Value-Based Costing of Anti-Cancer Drugs: An Ethical Perspective Grounded in Catholic Teachings on Human Dignity and the Common Good.

Americans have benefited from a declining cancer incidence and improving prognosis over the past two decades, during which time rising prices for anti-cancer drugs have proportionally outstripped rising expenditures for overall cancer care and total national health expenditures. To meet the economic challenges, remedies have been proposed to base compensation on relative survival measurements perhaps taking into account associated drug toxicities, disabilities, and disease progression. While there are advantages for knowing the economic costs determined from so-called, "value-based" methodologies, it must be recognized that the measured values are impersonal, incomplete, and always biased. This article examines value-based costing of anti-cancer drugs in an individual and societal framework and advocates grounding decisions regarding cancer care and pharmaceutical costs on the ethical principles of human dignity and the common good.

Endometriosis: A Malignant Fingerprint.

BACKGROUND: Endometriosis is complex, but identifying the novel biomarkers, inflammatory molecules, and genetic links holds the key to the enhanced detection, prediction and treatment of both endometriosis and endometriosis related malignant neoplasia. Here we review the literature relating to the specific molecular mechanism(s) mediating tumorigenesis arising within endometriosis. METHODS: Guidance (e.g. Cochrane) and published studies were identified. The Published studies were identified through PubMed using the systematic review methods filter, and the authors' topic knowledge. These data were reviewed to identify key and relevant articles to create a comprehensive review article to explore the molecular fingerprint associated with in endometriosis-driven tumorigenesis. RESULTS: An important focus is the link between C3aR1, PGR, ER1, SOX-17 and other relevant gene expression profiles and endometriosis-driven tumorigenesis. Further studies should also focus on the combined use of CA-125 with HE-4, and the role for OVA1/MIA as clinically relevant diagnostic biomarkers in the prediction of endometriosis-driven tumorigenesis. CONCLUSIONS: Elucidating endometriosis' molecular fingerprint is to understand the molecular mechanisms that drive the endometriosis-associated malignant phenotype. A better understanding of the predictive roles of these genes and the value of the biomarker proteins will allow for the derivation of unique molecular treatment algorithms to better serve our patients.

Dr. Bernard Nathanson: A story of metanoia.

Bernard A. Nathanson (1926-2011), was a professionally well-recognized and successful New York obstetrician and gynecologist. An avowed atheist as a young man through his middle age, Nathanson was a co-founder of the National Association for the Repeal of Abortion Laws, whose activities are credited with hastening the liberalization of abortion law in New York State. Intent on increasing the accessibility and promoting the acceptance of abortion on demand, Dr. Nathanson taught and published journal articles on the operative techniques and on the results from large numbers of these procures. During his tenure as director of the largest abortion clinic in the Western World, Nathanson presided over 60,000 abortions, and he performed more than 1,500 in his own practice. His studies of embryology and evidence from emerging technologies to monitor and examine intrauterine fetal development led Nathanson to question the morality of voluntarily interrupting pregnancy, thence to rejecting abortion procedures from his own clinical practice altogether, and eventually to become involved in anti-abortion, pro-life activities. An influential writer, speaker and film maker, these experiences and witnessing the love and prayer of other pro-life supporters turned Nathanson to notions of God, and finally reading and personal prayer guided him from secular atheism to Christianity.

Reducing the Risk of Gynecologic Cancer in Hereditary Breast Ovarian Cancer Syndrome Mutation Carriers: Moral Dilemmas and the Principle of Double Effect.

Hereditary breast ovarian cancer (HBOC) syndrome is an autosomal dominant disease linked to mutations in the BRCA1 and BRCA2 genes in 90 percent of affected families. Female mutation carriers are highly susceptible to aggressive, often disseminated, usually fatal pelvic-abdominal carcinomatosis. This cancer risk can be markedly reduced by surgical removal of the internal gynecologic organs before the end of the fourth decade of life and by using estrogen-progestin formulations marketed for many years as combined oral contraceptives (COCs). Both risk-reducing methods are associated with unfavorable effects. Relying on the principle of double effect, this essay argues for the ethical justification of prophylactic surgery and the use of COC to reduce the risk of gynecologic cancer in HBOC syndrome mutation carriers. Summary: Hereditary breast ovarian cancer syndrome is an autosomal dominant disease linked to mutations in the BRCA1 and BRCA2 genes in most affected families. Female mutation carriers are highly susceptible to aggressive, often disseminated, usually fatal pelvic-abdominal carcinomatosis. This cancer risk can be markedly reduced by surgical removal of the internal gynecologic organs before the end of the fourth decade of life and by using estrogen-progestin formulations marketed for many years as combined oral contraceptives. Both risk-reducing methods are associated with unfavorable effects. Relying on the principle of double effect, this essay argues for the ethical justification for those unfavorable effects.

