Predictors of Acute Hematologic Toxicity in Women Receiving Extended-Field Chemoradiation for Cervical Cancer: Do Known Pelvic Radiation Bone Marrow Constraints Apply?

Purpose: Patients with cervical cancer who are at high risk for para-aortic lymphatic involvement may receive extended-field chemoradiation (EF-CRT), with inclusion of the para-aortic region. Increased radiation to bone marrow (BM) may heighten hematologic toxicity (HT) and affect timely delivery of chemoradiation. Factors associated with HT in this setting have not been well studied. Methods and Materials: This study was a retrospective analysis of women treated with EF-CRT from 2012 to 2018 with platinum-based chemotherapy. Factors including age, body mass index (BMI), race, Charlson Comorbidity Index (CCI), and nadirs for white blood cell count, absolute neutrophil count, hemoglobin, and platelet count were collected. The BM metrics included V5Gy, V10Gy, V15Gy, V20Gy, V25Gy, V30Gy, V35Gy, V40Gy and V45Gy (VxGy was defined as the percentage of BM volume receiving x Gy). Hematologic toxicity was defined as grade ≥2 (Cooperative Group Common Toxicity Criteria) leukopenia, anemia, neutropenia, or thrombocytopenia. Univariate analysis (UVA) and multivariate analysis (MVA) were performed using the χ2 test, the Fisher exact test, and logistic regression. Previously published dosimetric BM constraints were examined as detailed in each respective study. Results: Fifty-two women underwent EF-CRT with cisplatin. UVA showed no association between HT and age, BMI, or CCI. When accounting for race, V5Gy ≥98% was associated with grade ≥2 leukopenia (P = .02) and grade ≥2 HT (P = .05). Most previously described radiation metrics were not reproduced in our cohort, but a similar constraint, V20Gy <70%, was associated with reduced leukopenia of grade ≥2 on UVA (P = .02) and MVA (P < .05). Conclusions: Acute HT in patients receiving EF-CRT was associated with large volumes of low-dose radiation to the BM and was also associated with race. Restricting the BM V20Gy to less than 70% to 75% may be beneficial in reducing HT, but other pelvic radiation BM constraints may not be applicable to this population.

Opioid Use in Patients With Cervical Cancer at Two Urban Medical Centers.

Purpose: Patients with cervical cancer are at high risk for opioid use. This study aimed to characterize opioid prescribing patterns at 2 urban hospitals. Methods and Materials: Data from patients with cervical cancer treated with curative intent from 2011 to 2018 were retrospectively collected. Women with unrelated chronic opioid use before diagnosis, persistent/recurrent disease at 3 months after initiation of treatment, or initiation of opioids >6 months after treatment were excluded. Demographics, disease characteristics, treatment, and outpatient prescription practices were collected. Endpoints included duration of opioid use ≥6 and ≥12 months. Results: There were 106 women included, of whom 83% received definitive radiation. Most patients (n = 91, 85.8%) received outpatient opioids. Most common timing of prescriptions were before cancer therapy (35.9%), postprocedure (26.4%), and during radiation therapy (17.0%). Median duration was 3 (interquartile range, 1-11) months; 35.2% of these patients received opioids ≥6 months and 22% received opioids ≥12 months. Greater International Federation of Gynaecology and Obstetrics (FIGO) stage, recurrent/residual disease, initiation of opioids before treatment, history of depression or anxiety, and use of gabapentin or steroids were associated with long-term opioid use. Conclusions: Most patients were prescribed outpatient opioids, many of whom used opioids for 12 months. Improvement in provider communication and education, increased posttreatment monitoring, and further evaluation of nonopioid therapies are needed in this patient population to reduce long-term opioid use.

Coexistent Dedifferentiated Endometrioid Carcinoma of the Uterus and Adenocarcinoma of the Bladder in Lynch Syndrome: Case Report and Review of the Literature.

