Pharmakokinetische, fluoreszenzmikroskopische Studie zur Gewebeaufnahme und Verteilung von 5-Aminolävulinsäure aus 5-ALA-Thermogel bei zervikaler intraepithelialer Neoplasie (CIN 1-3)

Die photodynamische Diagnostik und Therapie sind relativ neue Methoden zur Detektion und Behandlung von CIN-Läsionen. Sie erfolgen nach Applikation einer photosensibilisierenden Substanz vor der Portio und einer Illumination mittels Laserlicht einer definierten Wellenlänge. In den von uns durchgeführten Untersuchungen wurde als photosensibilisierende Substanz 5-ALA-Thermogel verwendet. Diese Präparation geht bei mehr als +31° C in einen gelartigen Zustand über. Die Lösung wird unter Zuhilfenahme einer Zervixkappe aufgebracht. Durch die Gewebetemperatur erfolgt dann die Umwandlung zum Gel. Das Ziel der Untersuchungen war die Feststellung der optimalen Applikationsdauer und der optimalen Applikationsdosis für die Durchführung der photodynamischen Therapie (PDT) bei Patientinnen mit Zervixdysplasie (CIN 1-3). Im Zeitabschnitt zwischen Dezember 2001 und April 2002 wurden 27 nicht schwangere Patientinnen mit zytologisch bzw. histologisch nachgewiesener CIN 1, CIN 2 und CIN 3 nach Beachtung von Einschluss- und Ausschlusskriterien in die Studie einbezogen. 0,5 bis 12 Stunden vor therapeutischer Konisation wurden 10 ml eines 4%, 10% oder 20%igen 5-ALA-Thermogels auf die Portio uteri aufgetragen. Weiterhin wurden bei allen Patientinnen Biopsien entnommen, die histologisch untersucht wurden. Die Biopsien von 25 Patientinnen wurden der semiquantitativen, topografischen Fluoreszenzmikroskopie und der quantitativen Fluoreszenzspektrometrie unterzogen. Die Ergebnisse der durchgeführten Untersuchungen zeigen, dass die PPIX-Fluoreszenz ihr Maximum bei der Applikation von 10%igem 5-ALA-Thermogel und einem Inkubationsintervall von über 2 Stunden erzielt. Eine höhere Konzentration des 5-ALAThermogels verursachte keinen weiteren Anstieg der PPIX-Fluoreszenzintensität. Aufgrund dieser Ergebnisse empfehlen wir für die PDT 10%iges 5-ALA-Thermogel, das eine maximale PPIX-Sättigung (PPIX-Fluoreszenzintensität) im Gewebe ergibt und dadurch eine maximale Effektivität für die Therapie erwarten lässt. Es sollte jedoch für eine PDT nicht nur eine maximale PPIX-Sättigung im Gewebe erzielt werden, sondern auch eine entsprechend hohe Selektivität nur für dysplastisch veränderte Zellen. In dieser Studie wurde eine statistisch signifikante höhere PPIXFluoreszenzintensität in den CIN-Arealen festgestellt im Vergleich zum normalen umgebenden Plattenepithel (p<0,05). Dies weist auf eine relativ selektive Aufnahme bzw. Konversion von 5-ALA bzw. Protoporphyrin IX aus Thermogel ins CIN-Gewebe hin. Eine statistisch signifikante Differenz zwischen CIN 1, CIN 2 und CIN 3 wurde nicht beobachtet. Nach 4-6 Stunden war eine maximale PPIX-Fluoreszenzintensität im dysplastischen Epithel zu detektieren. Aber auch im normalen Epithel fand sich eine wenn auch schwächere Fluoreszenz mit Maximum ebenfalls nach 4 bis 6 Stunden. Es wird postuliert, dass das Ansprechen auf eine PDT mit der maximalen Fluoreszenz korreliert. Daher wird für den klinischen Einsatz des 5-ALA-Thermogels ein Inkubationsintervall von 4 bis 6 Stunden empfohlen. In diesem Zeitabschnitt dürfte die durchgeführte PDT maximale Effektivität haben. Die für eine selektiv wirkende PDT relevante Inkubationszeit, nach der eine maximale Fluoreszenz-Ratio zwischen verändertem und gesundem Gewebe zu erzielen ist (Tumorselektivität) betrug 2-6 Stunden, unabhängig vom Schweregrad der CIN. Die Tumorselektivität des Photosensibilisators ist ein wichtiges Kriterium für die PDT, weil hierdurch eine selektive Therapie dysplastischer Areale unter weitgehender Schonung der gesunden Schleimhaut erwartet werden darf. Bei Analyse der stadienabhängigen Fluoreszenzratio zum normalen Gewebe zeigte sich, dass die maximale Tumorselektivität von ca. 4 bei Patientinnen mit CIN 3 nach einer Inkubation von 3-4 Stunden beobachtet wurde und gegenüber CIN 1 signifikant erhöht war. Im Vergleich zur Studie von Pahernik et al., der mit 5-ALA-Kieselgel-Lösung eine inhomogene PPIX-Fluoreszenz und eine wesentlich geringere Tumorselektivität nachgewiesen hat, konnten wir in unserer Studie belegen, dass das 5-ALA-Thermogel wohl zu einer besseren Aufrechterhaltung hoher lokaler ALA-Konzentration vor der Portio uteri führt. Das dürfte eine höhere Effektivität der PDT im klinischen Setting und eine verbesserte Selektivität bei Patientinnen mit hochgradiger CIN ergeben. In der semiquantitativen, topografischen Fluoreszenzmikroskopie zeigte sich eine statistisch signifikante Differenz in der PPIX-Fluoreszenzausprägung zwischen der CIN 1-3 und dem normalen umgebenden Plattenepithel (p<0,05). Diese Ergebnisse stimmen mit den Studienergebnissen der quantitativen Fluoreszenzspektrometrie gut überein und bestätigen die Kongruenz der subjektiven mit der quantitativen Methode. Ziel dieser Arbeit war es, die Pharmakokinetik von 5-ALA-Thermogel zu beurteilen im Hinblick auf einen klinischen Einsatz der 5-ALA PDT bei Patientinnen mit CIN. Aufgrund dieser fluoreszenzmikroskopischen und spektroskopischen Ergebnisse empfehlen wir für die PDT die Verwendung von 10%igem 5-ALA-Thermogel mit einem Zeitintervall von 4-6 Stunden