Efficacy of proximal colectomy for surgical management of right-sided first colorectal cancer in Lynch Syndrome mutation carriers.

BACKGROUND: This study analyzes the occurrence of colorectal cancer (CRC) in Lynch syndrome (LS) mutation carriers, interval until diagnosis of metachronous CRC, and survival after proximal colectomy (PC) compared with total (TC) and subtotal colectomy (STC) for right-sided first CRC in LS mutation carriers. METHODS: Sixty-four LS mutation carriers with right-sided first CRC treated with PC or TC + STC were confirmed by clinical records. Bivariate analyses were examined for significance and life tables were generated for risk of metachronous CRC and survival estimates following surgery. RESULTS: One of 16 (6.3%) mutation carriers treated with TC + STC developed subsequent CRC compared with 13/48 (27%) treated by PC. There was no significant difference in survival estimates between PC compared with TC + STC through 25 years after surgery. CONCLUSION: Risk of subsequent CRC and survival estimates following PC and TC + STC should be considered in surgical management of right-sided first CRC in LS mutation carriers.

Phenotypic and genotypic heterogeneity of Lynch syndrome: a complex diagnostic challenge.

Lynch syndrome is the hereditary disorder that most frequently predisposes to colorectal cancer as well as predisposing to a number of extracolonic cancers, most prominently endometrial cancer. It is caused by germline mutations in the mismatch repair genes. Both its phenotype and genotype show marked heterogeneity. This review gives a historical overview of the syndrome, its heterogeneity, its genomic landscape, and its implications for complex diagnosis, genetic counseling and putative implications for immunotherapy.

Müllerian intra-abdominal carcinomatosis in hereditary breast ovarian cancer syndrome: implications for risk-reducing surgery.

More than 40 years ago Lynch et al. described several multigenerational breast cancer family pedigrees which demonstrated autosomal dominant inheritance of a trait(s) that increased risks for both breast and ovarian cancers. Mutation carriers in at least 90 % of these hereditary breast ovarian cancer (HBOC) syndrome families have been linked to cancer-associated mutations in the genes BRCA1 and BRCA2. This review focuses on the contributions of Lynch, colleagues and collaborators and pertinent literature, toward defining the HBOC syndrome, the cancer risks that the inherited adverse mutations convey, the gynecologic tissues and organs from which the malignancy may arise to disseminate throughout the pelvic and abdominal organs and peritoneum and how this information can be used to reduce the risk and morbidities of intra-abdominal carcinomatosis in effected individuals.

Dignum et justum est: Obamacare and Travail of the Little Sisters.

This essay traces the Affordable Care Act from initiation through the bureaucratic unfolding of required preventive health services for women and presents the ethically reasoned objections to provision of certain services and compliance with regulations for implementation by the Little Sisters of the Poor, an international order of consecrated nuns dedicated to care of the elderly poor. The author's intent is to understand and intelligently convey the fundamental issues raised by their challenge.

Endometrial cancers in mutation carriers from hereditary breast ovarian cancer syndrome kindreds: report from the Creighton University Hereditary Cancer Registry with review of the implications.