Lynch syndrome is an autosomal dominant disorder, caused by an abnormality in DNA mismatch repair genes and characterized by the development of a variety of cancers. Upper urinary tract urothelial carcinoma is well characterized in Lynch syndrome; however, support for the inclusion of bladder urothelial carcinoma is limited, except for MSH2 mutation carriers. Urologic adenocarcinoma has not been documented in Lynch syndrome. Here we report, to the best of our knowledge, the first case of bladder adenocarcinoma, synchronous with uterine endometrioid dedifferentiated endometrioid adenocarcinoma in a patient with Lynch syndrome. We present a 47-year-old woman with an MLH1 gene mutation (G133X 397G>T) who presented with menorrhagia. Eleven family members have this mutation, 6 with carcinoma: 5 colorectal and 1 with a gynecologic primary of unknown type. Colonoscopy and endoscopy were unremarkable. Positron emission and computed tomography revealed a 3 cm anterior dome bladder mass without additional extrauterine disease or uterine connection. She underwent partial cystectomy, laparoscopic hysterectomy, bilateral salpingo-oophorectomy, and lymphadenectomy. The uterus demonstrated a dedifferentiated endometrioid adenocarcinoma, immunohistochemically positive for vimentin, ER, CK7, MSH2, MSH6, and p53 (focally) and negative for CEA, CDX2, CK20, ß-catenin, MLH1, and PMS2. The bladder demonstrated a well-differentiated, enteric-type adenocarcinoma without muscularis propria invasion, positive for CEA, CDX2, CK20, p53, MSH2, and MSH6 and negative for vimentin, ER, CK7, MLH1, and PMS2. Eleven nodes were negative for carcinoma. The morphologic, immunohistochemical, and clinical findings support synchronous bladder adenocarcinoma, enteric type, and uterine dedifferentiated endometrioid adenocarcinoma, in a patient with Lynch syndrome.

Management and survival of patients with Mullerian adenosarcoma of the cervix without sarcomatous overgrowth desiring fertility preservation, a case report and review of the literature.

•Cervical Mullerian adenosarcoma is a tumor that affects reproductively aged women.•Hysterectomy had been the standard of care for these premenopausal women.•This case reports the most minimally invasive approach with no recurrence.•Accurate pathology interpretation is essential to diagnose and treat patients.•This is a rare tumor that if misdiagnosed or mischaracterized could be lethal.

Cervical cancer survivors' attitudes and understanding of menopause and hormone therapy.

OBJECTIVE: We designed a survey study to assess the presence and severity of climacteric symptoms, in addition to better understand patients' knowledge and understanding of hormone therapy (HT). METHODS: We administered a 23-question survey during a patient's clinic visit or over the phone. Study enrollment spanned from March, 2019 to May, 2019. The primary outcomes were severity of menopausal symptoms and willingness to try HT, calculated as a summarized overall score. Chi-square and logistic regression were used for analysis. RESULTS: Our response rate was 38% (n = 34). Our participants were diverse-67% women were black and 21% women were Hispanic. Stage 1 and 2 disease was reported in 32% and 41% of women. Also, 82% and 94% of women reported ever receiving any chemotherapy or radiation therapy. There was no association between willingness to try HT for relief of menopausal symptoms and income (χ [1, 29] = 0.56, P = 0.81) or education level (χ [1, 29] = 2.78, P = 0.10). The most common climacteric symptoms experienced were hot flushes (85%) and decreased libido (77%). Neither symptom severity (odds ratio [OR] 1.31, 95% confidence interval [CI] 0.89-1.94) nor concern for side effects (OR 1.06, 95% CI 0.82-1.36) of HT significantly predicted willingness to try HT. CONCLUSIONS: Menopausal symptoms were prevalent in this population. Our data indicate that women are experiencing climacteric symptoms, but are overall unmotivated to address symptoms using HT. Factors such as symptom severity, fear of side effects, income level, or education level were not associated with acceptability of HT for premature menopause.

Phase I Study of IGF-Methotrexate Conjugate in the Treatment of Advanced Tumors Expressing IGF-1R.

OBJECTIVES: Insulin-like growth factor-methotrexate (IGF-MTX) is a conjugate of methotrexate and 765IGF, a variant of IGF-1 with high affinity for insulin-like growth factor type 1 receptor. The study aim was to determine the maximum tolerated dose of IGF-MTX in refractory solid organ and hematologic malignancies expressing insulin-like growth factor type 1 receptor. MATERIALS AND METHODS: This phase I trial used a modified toxicity probability interval design with 5 cohort dose levels, and expansion cohort at maximum tolerated dose. IGF-MTX was given intravenously over 90 minutes on days 1, 8, and 15 of a 28-day cycle. RESULTS: A total of 17 patients were enrolled. The highest tolerated dose tested was 0.80 µEq/kg with dose-limiting toxicity of grade 3 hypoglycemia. Drug-related grade 3 and 4 toxicities included abdominal pain (26%), hypoglycemia (10%), and hypotension (10%). Of the 15 evaluable for response, 3 patients (20%) had stable disease, including the patient with Hodgkin lymphoma with stable disease for 12 cycles of therapy. IGF-MTX concentrations declined rapidly, with half-lives of 5.2 to 14 minutes for the initial distribution phase and 6.5 to 7.5 hours for the terminal elimination phase. Higher IGF-R1 expression did not correlate with better outcome. CONCLUSIONS: IGF-MTX is well tolerated. IGF-MTX pharmacokinetics suggest rapid cellular uptake. The activity of IGF-MTX in Hodgkin lymphoma should be explored.

Whole Cell MALDI Fingerprinting Is a Robust Tool for Differential Profiling of Two-Component Mammalian Cell Mixtures.

