Tony G. Zreik

Benefit of Consolidative Radiation Therapy in Patients With Diffuse Large B-Cell Lymphoma Treated With R-CHOP Chemotherapy

PURPOSEnThe current standard therapy for patients with diffuse large B-cell lymphoma (DLBCL) is rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). The role of consolidative radiation therapy (RT) in the setting of R-CHOP chemotherapy is not well reported. This retrospective analysis is an attempt to clarify this role.nnnPATIENTS AND METHODSnSubjects were 469 patients with histologically confirmed DLBCL treated between January 2001 and December 2007. Variables including age, sex, Ann Arbor disease stage, bulky disease status, standardized uptake values (SUVs) on positron emission tomography (PET), International Prognostic Index (IPI), and Ki67 staining (proliferation).nnnRESULTSnOf 469 patients, 190 (40.5%) had stage I or II disease and 279 (59.5%) had stage III or IV disease, 327 (70%) had at least six cycles of R-CHOP, and 142 (30.2%) had involved-field RT (dose, 30 to 39.6 Gy) after complete response to chemotherapy. Median follow-up was 36 months (range, 8 to 85 months). Multivariate analysis showed that RT (P < .0001), IPI score (P = .001), response to therapy (P = .001), use of six to eight cycles of R-CHOP (P < .001), and combined presence (P = .006) or absence (P = .025) of high Ki67, high PET SUV, and bulky disease influenced overall survival (OS) and progression-free survival (PFS). Matched-pair analyses of patients who received six to eight cycles of R-CHOP with stage I or II disease (44 pairs) and all stages (74 pairs) indicated that RT improved OS (hazard ratio [HR], 0.52 and 0.29, respectively) and PFS (HR, 0.45 and 0.24, respectively) compared with no RT.nnnCONCLUSIONnThis study showed significant improvements in OS and PFS among patients who received consolidation RT after R-CHOP chemotherapy for DLBCL.

Cryomyolysis, a new procedure for the conservative treatment of uterine fibroids

Conservative surgical options for uterine myomata traditionally were abdominal myomectomy, laparoscopic myomectomy, and, more recently, myolysis. Each of these procedures has distinct advantages, but also apparent disadvantages. We attempted to introduce an additional option for conservative surgical treatment of fibroids by freezing the structures, a procedure termed cryomyolysis. In this pilot study, 14 women were pretreated with a gonadotropin-releasing hormone (GnRH) agonist for a minimum of 2 months preoperatively to minimize uterine and myoma size. Cryomyolysis was performed and the GnRH agonist was discontinued. Magnetic resonance imaging scans were performed in 10 of the 14 women after GnRH agonist treatment but before surgery, and 4 months postoperatively. Total uterine volume ranged from 41.3 to 1134.8 ml preoperatively, and 49.5 to 1320 ml postoperatively (mean increase 22% after discontinuation of GnRH agonist). Normal uterine volume ranged from 35.6 to 548.7 ml preoperatively and 45.1 to 729.6 ml postoperatively (mean increase 40%); however, myoma volume showed a mean decrease of 6% (range -87-28%). Analysis of only frozen myomata revealed a mean volume decrease of 10%. Cryomyolysis maintains at or slightly reduces these lesions to post-GnRH agonist size, and all other uterine tissue returns to pretreatment size. We believe cryomyolysis may be an effective conservative surgical approach to uterine fibroids.

Parametrial involvement, regardless of nodal status: a poor prognostic factor for cervical cancer.

Objective To evaluate the effect of resection of central disease when the parametria are involved by tumor in high-risk stage I cervical cancer patients. Methods Thirty-two patients with high-risk stage I cervical cancer who underwent radical hysterectomy and had pathologic findings of positive lymph nodes (N = 13), positive parametria (N = 7), or both (N = 12) were identified retrospectively. The effects of various histopathologic findings on disease-free interval and survival were evaluated, including the effect of resection of central disease with and without positive nodal disease. Kaplan-Meier survival curves were compared with the log-rank test. Multivariate analyses nusing a stepwise regression model were performed. Results Compared with other histologies, adenocarcinoma was associated with a significantly shorter disease-free interval (P = .037). Among patients with parametrial involvement, lymph node status did not affect disease-free interval or survival. However, when patients with positive lymph nodes were examined, the additional finding of parameterial positivity significantly worsened both diseasefree interval (P = .039) and survival (P = .036). When the 19 patients with positive parametria, regardless of lymph node status, were compared with those with positive lumph nodes alone, the former group had a significantly shorter disease-free interval (P = .038). The tumor recurred in 12 of these 19 patients; all cases involved the pelvis, with a median time to recurrence of 15 months. Multivariate analysis showed that adenocarcinoma histology (P = .038) and parametrial involvement (P = .043) were independent, poor prognostic indicators for disease-free interval. Conclusion Involvement of the parametria, regardless of lumph node status, and adenocarcinoma histology confer a poor prognosis in high-risk patients undergoing radical hysterectomy. Caution should be used when contemplating resection of bulky tumors as part of primary therapy if the parametria appear to be involved by tumor.

