Cigarette smoking cessation, duration of smoking abstinence, and head and neck squamous cell carcinoma prognosis.

BACKGROUND: Tobacco use is a major risk factor for developing head and neck squamous cell carcinoma (HNSCC). However, the prognostic associations with smoking cessation are limited. The authors assessed whether smoking cessation and increased duration of abstinence were associated with improved overall (OS) and HNSCC-specific survival. METHODS: Clinicodemographic and smoking data from patients with HNSCC at Princess Margaret Cancer Center (2006-2019) were prospectively collected. Multivariable Cox and Fine and Gray competing-risk models were used to assess the impact of smoking cessation and duration of abstinence on overall mortality and HNSCC-specific/noncancer mortality, respectively. RESULTS: Among 2482 patients who had HNSCC, former smokers (adjusted hazard ratio [aHR], 0.71; 95% CI, 0.58-0.87; p = .001; N = 841) had a reduced risk of overall mortality compared with current smokers (N = 931). Compared with current smokers, former smokers who quit >10 years before diagnosis (long-term abstinence; n = 615) had the most improved OS (aHR, 0.72; 95% CI, 0.56-0.93; p = .001). The 5-year actuarial rates of HNSCC-specific and noncancer deaths were 16.8% and 9.4%, respectively. Former smokers (aHR, 0.71; 95% CI, 0.54-0.95; p = .019) had reduced HNSCC-specific mortality compared with current smokers, but there was no difference in noncancer mortality. Abstinence for >10 years was associated with decreased HNSCC-specific death compared with current smoking (aHR, 0.64; 95% CI, 0.46-0.91; p = .012). Smoking cessation with a longer duration of quitting was significantly associated with reduced overall and HNSCC-specific mortality in patients who received primary radiation. CONCLUSIONS: Smoking cessation before the time of diagnosis reduced overall mortality and cancer-specific mortality among patients with HNSCC, but no difference was observed in noncancer mortality. Long-term abstinence (>10 pack-years) had a significant OS and HNSCC-specific survival benefit.

A pharmacokinetic and pharmacogenetic evaluation of contraceptive implants and antiretroviral therapy among women in Kenya and Uganda.

OBJECTIVES: To evaluate pharmacokinetics and pharmacogenetics of contraceptive implant progestin concentrations in HIV-positive women initiating efavirenz (EFV)-containing or nevirapine (NVP)-containing antiretroviral therapy (ART). DESIGN: We analyzed stored samples from women self-reporting implant use in the Partners PrEP Study. METHODS: Plasma samples collected every 6 months were analyzed for levonorgestrel and etonogestrel concentrations. Progestin concentrations from samples collected after ART initiation were compared with pre-ART concentrations for intraindividual comparisons. We used adjusted linear mixed models to compare hormone concentrations between individuals on EFV and NVP to a no ART group. We then evaluated whether possessing certain alleles with known or possible influences on EFV, NVP, or progestin metabolism were associated with changes in progestin concentrations or modified the association between ART use and progestin concentrations. RESULTS: Our analysis included 11 women who initiated EFV, 13 who initiated NVP, and 36 who remained ART-naive. In the EFV group, the adjusted geometric mean ratio (aGMR) of levonorgestrel was 0.39 [90% confidence intervals (0.31, 0.49); P < 0.001] and the etonogestrel aGMR was 0.51 (0.34, 0.76; P = 0.006) compared with the control group. No difference was observed in the NVP group compared with controls [levonorgestrel 0.93 (0.74, 1.18); P = 0.64; etonogestrel 1.07 (0.77, 1.50); P = 0.73]. Possession of four allele variants were found to result in further reductions in progestin concentrations among those receiving EFV. CONCLUSION: Concomitant use of EFV significantly reduces levonorgestrel or etonogestrel concentrations by 61 and 49%, respectively, compared with no ART use. We also report allelic variants in hepatic enzymes that influenced the extent of the observed drug-interaction between progestins and EFV.

Fibrolytic Bacteria Isolated from the Rumen of North American Moose (Alces alces) and Their Use as a Probiotic in Neonatal Lambs.

Fibrolytic bacteria were isolated from the rumen of North American moose (Alces alces), which eat a high-fiber diet of woody browse. It was hypothesized that fibrolytic bacteria isolated from the moose rumen could be used as probiotics to improve fiber degradation and animal production. Thirty-one isolates (Bacillus, n = 26; Paenibacillus, n = 1; and Staphylococcus, n = 4) were cultured from moose rumen digesta samples collected in Vermont. Using Sanger sequencing of the 16S rRNA gene, culturing techniques, and optical densities, isolates were identified and screened for biochemical properties important to plant carbohydrate degradation. Five isolates were selected as candidates for use as a probiotic, which was administered daily to neonate lambs for 9 weeks. It was hypothesized that regular administration of a probiotic to improve fibrolysis to neonate animals through weaning would increase the developing rumen bacterial diversity, increase animal production, and allow for long-term colonization of the probiotic species. Neither weight gain nor wool quality was improved in lambs given a probiotic, however, dietary efficiency was increased as evidenced by the reduced feed intake (and rearing costs) without a loss to weight gain. Experimental lambs had a lower acetate to propionate ratio than control lambs, which was previously shown to indicate increased dietary efficiency. Fibrolytic bacteria made up the majority of sequences, mainly Prevotella, Butyrivibrio, and Ruminococcus. While protozoal densities increased over time and were stable, methanogen densities varied greatly in the first six months of life for lambs. This is likely due to the changing diet and bacterial populations in the developing rumen.