OBJECTIVE: The aim of this study was to categorize and report endometrial cancers in mutation carriers from hereditary breast ovarian cancer families. METHODS: Our Hereditary Cancer Registry was searched for gynecologic and peritoneal cancers linked to mutations in BRCA1 or BRCA2. Invasive cancers were registered in 101 mutation carriers with complete pathology reports. Efforts were made to secure diagnostic surgical pathology tissues for review. All records and available diagnostic slides were meticulously studied, and primary cancers were classified. FINDINGS: Eight malignancies were classified as primary endometrial cancers. Five of these were low- or intermediate-grade endometrioid carcinomas, and 3 were pure serous carcinomas or contained serous carcinoma elements mixed with high-grade endometrioid carcinoma. Breast cancers were diagnosed in 5 patients before and in 1 patient after endometrial carcinoma. Three endometrioid carcinomas were preceded by estrogen treatment, 2 for many years and the other for only 2 months, and 2 of the patients with serous carcinoma had been treated with tamoxifen. CONCLUSIONS: The finding that 8 of gynecologic and peritoneal cancers in 101 mutation carriers were endometrial cancers with a smaller proportion of endometrioid carcinomas than reported in general populations is added to the current controversial literature on endometrial cancer, particularly regarding serous carcinomas, in hereditary breast ovarian cancer syndrome. Well-designed prospective programs for standardized surgical and pathologic handling, processing, and reporting are essential for working out the pathogenesis, true risks, and best management of this disease in carriers of deleterious BRCA1 and BRCA2 germline mutations.

Therapeutic, prophylactic, untoward, and contraceptive effects of combined oral contraceptives: catholic teaching, natural law, and the principle of double effect when deciding to prescribe and use.

Combined oral contraceptives (COC) have been demonstrated to have significant benefits for the treatment and prevention of disease. These medications also are associated with untoward health effects, and they may be directly contraceptive. Prescribers and users must compare and weigh the intended beneficial health effects against foreseeable but unintended possible adverse effects in their decisions to prescribe and use. Additionally, those who intend to abide by Catholic teachings must consider prohibitions against contraception. Ethical judgments concerning both health benefits and contraception are approached in this essay through an overview of the therapeutic, prophylactic, untoward, and contraceptive effects of COC and discussion of magisterial and traditional Catholic teachings from natural law. Discerning through the principle of double effect, proportionate reason, and evidence gathered from the sciences, medical and moral conclusions are drawn that we believe to be fully compliant with good medicine and Catholic teaching.

Phenotypic heterogeneity of hereditary gynecologic cancers: a report from the Creighton hereditary cancer registry.

To determine the validity of observations suggesting a significant dichotomy of gynecologic cancers determined by linkage to specific genetic defects associated with two major autosomal dominant hereditary cancer syndromes; the Creighton University Hereditary Cancer Registry was searched for female carriers of germ line mutations in BRCA1 and BRCA2, associated with the Hereditary Breast Ovarian Cancer syndrome, and in the mismatch repair (MMR) genes MLH1, MSH2 and MSH6, associated with Lynch syndrome, who were registered with invasive uterine, ovarian, fallopian tube or peritoneal cancers between January 1, 1959 and December 31, 2010. From 217 such cases, a total of 174 subjects, consisting of 95 BRCA1 and BRCA2 mutation carriers and 79 carriers of mutations in MMR genes, were identified who had current signed Health Insurance Portability and Accountability Act forms and complete primary diagnostic pathology reports and clinical records. Data meticulously extracted from these cases were categorized and statistically analyzed. There were highly significant differences between carriers of BRCA1 and BRCA2 mutations and carriers of MMR gene mutations in the proportion of serous carcinomas compared with endometrioid carcinomas of the uterus, including cervix and endometium (p < 0.002), ovaries (p < 0.001) and overall, including fallopian tube and peritoneum cancers (p < 0.001). Endometrioid carcinoma was found in one and transitional carcinoma in another of the 14 BRCA1 mutation carriers with fallopian tube cancer, and endometrioid carcinoma was found in two of four MMR gene mutation carriers with fallopian tube cancers. All other fallopian tube cancers were serous carcinomas. Seven BRCA1 and one BRCA2 mutation carriers were diagnosed with primary peritoneal serous carcinoma; no peritoneal carcinomas were registered in MMR gene mutation carriers. Nine of 14 gynecologic cancers with associated endometriosis in mutation carriers were endometrioid or endometrioid mixed carcinomas compared with just three of other histologic types. Primary breast cancers, that characterize the HBOC syndrome, were much more frequent in BRCA1 and BRCA2 mutation carriers; while multiple gynecologic cancers and associated colorectal and urinary tract cancers, which are features of Lynch syndrome, were more common in MMR gene mutation carriers. Both serous and endometrioid carcinomas were diagnosed in MMR gene mutation carriers at significantly younger ages than in BRCA1 and BRCA2 mutation carriers (p < 0.0006). These findings confirm a clear dichotomy of uterine, ovarian and fallopian tube cancers associated with inheritance of mutations in BRCA1 and BRCA2 contrasted with inheritance of MMR gene mutations. This opens possibilities for new approaches to molecular genetic research into carcinogenic pathways and raises important new considerations regarding counseling, screening, prophylaxis and treatment of mutation carriers.

