Genomic analysis of response to bacillus Calmette-Guérin (BCG) treatment in high-grade stage 1 bladder cancer patients.

BACKGROUND: Intravesical bacillus Calmette-Guérin (BCG) therapy is standard treatment for high-risk non-muscle invasive bladder cancer (NMIBC) but overall efficacy is low, and no reliable predictive biomarkers currently exist to refine patient selection. We performed genomic analysis on high-grade (HG) T1 NMIBCs to determine if response to therapy is predicted by certain mutational and/or expressional changes. METHODS: Patients with HG T1 NMIBC treated with induction BCG were stratified by response into durable and non-durable responders. Baseline tumor samples were subjected to targeted DNA sequencing and whole-exome RNAseq. Genomic variants differing significantly between response groups were analyzed using Ingenuity Pathway Analysis (IPA) software. Variant selection was refined to target potential biomarker candidates for responsiveness to BCG. RESULTS: Among 42 patients, the median follow-up was 51.7 months and 40.5% (n=17) were durable BCG responders. Deleterious mutations in the RNA sequence of JCHAIN, S100A7, CLEC2B, and ANXA10 were more common in non-durable responders. Mutations in MCL1 and MSH6 detected on targeted sequencing were more commonly found in durable responders. Of all deleterious DNA and RNA mutations identified, only MCL1 was significantly associated with longer recurrence free survival (RFS) (P=0.031). CONCLUSIONS: Differences in the genomic profiles of HG T1 NMIBC tumors exist between those who show durable response to BCG and those who do not. Using pathway analysis, those differences imply upregulation of several interconnected inflammatory pathways among responders. Specific variants identified here, namely MCL1, are candidates for further study and, if clinically validated, may serve as useful biomarkers in the future.

A Rare Presentation of Stage IV Large Cell Neuroendocrine Carcinoma of the Cervix with Metastasis to the Cranium.

Neuroendocrine tumors (NETs) are aggressive diseases developing from neuroendocrine cells that most frequently involve the gastro-entero-pancreatic tract and the lung, but more rarely are found in almost all body tissues. Limited biological and clinical data are currently available for NETs in uncommon sites, such as female genital tract. NETs represent 0.9% to 1.5% of the tumors of the uterine cervix. This case is reported on a 75-year-old Caucasian woman, presenting with dental and generalized pain for two weeks. Later during her admission, facial droop and diplopia were noticed. Radiological findings ruled out cerebrovascular accident but revealed multiple bone marrow lesions involving the left and the right clivus, right Meckel's cave, and posterior margin of the right cavernous sinus. Findings also included pulmonary nodules and adenopathy supporting diagnosis of likely stage IV metastatic carcinoma. Further imaging revealed homogeneous enhancement of the uterus suggestive of diffusely infiltrative carcinoma; pathology results confirmed large cell neuroendocrine carcinoma of the uterine cervix (LCNEC) giving her a 1.5-month median survival range.

Strategies in the management of renal tumors amenable to partial nephrectomy.

PURPOSE: The laparoscopic approach to radical and partial nephrectomy is becoming the standard of care for treating patients with renal tumors. Hand-assisted laparoscopic partial nephrectomy (HALPN) provides some advantages over the pure laparoscopic approach which include manual manipulation of the kidney, tactile feedback, and timely specimen removal. MATERIALS AND METHODS: We describe our technique for HALPN and emphasize the implementation of an in-room pathologist to examine gross margins during the period of renal arterial occlusion. Between 2004 and 2007, 46 patients underwent HALPN performed by the same surgeons. Mean patient age was 59.5 years and mean tumor size was 2.55 cm. Twelve of these patients underwent significant concomitant procedures. RESULTS: Our mean operating time was 173.26 min (range 90-306 min) and our mean warm ischemic time was 28.32 min (range 14-54 min). Average estimated blood loss was 116.82 ml (range 10-1000 ml) with no transfusions. Thirty-six (78%) tumors were renal cell carcinoma, seven (15%) were oncocytomas, and three (7%) were angiomyolipomas. The average length of stay was 5.17 days (range 3-9 days) and there were no positive margins. There was one postoperative bleed (2%) and two postoperative urine leaks (4.3%). DISCUSSION: In our institution, the hand-assist approach to laparoscopic partial nephrectomy has resulted in favorable perioperative outcomes. The use of an in-room pathologist to provide real-time assessment of gross tumor margins has allowed us to achieve a 0% positive final margin rate. We believe that the use of an in-room pathologist during the timely extraction of the specimen made possible by the hand-assisted approach provides a great advantage over pure laparoscopic partial nephrectomy. This low positive margin rate is also the result of maintaining a bloodless field of resection with temporary renal arterial occlusion as well as the avoidance of visual tissue distortion with cold, sharp scissor dissection.