Are patients with breast cancer satisfied with their decision making?: a comparison over time.

Choosing between lumpectomy with radiation versus mastectomy is difficult for women with early-stage breast cancer, and doubt can decrease women's confidence and satisfaction. As a result, the current study surveyed satisfaction before and after surgery in a convenience sample of women with early-stage breast cancer from a single practice. All women received either total mastectomy or lumpectomy plus radiation based on their informed choice of surgical options. The surgeon and the principal investigator educated patients about both surgeries at the time of consent. Participants answered a survey about satisfaction with their decision making before their chosen surgical procedure and again by telephone six months later. Participants felt that they had made an informed choice at the time of decision (87%) and at follow-up (93%). In addition, most women were satisfied with their choice of surgical procedure at time of decision (87%) as well as six months after surgery (96%). This study allowed women to significantly participate in their care through surgical decision making, which improved satisfaction. Nurses are uniquely positioned to support women with early-stage breast cancer in their decision-making process.

Are patients with breast cancer satisfied with their decision making? A pilot study.

This pilot study measured participants' comfort with their decision making to have a lumpectomy and radiation or total mastectomy to treat their breast cancer. Findings showed 87% of the patients believed they had made an informed choice and were satisfied with their decision making regarding their surgical procedure selection.

Agglomerative epigenetic aberrations are a common event in human breast cancer.

Changes in DNA methylation patterns are a common characteristic of cancer cells. Recent studies suggest that DNA methylation affects not only discrete genes, but it can also affect large chromosomal regions, potentially leading to LRES. It is unclear whether such long-range epigenetic events are relatively rare or frequent occurrences in cancer. Here, we use a high-resolution promoter tiling array approach to analyze DNA methylation in breast cancer specimens and normal breast tissue to address this question. We identified 3,506 cancer-specific differentially methylated regions (DMR) in human breast cancer with 2,033 being hypermethylation events and 1,473 hypomethylation events. Most of these DMRs are recurrent in breast cancer; 90% of the identified DMRs occurred in at least 33% of the samples. Interestingly, we found a nonrandom spatial distribution of aberrantly methylated regions across the genome that showed a tendency to concentrate in relatively small genomic regions. Such agglomerates of hypermethylated and hypomethylated DMRs spanned up to several hundred kilobases and were frequently found at gene family clusters. The hypermethylation events usually occurred in the proximity of the transcription start site in CpG island promoters, whereas hypomethylation events were frequently found in regions of segmental duplication. One example of a newly discovered agglomerate of hypermethylated DMRs associated with gene silencing in breast cancer that we examined in greater detail involved the protocadherin gene family clusters on chromosome 5 (PCDHA, PCDHB, and PCDHG). Taken together, our results suggest that agglomerative epigenetic aberrations are frequent events in human breast cancer.

Epigenetic silencing of DSC3 is a common event in human breast cancer.

INTRODUCTION: Desmocollin 3 (DSC3) is a member of the cadherin superfamily of calcium-dependent cell adhesion molecules and a principle component of desmosomes. Desmosomal proteins such as DSC3 are integral to the maintenance of tissue architecture and the loss of these components leads to a lack of adhesion and a gain of cellular mobility. DSC3 expression is down-regulated in breast cancer cell lines and primary breast tumors; however, the loss of DSC3 is not due to gene deletion or gross rearrangement of the gene. In this study, we examined the prevalence of epigenetic silencing of DSC3 gene expression in primary breast tumor specimens. METHODS: We used bisulfite genomic sequencing to analyze the methylation state of the DSC3 promoter region from 32 primary breast tumor specimens. We also used a quantitative real-time RT-PCR approach, and analyzed all breast tumor specimens for DSC3 expression. Finally, in addition to bisulfite sequencing and RT-PCR, we used an in vivo nuclease accessibility assay to determine the chromatin architecture of the CpG island region from DSC3-negative breast cancer cells lines. RESULTS: DSC3 expression was downregulated in 23 of 32 (72%) breast cancer specimens comprising: 22 invasive ductal carcinomas, 7 invasive lobular breast carcinomas, 2 invasive ductal carcinomas that metastasized to the lymph node, and a mucoid ductal carcinoma. Of the 23 specimens showing a loss of DSC3 expression, 13 (56%) were associated with cytosine hypermethylation of the promoter region. Furthermore, DSC3 expression is limited to cells of epithelial origin and its expression of mRNA and protein is lost in a high proportion of breast tumor cell lines (79%). Lastly, DNA hypermethylation of the DSC3 promoter is highly correlated with a closed chromatin structure. CONCLUSION: These results indicate that the loss of DSC3 expression is a common event in primary breast tumor specimens, and that DSC3 gene silencing in breast tumors is frequently linked to aberrant cytosine methylation and concomitant changes in chromatin structure.