Ethical dilemma of mandated contraception in pharmaceutical research at catholic medical institutions.

The Catholic Church proscribes methods of birth control other than sexual abstinence. Although the U.S. Food and Drug Administration (FDA) recognizes abstinence as an acceptable method of birth control in research studies, some pharmaceutical companies mandate the use of artificial contraceptive techniques to avoid pregnancy as a condition for participation in their studies. These requirements are unacceptable at Catholic health care institutions, leading to conflicts among institutional review boards, clinical investigators, and sponsors. Subjects may feel coerced by such mandates to adopt contraceptive techniques inconsistent with their personal situation and beliefs; women committed to celibacy or who engage exclusively in non-heterosexual activities are negatively impacted. We propose principles to insure informed consent to safeguard the rights of research subjects at Catholic institutions while mitigating this ethical conflict. At the same time, our proposal respects the interests of pharmaceutical research agencies and Catholic moral precepts, and fully abides by regulatory guidance.

Hereditary ovarian carcinoma: heterogeneity, molecular genetics, pathology, and management.

Hereditary ovarian cancer accounts for at least 5% of the estimated 22,000 new cases of this disease during 2009. During this same time, over 15,000 will die from malignancy ascribed to ovarian origin. The bulk of these hereditary cases fits the hereditary breast-ovarian cancer syndrome, while virtually all of the remainder will be consonant with the Lynch syndrome, disorders which are autosomal dominantly inherited. Advances in molecular genetics have led to the identification of BRCA1 and BRCA2 gene mutations which predispose to the hereditary breast-ovarian cancer syndrome, and mutations in mismatch repair genes, the most common of which are MSH2 and MLH1, which predispose to Lynch syndrome. These discoveries enable relatively certain diagnosis, limited only by their variable penetrance, so that identification of mutation carriers through a comprehensive cancer family history might be possible. This paper reviews the subject of hereditary ovarian cancer, with particular attention to its molecular genetic basis, its pathology, and its phenotypic/genotypic heterogeneity.

Intra-abdominal carcinomatosis after prophylactic oophorectomy in women of hereditary breast ovarian cancer syndrome kindreds associated with BRCA1 and BRCA2 mutations.

OBJECTIVE: Prophylactic surgical removal of the ovaries has been offered for many years as a potential preventative of ovarian cancer in women deemed to be at increased hereditary risk for this disease. Now, it is possible to test for specific mutations of the BRCA1 and BRCA2 genes that render members of hereditary breast ovarian cancer (HBOC) syndrome families susceptible to cancer. Widespread intra-abdominal carcinomatosis, which mimics metastatic ovarian serous carcinoma, has been reported following oophorectomy in individuals at increased hereditary risk. This study was undertaken to examine and report particularly the occurrence of intra-abdominal carcinomatosis, as well as other cancers, following prophylactic oophorectomy in patients who carry cancer susceptibility mutations of BRCA1 and BRCA2 and to assess the cumulative risks for this disease in order to assist in developing appropriate surgical interventions, based on currently available information, and to counsel patients who choose prophylactic surgery, concerning the potential prognosis, thereafter. METHODS: The Creighton University Hereditary Cancer Institute registry was searched for members of HBOC syndrome families who had undergone prophylactic oophorectomy. The histories and results of DNA testing for the BRCA1 and BRCA2 mutations carried in their families were recorded, tabulated and examined, and the aggregate data are reported along with pertinent details of those individuals who developed neoplastic diseases after prophylactic oophorectomy. All available histologic and cytologic materials of patients who were diagnosed with intra-abdominal carcinomatosis were reviewed, and life-table calculations were performed to assess cumulative risks for this disease following prophylactic oophorectomy. RESULTS: From 72 HBOC syndrome families that carried either BRCA1 or BRCA2 cancer-associated mutations, 238 individuals who had undergone prophylactic oophorectomy were recorded in our registry between January 1985 and December 2002. During a mean follow-up of 9.3 years, cancers were diagnosed in 27 subjects, including 16 individuals with breast cancer and five patients with intra-abdominal carcinomatosis. Breast cancers were stage I in 10 of 12 proven carriers of cancer-associated mutations. All five cases of intra-abdominal carcinomatosis were serous carcinomas, and all occurred in BRCA1 mutation carriers. Histologic review of the prophylactically removed ovaries found borderline lesions in two cases, one with possible early stromal invasion. Two of the five patients who developed intra-abdominal carcinomatosis were among 78 patients in this series who were diagnosed and treated for breast cancer before prophylactic oophorectomy. A 3.5% cumulative risk for all mutation carriers and a 3.9% cumulative risk for BRCA1 mutation carriers were calculated through 20 years of follow-up after prophylactic oophorectomy. CONCLUSIONS: Intra-abdominal carcinomatosis in our series was diagnosed only in BRCA1 mutation carriers. The calculated cumulative risks of developing intra-abdominal carcinomatosis after prophylactic oophorectomy in members of HBOC syndrome families, specifically those who carry deleterious mutations, are well below the estimated risks of ovarian cancer published in the literature for similar patients. Breast cancers, which tended to be small and localized, were the most common malignancy in BRCA1 and BRCA2 mutation carriers after prophylactic oophorectomy.