Electronic patient-reported outcomes from home in patients recovering from major gynecologic cancer surgery: A prospective study measuring symptoms and health-related quality of life

We previously reported on the feasibility of a Web-based system to capture patient-reported outcomes (PROs) in the immediate postoperative period. The purpose of this study was to update the experience of these patients and assess patient and provider satisfaction and feedback regarding the system

Isolated torsion of the utero‐ovarian ligament

Key Clinical Message Isolated utero‐ovarian torsion poses a challenge to diagnosing adnexal torsion, as it may not present with imaging findings. Clinicians with high suspicion for torsion but lack of evidence on ultrasonography should proceed to diagnostic laparoscopy. Abstract Adnexal torsion occurs when the ovary rotates around its supporting ligaments, the infundibulopelvic and utero‐ovarian (UO) ligaments, often causing disruption of blood supply. This pathology often presents with acute pelvic pain and is a gynecologic surgical emergency. Diagnosis is typically made with Doppler ultrasound, although dual blood supply to the ovary poses additional diagnostic challenges and sensitivity of this tool is debated. In this case study, we present a case of missed torsion due to isolated compromise of UO ligament

Delayed presentation of placenta accreta following a first‐trimester medical abortion

Key Clinical Message Placenta accreta can rarely present as a uterine mass on imaging months after a first trimester medical abortion, even in patients at low‐risk for abnormal placentation. Early and accurate diagnosis can be crucial to reduce morbidity and mortality associated with this disease, particularly for those desiring fertility preservation

Incisional infiltration versus transversus abdominis plane block of liposomal bupivacaine after midline vertical laparotomy for suspected gynecologic malignancy: a pilot study

