Diet-microbiome interactions in cancer treatment: Opportunities and challenges for precision nutrition in cancer.

Dietary patterns contribute to cancer risk. Separately, microbial factors influence the development of several cancers. However, the interaction of diet and the microbiome and their joint contribution to cancer treatment response needs more research. The microbiome significantly impacts drug metabolism, immune activation, and response to immunotherapy. One of the critical factors affecting the microbiome structure and function is diet. Data demonstrate that the diet and microbiome composition affects the immune response. Moreover, malnutrition is a significant confounder to cancer therapy response. There is little understanding of the interaction of malnutrition with the microbiome in the context of cancer. This review aims to address the current knowledge of dietary intake patterns and malnutrition among cancer patients and the impact on treatment outcomes. Second, this review will provide evidence linking the microbiome to cancer treatment response and provide evidence of the potentially strong effect that diet could have on this interaction. This review will formulate critical questions that will need further research to understand the diet-microbiome relationship in cancer treatment response and directions for future research to guide us to precision nutrition therapy to improve cancer outcomes.

Cervical cancer complicating pelvic organ prolapse, and use of a pessary to restore anatomy for optimal radiation: A case report.

Cervical cancer is the most common gynecologic malignancy worldwide and the third most common gynecologic cancer in the USA. Improved screening methods such as liquid-based cytology accompanied by Human Papilloma Virus (HPV) co-testing have contributed to a declining incidence of cervical cancer. There are approximately 13,000 new cases per year in the United States, accounting for 4200 deaths (Siegel et al., 2011). Pelvic organ prolapse increases with age, obesity and parity. In the absence of bothersome urinary, gastrointestinal or pressure symptoms, patients may choose conservative management options. The index patient was a 72 year old woman with a known history of pelvic organ prolapse who had been managed by her primary physician for 7 years until she developed new-onset vaginal bleeding. One month following worsening prolapse and increased vaginal bleeding she presented to the emergency department and was evaluated. On physical examination the cervix appeared as an 8 cm exophytic fungating mass extruding from the vagina and bled easily from areas of apparent necrosis. Multiple biopsies confirmed an invasive squamous cell carcinoma. The patient underwent the insertion of a Gelhorn pessary and perineorrhaphy to reduce her procidentia, cystocele and enterocele. Chemotherapy with Cisplatin and radiation therapy in the form of brachytherapy and external beam radiation therapy were then administered with curative intent. Cervical cancer complicating a uterine procidentia in an elderly patient is a rare occurrence in the United States and requires a multidisciplinary approach involving a urogynecologist, a gynecologic oncologist and a radiation oncologist. Nonetheless, in carefully selected patients, the outcome can be successful.

Bladder cancer incidence and mortality in patients treated with radiation for uterine cancer.

OBJECTIVE: To estimate the effect of radiation therapy (RT) administered for uterine cancer (UtC) on bladder cancer (BC) incidence, tumour characteristics at presentation, and mortality. PATIENTS AND METHODS: In this retrospective cohort study, records of 56 681 patients diagnosed with UtC as their first primary malignancy during 1980-2005 were obtained from the Surveillance, Epidemiology and End-Results (SEER) database. Follow-up for incident BC ended on 31 December 2008. Occurrences of BC diagnoses and BC deaths in patients with UtC managed with or without RT were summarised with counts and person-time incidence rates (counts divided by person-years of observation). Age adjustment of rates was performed by direct standardisation. Incident BC cases were described in terms of histological types, grades and stages. RESULTS: With a mean follow-up of 15 years, BC was diagnosed in 146 (0.93%) of 15 726 patients with UtC managed with RT, and in 197 (0.48%) of 40 955 patients with UtC managed without RT, with an age-adjusted rate ratio of 2.0 (95% confidence interval [CI] 1.6-2.5). Fatal BC occurred in 39 (0.25%) and 36 (0.09%) of patients with UtC managed with vs without RT, respectively, with an age-adjusted rate ratio of 2.9 (95% CI 1.8-4.6). Incident BC cases diagnosed in patients with UtC managed with vs without RT had similar distributions of histological types, grades, and stages. CONCLUSIONS: Use of RT for UtC is associated with increased BC incidence and mortality later in life. Heightened awareness should help identify women with new voiding symptoms or haematuria, all of which should be fully evaluated.