Prospective, randomized, crossover study to evaluate the benefit of human chorionic gonadotropin–timed versus urinary luteinizing hormone–timed intrauterine inseminations in clomiphene citrate–stimulated treatment cycles

OBJECTIVEnTo compare two methods of timing IUI, urinary LH monitoring and transvaginal ultrasonography/ hCG timing of ovulation, in patients receiving clomiphene citrate.nnnDESIGNnProspective, randomized, crossover study.nnnSETTINGnYale University Reproductive Medicine Center.nnnPATIENT(S)nInfertile couples undergoing IUI because of unexplained infertility, anovulation, or male factor infertility.nnnINTERVENTION(S)nPatients received clomiphene citrate on days 3-7 of the menstrual cycle and were randomized initially to one of two monitoring protocols. In protocol A, urinary LH monitoring was used to time IUI. Urinary LH levels were determined daily with the use of commercial kits, starting on day 10 of the cycle. When urinary LH was detected, IUIs were performed daily for the next 2 days. In protocol B, ultrasound monitoring of folliculogenesis was performed until a leading follicle of > or = 18 mm was noted, at which time hCG (10,000 IU) was given intramuscularly and IUIs were performed daily for the next 2 days. If no pregnancy occurred, the couple crossed over to the alternate protocol for the next cycle and continued this alternating therapy for a total of four cycles.nnnMAIN OUTCOME MEASURE(S)nPregnancy rate per cycle.nnnRESULT(S)nOne hundred forty-one cycles were completed. In these cycles, six pregnancies occurred, for an overall pregnancy rate of 4.26% per cycle. The pregnancy rate with LH-timed IUI was 4.29% (3/70) and that with hCG-induced ovulation was 4.23% (3/71); the difference was not statistically significant.nnnCONCLUSION(S)nTiming IUI with the use of a relatively expensive and time-consuming method such as ultrasound monitoring of folliculogenesis and hCG induction of ovulation does not appear to produce an increased pregnancy rate over urinary LH monitoring of ovulation.

Psammoma bodies in cervicovaginal smears.

Objective To estimate the prevalence of psammoma bodies in routine cervical cytology specimens and describe clinical diagnoses associated with them in pre- and postmenopausal women. Methods We identified all reports that contained psammoma bodies from a retrospective review of 34,816 cytology reports over 4 consecutive years from the computerized pathology database at Yale New-Haven Medical Center. Slides were reviewed to confirm and qualify psammoma bodies. Medical records of women with psammoma bodies were reviewed and information on follow-up was collected. Results We identified 18 women with psammoma bodies on their Papanicolaou smears. The median age was 49.5 years (range 17–78 years). Seven of eight postmenopausal women had gynecologic malignancies. Five presented with postmenopausal bleeding and had uterine serous or clear-cell carcinomas. One presented with a pelvic mass that was ovarian serous carcinoma. Another had a serous carcinoma of the fallopian tube with only psammoma bodies on Papanicolaou smears. Only one of the remaining 11 nonmalignant cases was a postmenopausal woman. Conclusion The prevalence of psammoma bodies in consecutively screened Papanicolaou smears was 18 of 34,816. Psammoma bodies on Papanicolaou smears are ominous in postmenopausal women. Their presence in asymptomatic premenopausal women warrants further evaluation, but not necessarily surgical exploration

Endometrial cryoablation, a minimally invasive procedure for abnormal uterine bleeding

STUDY OBJECTIVEnTo evaluate the effectiveness of endometrial cyroablation for abnormal uterine bleeding.nnnDESIGNnProspective study with 22 months follow-up (Canadian Task Force classification II-2).nnnSETTINGnUniversity Medical Center.nnnPATIENTSnFifteen consecutive patients treated for metrorrhagia or menorrhagia refractory to medical or surgical therapy, and who were either not operative candidates or did not desire hysterectomy.nnnINTERVENTIONnCyroablation of the endometrium.nnnMEASUREMENTS AND MAIN RESULTSnFifteen patients underwent 16 procedures for dysfunctional uterine bleeding. Uterine sounding depth was 6 to 15 cm. One patient had spinal anesthesia, seven had general anesthesia, and seven had intravenous conscious sedation with a cervical block. Eight patients underwent cryosurgery while fully anticoagulated. Posttreatment endometrial biopsies were performed on three patients and showed only granulation tissue. Life table calculations give amenorrhea rates of 75.5% at 6 months and 50.3% at 22 months. One woman underwent a repeat procedure, resulting in hypomenorrhea at 7-month follow-up.nnnCONCLUSIONnThis pilot study suggests that endometrial cryoablation may be performed simply and effectively. Future studies should be designed to optimize the technical aspects of the procedure, determine its relative efficacy, and investigate the indications.