Background: To evaluate whether incisional infiltration of liposomal bupivacaine would decrease opioid requirement and pain scores after midline vertical laparotomy for suspected or known gynecologic malignancy compared with transversus abdominis plane (TAP) block with liposomal bupivacaine. Methods: A prospective, single blind randomized controlled trial compared incisional infiltration of liposomal bupivacaine plus 0.5% bupivacaine versus TAP block with liposomal bupivacaine plus 0.5% bupivacaine. In the incisional infiltration group, patients received 266 mg free base liposomal bupivacaine with 150 mg bupivacaine hydrochloride. In the TAP block group, 266 mg free base bupivacaine with 150 mg bupivacaine hydrochloride was administered bilaterally. The primary outcome was total opioid use during the first 48-hour postoperative period. Secondary outcomes included pain scores at rest and with exertion at 2, 6, 12, 24 and 48 h after surgery. Results: Forty three patients were evaluated. After interim analysis, a three-fold higher sample size than originally calculated was required to detect a statistically significant difference. There was no clinical difference between the two arms in mean opioid requirement (morphine milligram equivalents) for the first 48 h after surgery (59.9 vs. 80.8, p = 0.13). There were no differences in pain scores at rest or with exertion between the two groups at pre-specified time intervals. Conclusion: In this pilot study, incisional infiltration of liposomal bupivacaine and TAP block with liposomal bupivacaine demonstrated clinically similar opioid requirement after gynecologic laparotomy for suspected or known gynecologic cancer. Given the underpowered study, these findings cannot support the superiority of either modality after open gynecologic surgery

HOXA11 is critical for development and maintenance of uterosacral ligaments and deficient in pelvic prolapse

Pelvic organ prolapse (POP) is a common, debilitating disorder affecting millions of women. Uterosacral ligaments (USLs) are the main supportive structures of the uterus and vagina and are often attenuated in women with POP. Although the mechanical strength of USLs is known to be dependent on collagen synthesis and catabolism and the degradation protein MMP2 has been implicated in POP, the molecular mechanisms involved in the development of POP are currently unknown. Homeobox (HOX) genes are transcriptional regulators that orchestrate embryonic development of the urogenital tract. We demonstrated here that HOXA11 was essential for organogenesis of the USL by showing that USLs were absent in Hoxa11-null mice. We compared expression of HOXA11, collagen type I, collagen type III, MMP2, and MMP9 in USLs of women with and without POP. Expression of HOXA11 and both collagens was dramatically decreased while MMP2 was increased in women with POP. Constitutive expression of Hoxa11 in murine fibroblasts resulted in significantly increased expression of collagen type III and decreased expression of MMP2. These results identified HOXA11 as an essential gene for the development of the USL and suggested that women with POP might have weakened connective tissue due to changes in a signaling pathway involving HOXA11, collagen type III, and MMP2

The value of 18F-FDG PET/CT in recurrent gynecologic malignancies prior to pelvic exenteration

OBJECTIVE: In patients undergoing pelvic exenteration for recurrent gynecological malignancies, we assessed the performance of [(18)F]-FDG PET/CT for delineating disease extent and evaluated the association between quantitative FDG uptake metrics (SUVmax, total lesion glycolysis [TLG] and metabolic tumor volume [MTV]) and progression-free survival (PFS) and overall survival (OS). METHODS: Retrospective study of patients undergoing pelvic exenteration for gynecologic malignancies between January 2002 and November 2011 who had FDG PET/CT within 90days before surgery. Two readers (R1, R2) independently determined the presence of bladder, rectum, vagina, cervix and pelvic side wall invasion and measured SUVmax, TLG and MTV in each patient. Areas under the curve (AUCs), for detecting organ invasion were calculated. Kaplan-Meier graphs were used to determine associations between FDG uptake and PFS/OS. Inter-reader agreement was assessed. RESULTS: 33 patients (mean age 56years, range: 28-81) were included; primary sites of disease were the cervix (n=18), uterus (n=8) and vagina/vulva (n=7). AUCs for organ invasion ranged from 0.74 to 0.96. There was a significant association between FDG uptake metrics incorporating tumor volume (TLG and MTV) and OS (p≤0.001) as well as between MTV and PFS (p=0.001). No significant association was identified between SUVmax and OS/PFS (p=0.604/0.652). Inter-reader agreement for organ invasion was fair to substantial (k=0.36-0.74) and almost perfect for FDG quantification (ICC=0.97-0.99). CONCLUSION: In patients undergoing pelvic exenteration for recurrent gynecological malignancies, (18)F-FDG PET/CT is useful for preoperative assessment of disease extent. Furthermore, quantitative metrics of FDG uptake incorporating MTV serve as predictive biomarkers of progression-free and overall survival in this population