MALDI fingerprinting was first described two decades ago as a technique to identify microbial cell lines. Microbial fingerprinting has since evolved into an automated platform for microorganism identification and classification, which is now routinely used in clinical and environmental sectors. The extension of fingerprinting to mammalian cells has yet to progress partly due to compartmentalization of eukaryotic cells and overall higher cellular complexity. A number of publications on mammalian whole cell fingerprinting suggest that the method could be useful for classification of different cell types, cell states, and monitoring cell differentiation. We report the optimization of MALDI fingerprinting workflow parameters for mammalian cells and its application for differential profiling of mammalian cell lines and two-component cell line mixtures. Murine fallopian tube cells and high-grade ovarian carcinoma cell lines and their mixtures are used as model mammalian cell lines. Two-component cell mixtures serve to determine the method's feasibility for complex biological samples as the ability to detect cancer cells in a mixed cell population. The level of detection of cancer cells in the two-component mixture by principle component analysis (PCA) starts to deteriorate at 5% but with application of a different statistical approach, Wilcoxon rank sum test, the level of detection was determined to be 1%. The ability to differentiate heterogeneous cell mixtures will help further extend whole cell MALDI fingerprinting to complex biological systems. Graphical Abstract.

A rare case report of vulvar necrotizing fasciitis in a healthy patient.

INTRODUCTION: Necrotizing fasciitis (NF), a necrotizing infection of the soft tissue, is a medical emergency usually occurring in the lower extremities and abdominal regions and often difficult to diagnose promptly. PRESENTATION OF CASE: This case report looks at one atypical presentation of NF with the unusual location of the vulva and no known associated comorbidities or risk factors. DISCUSSION: Diagnosing this patient was particularly difficult due to the inconsistent clinical, laboratory and imaging findings. The CT scans and WBC count were indicative of NF, but the LRINEC score was not high enough to make the diagnosis of NF. As a result, we relied on the hemodynamic instability and clinical findings of the physical exam to be strong indicators of NF, and acted on that indication. CONCLUSION: Acting quickly on the hemodynamic findings and suspicion as opposed to waiting for a confirmed diagnosis resulted in a good prognosis since immediate surgical debridement is imperative to surviving this acute condition. Despite major advancements in the imaging modalities and the introduction of a laboratory score, our case suggests that the diagnosis still heavily relies on clinical findings, such as hemodynamic instability. Furthermore, our case suggests that NF should be included in the differential regardless of atypical location and lack of common clinical associations.

Three-dimensional modeling of the human fallopian tube fimbriae.

OBJECTIVE: Ovarian cancer is the most lethal gynecological malignancy that affects women. Recent data suggests that the disease may originate in the fallopian fimbriae; however, the anatomical origin of ovarian carcinogenesis remains unclear. This is largely driven by our lack of knowledge regarding the structure and function of normal fimbriae and the relative paucity of models that accurately recapitulate the in vivo fallopian tube. Therefore, a human three-dimensional (3D) culture system was developed to examine the role of the fallopian fimbriae in serous tumorigenesis. METHODS: Alginate matrix was utilized to support human fallopian fimbriae ex vivo. Fimbriae were cultured with factors hypothesized to contribute to carcinogenesis, namely; H2O2 (1mM) a mimetic of oxidative stress, insulin (5µg/ml) to stimulate glycolysis, and estradiol (E2, 10nM) which peaks before ovulation. Cultures were evaluated for changes in proliferation and p53 expression, criteria utilized to identify potential precursor lesions. Further, secretory factors were assessed after treatment with E2 to identify if steroid signaling induces a pro-tumorigenic microenvironment. RESULTS: 3D fimbriae cultures maintained normal tissue architecture up to 7days, retaining both epithelial subtypes. Treatment of cultures with H2O2 or insulin significantly induced proliferation. However, p53 stabilization was unaffected by any particular treatment, although it was induced by ex vivo culturing. Moreover, E2-alone treatment significantly induced its canonical target PR and expression of IL8, a factor linked to poor outcome. CONCLUSIONS: 3D alginate cultures of human fallopian fimbriae provide an important microphysiological model, which can be further utilized to investigate serous tumorigenesis originating from the fallopian tube.

Idiopathic Adrenal Hemorrhage in a Patient with Gestational Trophoblastic Neoplasia.

BACKGROUND: Idiopathic unilateral adrenal hemorrhage is rare. Described is the first case reported in the setting of nonmetastatic gestational trophoblastic neoplasia. CASE: A primigravida presented with abdominal pain, fever, and a right upper quadrant mass during the workup for gestational trophoblastic neoplasia. She was diagnosed with idiopathic unilateral adrenal hemorrhage. She was treated with surgical resection and single-agent chemotherapy and had complete remission. CONCLUSIONS: Idiopathic unilateral adrenal hemorrhage is a rare condition and must be considered in the presentation of abdominal pain, fever, and an abdominal mass.