Myometrial tissue in uterine septa

STUDY OBJECTIVEnTo assess the frequency of myometrial tissue in the septa of septate uteri.nnnDESIGNnRetrospective review (Canadian Task Force classification II-2).nnnSETTINGnUniversity-affiliated tertiary referral center.nnnPATIENTSnTwenty-nine consecutive women with uterine septa diagnosed by magnetic resonance imaging (MRI).nnnINTERVENTIONSnThe MRI examination was performed with a 1.5 Tesla scanner using high-resolution phased array coils with multiplanar fast-spin echo and T1-weighted sequences. Of resected septa, tissue was available in four for histologic evaluation for the presence of myometrial tissue.nnnMEASUREMENTS AND MAIN RESULTSnIn 17 women MRI showed a partial septum, all containing myometrium. The 12 patients with complete septum had evidence of myometrium in the upper part of the septum, with fibrous tissue constituting the lower part. Histology reviewed from four resected septa (2 partial, 2 complete) reported myometrial tissue.nnnCONCLUSIONnUterine septa are frequently composed of myometrial tissue.

Cryomyolysis in the conservative treatment of uterine fibroids

Conservative surgical options for uterine fibroids are abdominal myomectomy, laparoscopic myomectomy, and, more recently, myolysis. Another option for the conservative surgical treatment of fibroids is freezing the structures. This procedure, cryomyolysis, can be performed rapidly by laparoscopic or hysteroscopic access. We performed a pilot study of 14 women with uterine fibroids. All were pretreated with a gonadotropin-releasing hormone (GnRH) agonist for 3 months to reduce uterine and myoma size. Cryomyolysis was performed in each, and the GnRH agonist was discontinued. Magnetic resonance imaging scans were performed in 10 of the 14 women after GnRH agonist treatment before surgery and 4 months postoperatively. Total uterine volume ranged from 41.3 to 1134.8 ml preoperatively and 49.5 to 1320 ml postoperatively, for a mean increase of 22%. Normal uterine volume ranged from 35.6 to 548.7 ml preoperatively and 45.1 to 729.6 ml postoperatively, for a mean increase of 40%. Myoma volume showed a mean decrease of 6% (range 87-28%). Analysis of frozen fibroids revealed a mean volume decrease of 10%. We conclude that cryomyolysis is able to maintain (or slightly reduce) the uterine fibroid at its post-GnRH agonist size, whereas all other uterine tissues return to pretreatment size.

Decreased performance of skilled laparoscopic surgeons at microlaparoscopy versus traditional laparoscopy

The skill requirements for microlaparoscopy are significantly higher than those for the traditional technique. This program was designed to meet the demands of compensated two-dimensional depth perception, instrument accuracy, and ambidexterity. Three specialized drills were constructed and 60 experienced laparoscopists with advanced operative skills were evaluated. The three skill-assessment tasks were first performed using traditional laparoscopic instrumentation (10-mm laparoscopes, 5-mm accessory instruments). The performance of the study group was compared with an extensive database of over 1000 laparoscopic surgeons from around the world and did not reveal any significant deficits with traditional-size equipment. Next, the tasks were performed using miniature 2-mm laparoscopes and accessory instruments. Performance levels for all tasks were significantly lower than with traditional-size equipment. These results demonstrate the increased difficulty of performing laparoscopy with 2-mm instruments and underscore the importance of formal training and objective skill assessment. The relationship of skill to credentialing must be considered.

Addition of sphingosine-1-phosphate to human oocyte culture medium decreases embryo fragmentation.

Apoptosis is implicated in the fragmentation of preimplantation mammalian embryos, yet the extent of this association remains controversial. The aim of this study was to assess the ability of sphingosine-1-phosphate (S1P), a known anti-apoptotic substance, to reduce the fragmentation rate of human preimplantation embryos when added to their culture microenvironment. Mature human oocytes were inseminated using intracytoplasmic sperm injection, incubated for 3 days and evaluated for embryo quality and fragmentation by the same embryologist. Oocytes in the study group were manipulated and cultured in culture medium supplemented with S1P to a 20 micromol/l concentration. A total of 46 patients donated 177 mature oocytes for the study group and 546 oocytes for the control group. The fertilization rate was significantly lower in the S1P-supplemented group (52.4% versus 67.3%; P=0.002) and the proportion of grade I embryos with less than 15% fragmentation was significantly higher in the same group (79.5% versus 53.9%; P<0.0001). Sphingosine-1-phosphate added to the culture medium of human preimplantation embryos is associated with a significantly lower fragmentation rate and hence better quality embryos. The clinical significance of these findings on reproductive outcome remains highly speculative awaiting further studies to translate this improvement in embryo quality into better pregnancy rates.