Peritoneal carcinoma in women with genetic susceptibility: implications for Jewish populations.

Women from families with multiple cases of breast and ovarian cancer, specifically those who carry cancer-associated mutations of BRCA1 or BRCA2 are at increased life-time risk for peritoneal carcinoma, even after previous surgery to remove the ovaries, fallopian tubes and uterus. Hereditary breast-ovarian cancer (HBOC) syndrome and the associated BRCA1 and BRCA2 mutations are particularly prevalent in women of Jewish lineage, and specific BRCA1 and BRCA2 germline mutations have been linked with peritoneal carcinoma and HBOC syndrome in Jewish populations, especially those of Ashkenazi descent. This review presents the currently available data and looks forward toward further and better understanding of peritoneal carcinoma in women with inherited susceptibility. Over 90% of peritoneal cancer in patients from HBOC syndrome kindreds and associated with BRCA1 and BRCA2 mutations are serous carcinomas, which is equivalent with the proportion of ovarian cancers that are serous carcinomas in similar patients. The best indications are that while many peritoneal carcinomas in genetically susceptible women may arise directly from malignant transformation of the peritoneum, others might represent metastases from primary ovarian or fallopian tube carcinomas. Although the incidence of borderline ovarian tumors may not be increased in HBOC syndrome kindreds and those who carry cancer-associated BRCA1 and BRCA2 mutations, these individuals could be susceptible to malignant transformation of borderline lesions of the ovaries and peritoneum. Moreover, recent reports raise the question of possibly increased risk in Jewish carriers of germline BRCA1 mutations for uterine papillary serous carcinoma, which could be the source of metastasis to the peritoneum in some cases. The penetrance of cancer-associated BRCA1 mutations for ovarian cancer is estimated to be 11%-54%, and for BRCA2 mutations the penetrance for ovarian cancer is 11%-23%. So far, available screening methods appear to be insufficient for early detection of many ovarian cancers. Prophylactic oophorectomy has been found to reduce the risk for ovarian cancer in women from HBOC kindreds and those who carry cancer-associated BRCA1 and BRCA2 mutations, leaving a residual risk for peritoneal carcinomatosis of well less than 5%. Therefore, surgical removal of the ovaries, fallopian tubes and uterus, after child-bearing has been completed and by early in the fifth decade of life, are appropriate prophylactic procedures in women whose genetic susceptibility puts them at increased risk for cancers of mullerian tract origin, including ovarian and fallopian tube carcinomas and possibly serous carcinoma of the uterus. Hysterectomy, as well as salpingo-oophorectomy, removes the gynecologic organs targeted for malignant transformation in genetically susceptible women and simplifies decisions regarding hormone replacement therapy and chemical prophylaxis and treatment of breast cancer. Unless a transabdominal operative approach is otherwise indicated, laparoscopic-assisted transvaginal techniques are well suited for intra-abdominal exploration, cytology, biopsies and prophylactic salpingo-oophorectomy and hysterectomy in women with hereditary susceptibility to gynecologic cancer.