Synchronous Presentation of Cavernous Sinus Metastasis and Cervical Cancer: A Case Report and Review of Literature.

Uterine cervical cancers customarily spread by local extension to the adjacent viscera or through lymphatic embolization to the retroperitoneal lymph nodes. Distant hematogenous spread particularly to the brain is an uncommon and late event which heralds a poor prognosis. We report a case of uterine squamous cell carcinoma of the cervix with unusual simultaneous presentation of cavernous sinus metastasis and multiple brain metastases while reviewing the current literature on this clinical entity.

Evaluating the significance of location of lymph node metastasis and extranodal disease in women with stage IIIC endometrial cancer.

OBJECTIVE: To determine the prognostic significance of location of lymph node metastasis and extranodal disease for women with stage IIIC endometrial cancer. METHODS: Data were extracted from the Surveillance, Epidemiology, and End Results database between 1988 and 2005. Statistical analysis used Chi-square test, Kaplan-Meier method, and Cox proportional hazards model. RESULTS: A total of 2559 women were identified; 1453 stage IIIC1, and with 906 stage IIIC2 tumors. Compared to stage IIIC1; more stage IIIC2 patients demonstrated high-risk factors such as grade III disease (p<0.001), unfavorable histologic types (p=0.01), concurrent disease at other extrauterine sites (p<0.001), and greater than two positive lymph nodes (p<0.001). While the 5-year disease specific survival was comparable (p>0.05) among node positive patients found to have positive peritoneal cytology (44.0%), adnexal/serosal metastasis (42.9%), and vaginal/parametrial involvement (41.8%); it differed individually in all three categories from those with nodal metastasis alone (67.0%, p<0.001). Among women with extranodal disease, the location of nodal metastasis had no effect on survival (HR=0.92; 95% CI, 0.74-1.14). For women with node only stage IIIC tumors, those patients with positive para-aortic nodes were more likely to die from their tumors (HR=1.40; 95% CI, 1.12-1.75). CONCLUSION(S): Location of lymph node metastasis is prognostic in patients with nodal disease alone, and not in those with extranodal disease. Extranodal disease is associated with a poor prognosis and should be regarded in conjunction with location of lymph node metastasis for risk-stratification in stage IIIC endometrial cancer.

Stage III uterine carcinosarcoma: 2009 International Federation of Gynecology and Obstetrics Staging System and Prognostic Determinants.

OBJECTIVES: (1) To determine the significance of positive peritoneal cytology and pelvic versus para-aortic lymph node involvement in uterine carcinosarcoma. (2) To evaluate the impact of isolated retroperitoneal lymph node involvement (IIIC-N) versus retroperitoneal lymph node involvement plus other evidence of extrauterine disease spread (IIIC-N+) on survival in patients with stage IIIC uterine carcinosarcoma. METHODS: Data were extracted from the Surveillance, Epidemiology, and End Results database between 1988 and 2005. Statistical analysis used χ, Kaplan-Meier method, and Cox proportional hazards model. RESULTS: A total of 690 women were identified. When comparing overall survival between patients with disease spread to uterine serosa and/or adnexa and those with positive peritoneal cytology, there was no significant difference (25.4% vs 15.5%, P = 0.2). However, although the 5-year overall survival was comparable between patients with positive pelvic lymph nodes and those with positive para-aortic lymph nodes (22.1% vs 25.4%, P = 1.0), it was significantly worse in stage IIIC-N(+) compared to stage IIIC-N patients (15.0% vs 33.4%, P < 0.001). Only patient's age (P < 0.001), race (P = 0.03), stage (P < 0.03), and lymphadenectomy (P < 0.001) were independent predictors of survival after adjusting for other contributing factors. In addition, the results of unadjusted analysis concerning the survival difference between different stage groups were confirmed on multivariate analysis. CONCLUSIONS: Positive peritoneal cytology is associated with poor prognosis in uterine carcinosarcoma, comparable to current International Federation of Gynecology and Obstetrics stage IIIA classification of disease. Although there does not seem to be a significant survival difference between patients with positive pelvic versus those with para-aortic lymph nodes, the prognosis seems to be much worse in patients with stage IIIC uterine carcinosarcoma with other evidence of extrauterine disease spread, suggesting the need for more aggressive therapy.

Stage IIA1 versus stage IIA2 cervical cancer: does the new staging criteria predict survival?

