterior layer of the vesicouterine ligament that is located further on the ventral 330 side of the typical nerve tract, and some fibers pass through the anterior vaginal wall 39-331 42 . Fibers that run in relatively shallow layers must be cut, and in such patients, a reduction 332 in the nerve preservation rate is inevitable. The nerve-sparing technique is not a technique 333 of isolating only nerve fibers, but rather, it is a technique of preserving the lateral parametrium and paracolpium, which are expected to contain the majority of nerve fibers. For that reason, 335 it is extremely difficult to achieve 100% complete nerve preservation. We consider that the 336 variability in the results after nerve-sparing surgery is due to such individual differences in 337 nerve tracts. We also consider that in previous reports, the description of nerve-sparing 338 technique was ambiguous and that replication of the technique is sometimes very difficult 339 due to these individual differences in nerve tracts. 340 The main point of the surgical procedure we propose here is that when the posterior layer 341 of the vesicouterine ligament is dissected, it should not be cut from the outside more than is 342 necessary to avoid damage to the bladder branch that runs in the dorsolateral direction. In 343 addition, the procedure of peeling the pelvic plexus outward after dissecting the uterine 344 branch is stopped at the minimum necessary depth. With the above precautions, it is possible 345 to reduce the risk of damage to the nerve plexus due to the dissection procedure and to avoid 346 nerve damage during hemostasis for bleeding due to vascular damage of the 347 parametrium. There is a concern that these procedures will sacrifice curability because these 348 procedures are clearly limited surgically compared with conventional ones that do not 349 consider nerve preservation. A response to this concern is that nerve-sparing surgery had 350 previously been reported to have no adverse effect on the short-term prognosis of these patients, but the results of this study have shown that nerve-sparing surgery also has no 352 adverse effect on the long-term prognosis. 353 As stated above, the nerve-sparing technique is a limited surgery. However, the 354 modification of radical surgery that changes it to a limited surgery presents a conflict. The 355 reason for such an obvious reverse in course is required because radical surgery has been 356 performed as a standard treatment for early-stage cervical cancer, which has remained 357 unchanged for approximately a century. Is highly invasive surgery such as surgery that 358 involves dissection of the pelvic floor really needed in relatively early-stage patients with 359 cervical cancer that has not invaded beyond the cervix? In developed countries today, 360 preoperative staging is performed using various examinations including diagnostic imaging. 361 Specifically, in Japan, both computed tomography and magnetic resonance imaging have 362 become mandatory preoperative examinations. In other words, accurate preoperative 363 diagnosis is now possible compared with the time when RH was first developed. In addition, 364 postoperative adjuvant therapy has also advanced significantly, and some have questioned 365 further whether radical surgery is required for early-stage cervical cancer. Currently, patients 366 with a high risk of relapse are usually treated with additional chemotherapy or radiation 367 therapy or concurrent chemoradiotherapy. In this study, 72.1% of all the patients received 368 adjuvant therapy (55.7% of the patients received chemotherapy and 16.4% of the patients received either radiotherapy or concurrent chemoradiotherapy). This high rate of additional 370 treatment may be one of the reasons why the prognosis did not differ between the two 371 groups. If so, it is questionable whether radical surgery is needed for relatively early invasive 372 cancers, such as FIGO IB stage cancers. The revision of the FIGO classification in 2018 373 acknowledged the use of diagnostic imaging, such as computed tomography or magnetic 374 resonance imaging, to determine the preoperative FIGO classification, as global medical 375 capabilities have improved 43 . Accordingly, it is necessary to conduct a large-scale 376 prospective study to reconsider the optimal surgical method based on accurate preoperative 377

diagnoses. 378
The results of this study indicate that the nerve-sparing technique is effective for bladder 379 function preservation and does not adversely affect short-term or long-term 380 prognosis. However, this study has several limitations. One is that this study is a historical 381 controlled study. Within the enrollment period, patients in the RH group tended to receive 382 treatment relatively early, while patients in the NSRH group tended to receive treatment 383 relatively late. By setting the enrollment period around the transition period of the operative 384 procedure, patients were almost equally assigned to the two groups. In addition, no 385 fundamental treatment changes were implemented during this enrollment period except for 386 the introduction of nerve-sparing techniques. Second, this is a single-center study with a small sample size. This study evaluated the results of surgical procedures, and the accuracy 388 of the procedures should not vary. At this stage, we consider it appropriate to conduct single-389 center studies to perform accurate nerve-sparing techniques for all patients. In the future, it 390 will be necessary to perform more extensive research involving multiple surgeons who can 391 perform nerve-sparing surgery with uniformly high quality. 392 Our findings have shown that NSRH for cervical cancer can maintain satisfactory 393 postoperative bladder function. No difference was observed in local recurrence rates and no 394 adverse effects were seen on the long-term prognosis beyond five years. Therefore, we 395 consider NSRH to be one of the best treatment options for early cervical cancer. The deep uterine vein was cut distally and lifted toward the uterus. The pelvic nerve plexus 565 was located inside and dorsal to the venous plexus. Intersections formed by the 566 hypogastric nerve and the pelvic splanchnic nerve, which merged around the pelvic plexus, 567 and those of the uterine and bladder branches, which were the branching nerves, were 568 confirmed. 569

Figure 4 571
Only the uterine branch was cut from the intersection, and the pelvic plexus was peeled 572 outward with the cut site as the starting point.  Kaplan-Meier curves are shown. a shows the local recurrence-free rate. b shows the 585 disease-free survival. c shows the overall survival. According to the log-rank test, no 586 significant difference was observed in the curves shown in a, b, and c. 587