Pseudoinfiltrative tubal metaplasia of the endocervix: a potential form of in utero diethylstilbestrol exposure-related adenosis simulating minimal deviation adenocarcinoma.

We report three cases of unusual tubal-type endocervical glandular proliferations simulating minimal deviation adenocarcinoma in women with a history of in utero diethylstilbestrol (DES) exposure. The lesions were characterized by haphazard glandular proliferations extending from 3.4 to 6.1 mm into the endocervical stroma and to the margins of excision in all cases. Most of the glands were small to medium-sized and round; some exhibited a moderate degree of cystic dilatation, and occasional glands had curvilinear profiles. The glandular epithelium displayed extensive tubal-type differentiation in all cases. In two cases, the glands lacked cytologic atypia and mitotic activity, and in one case, there was mild to moderate nuclear atypia with occasional mitotic activity. Immunohistochemical studies showed diffuse expression of estrogen and progesterone receptors and essentially no expression of p16 in two cases tested; there was no expression of CD10 in one case that was tested. The Ki-67 proliferation index was zero in one case and 25% in another. Human papillomavirus DNA was not detected by in situ hybridization in one case that was tested. The proliferations lacked features of mucinous and tubo-endometrioid types of minimal deviation adenocarcinoma. The clinicopathologic findings suggest the lesions are benign, and the association with in utero DES exposure raises the possibility that these could be a form of DES-related adenosis.

Phase III trial of doxorubicin plus cisplatin with or without paclitaxel plus filgrastim in advanced endometrial carcinoma: a Gynecologic Oncology Group Study.

PURPOSE: To determine whether the addition of paclitaxel to doxorubicin plus cisplatin improves overall survival (OS) in women with advanced or recurrent endometrial carcinoma. Secondary comparisons included progression-free survival (PFS), response rate (RR), and toxicities. PATIENTS AND METHODS: Eligible, consenting patients received doxorubicin 60 mg/m(2) and cisplatin 50 mg/m(2) (AP), or doxorubicin 45 mg/m(2) and cisplatin 50 mg/m(2) (day 1), followed by paclitaxel 160 mg/m(2) (day 2) with filgrastim support (TAP). The initial doxorubicin dose in the AP arm was reduced to 45 mg/m(2) in patients with prior pelvic radiotherapy and those older than 65 years. Both regimens were repeated every 3 weeks to a maximum of seven cycles. Patients completed a neurotoxicity questionnaire before each cycle. RESULTS: Two hundred seventy-three women (10 ineligible) were registered. Objective response (57% v 34%; P <.01), PFS (median, 8.3 v 5.3 months; P <.01), and OS (median, 15.3 v 12.3 months; P =.037) were improved with TAP. Treatment was hematologically well tolerated, with only 2% of patients receiving AP, and 3% of patients receiving TAP experiencing neutropenic fever. Neurologic toxicity was worse for those receiving TAP, with 12% grade 3, and 27% grade 2 peripheral neuropathy, compared with 1% and 4%, respectively, in those receiving AP. Patient-reported neurotoxicity was significantly higher in the TAP arm following two cycles of therapy. CONCLUSION: TAP significantly improves RR, PFS, and OS compared with AP. Evaluation of this regimen in the high-risk adjuvant setting is warranted, but close attention should be paid to the increased risk of peripheral neuropathy.