OBJECTIVE: (1) To determine the correlation of 2008 International Federation of Gynecology and Obstetrics staging system with survival in patients with stage IIA cervical cancer, (2) to elucidate the treatment patterns in stage IIA1 and stage IIA2 cervical cancer, and (3) to investigate whether radical hysterectomy or radiation influenced overall survival. METHODS: Data were extracted from the Surveillance, Epidemiology and End Results database between 1988 and 2005. Statistical analysis used χ test, Kaplan-Meier method, Cox regression, and logistic regression. RESULTS: Of the 560 women, 271 (48.4%) had stage IIA1, and 289 (51.6%) had stage IIA2 cervical cancer. Stage IIA2 patients were younger than stage IIA1 patients (mean age, 49 years vs 54 years; P = 0.01). Stage IIA1, compared with stage IIA2, differed significantly regarding the administration of primary radiation (47.2% vs 64.7%, P < 0.001) and adjuvant radiation (60.5% vs 77.5%, P = 0.006). The following variables were significantly associated with the performance of radical hysterectomy: patient age, 65 years or younger, tumor size, ≤ 2 cm or lesser, high tumor grade, and nonsquamous tumor histology. The incidence of adjuvant radiation after radical hysterectomy was high (48% [tumor size, ≤ 2 cm] to 86% [tumor size, >6 cm]). The 5-year overall survival was not significantly different between stages IIA1 and IIA2 (65.8% vs 59.5%, P = 0.2). Only patient age (P = 0.01), tumor size (P = 0.02), and lymph node status (P = 0.002) were independent predictors of survival. When controlled for other contributing factors, there was no significant difference in survival between patients treated by radical hysterectomy and primary radiation. CONCLUSIONS: The 2008 International Federation of Gynecology and Obstetrics staging criteria is not an independent predictor of survival in stage IIA cervical cancer. Given the equivalent efficacy of radical hysterectomy and radiation, attention should be paid to the high risk of adjuvant radiation in these patients.

Intra-operative detection of nodal metastasis in early stage cervical cancer: a survey of the practice patterns of SGO members.

OBJECTIVES: To determine the practice patterns of members of Society of Gynecologic Oncologists (SGO) in different clinical situations involving the intra-operative detection of nodal metastasis in early stage cervical cancer. METHODS: A study questionnaire was mailed to the current members of SGO (n=874). Data were collected using an internet survey database. Frequency distributions were determined, and non parametric tests were performed. RESULTS: Thirty percent SGO members responded (n=274). Only 38.6% routinely performed an intra-operative frozen section evaluation of the lymph nodes. Of these; most (79%) did not abort the radical hysterectomy (RH) for an isolated microscopically positive pelvic lymph node. The likelihood of aborting RH for microscopic nodal involvement increased however with number of positive pelvic lymph nodes (21% with 1, 40% with 2-3, and 61% with >3 positive pelvic lymph nodes), involvement of para-aortic lymph nodes (61%), or bilaterally positive lymph nodes (54%). Similarly, a large number did not complete the RH due to gross involvement of pelvic (45%) or para-aortic lymph node/s (69%). Most (90%) completed the lymphadenectomy before aborting RH. When completing RH, the majority tailored its extent to perform a less radical resection. Variables significantly associated with the likelihood of completing RH in different clinical situations included: location of current practice (West), practice type (private), years in practice (>15 years), and number of cases seen per year (>10/month). CONCLUSION: Practice patterns of SGO members are considerably diverse, which is reflective of the conflicting evidence available in the literature. Well designed studies are required to determine the best overall approach.

Inhibition of the c-fms proto-oncogene autocrine loop and tumor phenotype in glucocorticoid stimulated human breast carcinoma cells.