The effect of age on the tolerability of intraperitoneal chemotherapy, complication rate, and survival in patients with ovarian cancer.

OBJECTIVE: We sought to determine if patient age influenced chemotherapy completion rate, complication rate, or progression free survival (PFS) among patients who received intraperitoneal (IP) chemotherapy for epithelial ovarian, fallopian tube, or primary peritoneal cancers. METHODS: Charts for patients receiving IP chemotherapy between January 2006 and September 2009 were reviewed at three institutions. Primary outcomes included completion rate of planned IP chemotherapy, complication rate, and PFS. Completion rates were categorized as 0-49%, 50-99%, or 100% of planned treatments were delivered. The tolerability of IP versus intravenous (IV) chemotherapy was also compared among patients ≥ 70 years. RESULTS: One hundred nine patients receiving IP chemotherapy were identified, 86 were < 70 years and 23 were ≥ 70 years. All patients received IP cisplatin and paclitaxel in combination with IV paclitaxel or docetaxel. Patients ≥ 70 years old were less likely to complete all planned cycles of IP chemotherapy than the younger cohort (OR = 0.33, 95% CI 0.13-0.83, p = 0.01), but there was no significant association between age and complication rate or PFS (p = 0.82 and p = 0.68, respectively). Optimally debulked patients ≥ 70 years receiving IV chemotherapy completed more cycles than patients ≥ 70 receiving IP chemotherapy (p < 0.01). CONCLUSIONS: Although elderly patients appear to tolerate fewer cycles of IP chemotherapy, they do not have higher objective complication rates or impaired PFS compared to younger patients. Age alone should not limit access to IP chemotherapy.

The prognostic significance of the triple negative phenotype in endometrial cancer.

OBJECTIVE: To determine if the triple negative phenotype (TNP) has prognostic significance in endometrial cancer with respect to various surgicopathologic outcomes and survival. METHODS: A tissue microarray was constructed of 396 endometrial cancers from patients who underwent surgical staging at the Ohio State University Medical Center. Immunohistochemistry was used to test for estrogen receptor, progesterone receptor, and HER2 expression. Fluorescent in-situ hybridization (FISH) was also used to test for HER2 amplification. TNP negative patients served as controls. Pearson's chi-square was used to evaluate the association of the TNP with variables associated with a poor prognosis. Cox proportional hazards model was used to perform univariate and multivariate analyses. Progression free survival (PFS) and overall survival (OS) were analyzed with Kaplan-Meier curves, and the log rank test was used to compare the groups. RESULTS: Twenty-seven percent of patients had the TNP. The TNP was associated with lymph node metastasis, myometrial invasion (>50%), high grade disease, non-endometrioid histology, and advanced staged disease (p<0.023 for lymph node metastasis and p<0.0001 for all others). The TNP was associated with a significantly worse survival, including a decreased PFS (p=0.009) and OS (p=0.01), but not in a fashion independent of other prognostic variables. CONCLUSIONS: The TNP is associated with advanced stage, high grade, and high risk histology, as well as poor survival. Continued investigation of the exploitation of this phenotype with targeted therapies is necessary.

Antiestrogen therapy in recurrent ovarian cancer resulting in 28 months of stable disease: a case report and review of the literature.

Hormonal therapy for adjuvant treatment of ovarian cancer may provide a low toxicity option in some patients with refractory disease. A 53 year-old patient with stage IIIC papillary serous ovarian cancer previously treated with multiple chemotherapy regimens with platinum-resistant disease was treated with antiestrogen therapy for 28 months before requiring reinstitution of cytotoxic chemotherapy. Hormonal therapy may be effective in a subset of epithelial ovarian cancer patients with endocrine sensitivity and should be considered in the treatment of platinum-resistant patients.

Stage IV endometrial cancer after failed conservative management: a case report.

BACKGROUND: With younger women becoming increasingly overweight, endometrial cancer is becoming a concern in this group. These women are likely to desire fertility preservation. There are no randomized controlled data to guide conservative therapy. CASE: A 24-year-old female with endometrial adenocarcinoma diagnosed in December 2003 was treated conservatively with Megace and levonorgestrel intrauterine device. She was lost to follow-up and represented in March 2006. Endometrial biopsy revealed grade 1 endometrial adenocarcinoma. Definitive surgical therapy was recommended, however, the patient declined surgery in the interest of preserving fertility until November 2006. Final pathology revealed a stage IV, grade 1 endometrioid endometrial cancer. CONCLUSION: Women with endometrial cancer who desire fertility preservation should be counseled regarding the possible risk of advanced disease if surgical therapy is delayed.