Role of preoperative MR imaging in the evaluation of patients with persistent or recurrent gynaecological malignancies before pelvic exenteration

PURPOSE: To determine the diagnostic performance of MRI in assessing local tumour extent and evaluate associations between MRI features and survival in patients undergoing MRI before pelvic exenteration for persistent or recurrent gynaecological cancers. METHODS AND MATERIALS: The study included 50 patients with persistent or recurrent gynaecological malignancies who underwent pelvic exenteration between January 1999 and December 2011 and had MRI at most 90 days before surgery. Two radiologists independently assessed invasion of adjacent organs (on a 5-point scale). Diagnostic accuracy, inter-reader agreement, and associations between organ invasion on MRI and patient survival were evaluated. RESULTS: Areas under receiver operating characteristic curves (AUCs) for invasion of the bladder, rectum and pelvic sidewall were 0.96, 0.90 and 0.98 for reader 1 and 0.95, 0.88 and 0.90 for reader 2. Corresponding sensitivities/specificities were 87.0 %/92.6 %, 81.3 %/97.0 % and 87.5 %/97.2 % for reader 1, and 87.0 %/100.0 %, 75.0 %/97.0 % and 75.0 %/94.4 % for reader 2. Inter-reader agreement was excellent for organ invasion (κ = 0.81-0.85). Pelvic sidewall invasion on MRI was associated with overall and recurrence-free survival (P = 0.01-0.04 for the two readers). CONCLUSION: Preoperative MRI is accurate in predicting organ invasion. It may guide surgical planning and serve as a predictive biomarker in patients undergoing pelvic exenteration for gynaecological malignancies. KEY POINTS: • MRI can accurately assess bladder and rectal wall invasion before major surgery. • MRI identifies patients requiring extended pelvic exenteration by detecting sidewall invasion. • Inter-reader agreement for detecting organ invasion and tumor size is excellent. • Pelvic sidewall invasion on MRI is associated with shorter overall and recurrence-free survival

Magnetic resonance imaging/positron emission tomography provides a roadmap for surgical planning and serves as a predictive biomarker in patients with recurrent gynecological cancers undergoing pelvic exenteration

OBJECTIVE: Magnetic resonance imaging (MRI) is the modality of choice for staging gynecological cancers owing to its superb soft tissue resolution, whereas F-fluorodeoxyglucose positron emission tomography/computed tomography (PET/CT) allows the assessment of glycolytic activity within the tumor microenvironment. In this study, we evaluated the incremental value of fused MRI/PET over MRI or fluorodeoxyglucose PET/CT alone for assessing local disease extent in patients with recurrent gynecological cancers undergoing pelvic exenteration and determined the associations between imaging findings and clinical outcomes in this patient population. MATERIALS AND METHODS: The institutional review board approved this retrospective, Health Insurance Portability and Accountability Act (HIPAA)-compliant study of 31 patients who underwent pelvic MRI and PET/CT 3 months or less before pelvic exenteration for recurrent cancers of the uterine cervix, corpus, or vulva/vagina. Using a 1 to 5 scale (1, definitely not present; 5, definitely present), 2 readers independently evaluated MRI, PET/CT, and fused MRI/PET images for the presence of bladder, rectum, and pelvic sidewall invasion. Surgical pathology constituted the reference standard. Measurements of diagnostic accuracy, interreader agreement, and associations between imaging findings and progression-free survival and overall survival were calculated. RESULTS: Compared with MRI or PET/CT, fused MRI/PET correctly improved readers' diagnostic confidence in detecting bladder, rectum, or pelvic sidewall invasion in up to 52% of patients. Interreader agreement was consistently in the highest ("almost perfect") range only for MRI/PET (κ = 0.84-1.0). The highest sensitivities (0.82-1.0), specificities (0.91-1.0), and predictive values (0.80-1.0) were consistently achieved with fused MRI/PET (although the differences were not statistically significant [P > 0.05]). Pelvic sidewall invasion on MRI/PET was the only finding significantly associated with both progression-free and overall survival for both readers (P = 0.0067-0.0440). CONCLUSIONS: In patients with recurrent gynecological cancers undergoing pelvic exenteration, fused MRI/PET served as a predictive biomarker and yielded greater diagnostic confidence and interreader agreement than either MRI or PET/CT