The c-fms proto-oncogene encoded CSF-1 receptor and its ligand represent a feedback loop, which in a paracrine manner, is well known to promote spread of breast cancers. The role of the autocrine feedback loop in promotion of breast tumor behavior, in particular in vitro, is less well understood. The physiologic stimulation of c-fms expression by glucocorticoids (GCs) in vitro and in vivo magnifies the tumor promoting effect seen in these cells from activated c-fms signaling by CSF-1. Targeted molecular therapy against c-fms could therefore abrogate both complementary feedback loops. Using breast cancer cells endogenously co-expressing receptor and ligand, we used complementary approaches to inhibit c-fms expression and function within this autocrine pathway in the context of GC stimulation. Silencing RNA (shRNA), antisense oligonucleotide therapy (AON), and inhibition of c-fms signaling, were all used to quantitate inhibition of GC-stimulated adhesion, motility, and invasion of human breast cancer cells in vitro. shRNA to c-fms downregulated GC-stimulated c-fms mRNA by fourfold over controls, correlating with over twofold reduction in cellular invasiveness. AON therapy was also able to inhibit GC stimulation of c-fms mRNA, and resulted in threefold less invasiveness and 1.5 to 2-fold reductions in adhesion and motility. Finally, the small-molecule c-fms inhibitor Ki20227 was able to decrease in a dose-response manner, breast cancer cell invasion by up to fourfold. Inhibition of this receptor/ligand pair may have clinical utility in inhibition of the autocrine as well as the known paracrine interactions in breast cancer, thus further supporting use of targeted therapies in this disease.

Enhanced ovarian cancer tumorigenesis and metastasis by the macrophage colony-stimulating factor.

Coexpression of the macrophage colony-stimulating factor (CSF-1) and its receptor (CSF-1R) in metastatic ovarian cancer specimens is a predictor of poor outcome in epithelial ovarian cancer. This suggests that an autocrine loop is produced by which ovarian tumors can secrete CSF-1 stimulating the CSF-1R resulting in a more aggressive phenotype. Our current work sought to validate this autocrine stimulation model using stable transfection of a 4-kb CSF-1 construct into otherwise nonvirulent Bix3 ovarian cancer cells. A representative clone, Bix3T8.2, produced a 72-fold increase in CSF-1 gene transcription rate (by nuclear run-off assays) and a 57-fold increase in secreted CSF-1 protein (by sandwich ELISA), compared to parent cells. Comparison of Bix3T8.2 invasion, adhesion, and motility in vitro and metastasis in vivo were made to parental and transfectant controls. Up to 12-fold higher invasiveness was seen with Bix3T8.2 and 2- and 6-fold higher adhesion and motility, respectively, over controls in vitro. In nude mice, i.p. injection of Bix3T8.2 produced a wide array of visceral, nodal, and distant metastasis with a degree of enhanced tumor burden not seen in any of the 10 mice inoculated with transfectant control cells. Complete absence of tumor take distinguished 40% of mice implanted with transfectant control cells. Disruption of this autocrine loop using antisense oligomer therapy against CSF-1R and 3' untranslated region knockdown of CSF-1 protein resulted in reversal of in vitro and in vivo tumor phenotypes. This CSF-1 feedback loop offers a model by which novel biologic therapies can potentially target multiple levels of this pathway.

Correlation of tumor phenotype with c-fms proto-oncogene expression in an in vivo intraperitoneal model for experimental human breast cancer metastasis.

Although proto-oncogene expression has been shown to correlate with clinical outcome in breast carcinoma, an experimental model has not been proposed to study this phenomenon in vivo. In addition, the ability to modulate this proto-oncogene in vivo to correlate with phenotypic behavior has not been determined. Utilizing an intraperitoneal model for metastatic spread with BT20 human breast carcinoma cells, clonally expanded cells expressing five fold higher c-fms protein were compared with parent BT20 cells as well as an underexpressing clone using intrasplenic injection following left flank cut-down in female nude and Severe combined immunodeficient (SCID) mice. Athymic BALB/c nude and SCID animals were observed for clinical evidence of tumorigenicity with necropsy performed at either 50 or 80 days unless compromised earlier. Immunohistochemistry (IHC) of the harvested tumors was performed to correlate c-fms expression from its original in vitro culture to the in vivo model. At day 50, differences in primary tumor take and spread to the pelvis were already evident favoring the c-fms over-expression group with IHC of these tumors revealing significantly higher intensity of staining for c-fms, (mean H score of 205 vs. 43 in the over-expression and parent groups, respectively). At day 80, tumor take and spread was comparable; however, tumor size in the over-expression group was significantly larger than the parent and under-expressing group in both the BALB/c and SCID experiments. Modulation of c-fms proto-oncogene expression was also achieved using the anti-glucocorticoid, RU-486, via oral administration to SCID mice with subsequent correlation to IHC staining. This model thus provides tumors of significant size and organ diversity which retain their phenotype early in tumorigenesis allowing an early endpoint to assess efficacy of novel treatments.