Aberrant methylation of the maspin promoter is an early event in human breast cancer.

The maspin gene functions as a tumor suppressor in human breasts, and its expression is frequently lost during breast cancer progression. In vitro models of human breast cancer indicate that the loss of maspin expression is closely linked to aberrant methylation of the maspin promoter. We conducted a study on 30 archival ductal carcinoma in situ (DCIS) specimens to determine if aberrant methylation of the maspin promoter occurred in vivo, and whether it occurred early in breast cancer evolution. Healthy tissue obtained from reduction mammoplasty was used as normal control. Results from immunohistochemical analysis indicate that maspin expression is lost in a substantial fraction of DCIS specimens (57%). Bisulfite sequencing of DNA isolated from laser capture-microdissected normal and neoplastic ducts showed that loss of maspin expression was often, but not always, linked to aberrant methylation of the maspin promoter, suggesting that other mechanisms, in addition to aberrant methylation, participate and/or cooperate to silence maspin gene expression. Taken together, these results indicate that aberrant methylation of the maspin promoter is an early event in human breast cancer.

The new melanoma staging system.

BACKGROUND: Classification schemas for cancers are useful for predicting overall survival and selecting patients for treatment. Historically, the most important factors in determining prognosis in patients with melanoma have been tumor thickness and lymph node status. Sentinel lymph node mapping defines a subset of patients with microscopic metastatic disease can be identified, offering greater accuracy in staging. METHODS: The authors reviewed studies evaluating the prognostic factors that are significant in predicting survival in patients with melanoma. The newly revised American Joint Committee on Cancer (AJCC) staging system for melanoma is compared with the 1997 AJCC staging system currently in use. RESULTS: The changes in the new AJCC melanoma staging system reflect the new prognostic factors that have been found to be important in predicting survival. These include primary tumor thickness (tumor depth in millimeters is more predictive than the level of invasion) and ulceration, number of metastatic lymph nodes, micrometastatic disease based on the sentinel lymph node biopsy technique or elective node dissection, the site(s) of distant metastatic disease and serum LDH levels. CONCLUSIONS: Major revisions have been made to form a new AJCC staging system for melanoma, which will become official in 2002. This system will provide more accurate and precise information regarding patient prognosis. Validation studies are needed to confirm the accuracy of this revised staging system.

Immunotherapy for melanoma.

BACKGROUND: Immunotherapy for cancers is based on the principle that the host's immune system is capable of generating immune responses against tumor cells. Currently available treatments for melanoma patients are limited by poor response rates. Interferon-a has been approved for adjuvant treatment of stage III melanoma with improved survival. New and more innovative approaches with improved efficacy are needed. METHODS: We reviewed the various new approaches and strategies for immunotherapy for the treatment of melanoma. RESULTS: Immunotherapy for melanoma includes a number of different strategies with vaccines utilizing whole cell tumors, peptides, cytokine-mediated dendritic cells, DNA and RNA, and antibodies. CONCLUSIONS: A variety of approaches can be used to enhance immune reactivity in patients with melanoma. Preclinical studies and initial clinical trials have shown promising results. Additional clinical trials are currently ongoing to evaluate the clinical efficacy and the associated toxicities of these novel treatment strategies.

Metastatic melanoma: chemotherapy to biochemotherapy.

BACKGROUND: Single-agent or combination chemotherapy regimens have not impacted the short median survival of patients with metastatic melanoma, and complete or durable responses are rare. Biologic response modifiers (interferon and interleukin-2) have produced durable remissions in a small cohort of patients, and phase II trials of biochemotherapy suggest more benefit. METHODS: The authors retrospectively reviewed the status of the current treatments of metastatic melanoma focusing on biochemotherapy. RESULTS: Regimens include both sequential and concurrent approaches for inpatient and outpatient treatment settings. Overall response rates in phase II trials are 40% to 60% with complete responses of 10% to 20% and median survivals in the 11- to 12-month range. Modifications of concurrent biochemotherapy regimens have maintained efficacy and reduced toxicity. Small phase III trials suggest a survival advantage of biochemotherapy (P=.05). CONCLUSIONS: Biochemotherapy remains a promising new treatment for metastatic melanoma. A large Intergroup trial E3695 comparing concurrent biochemotherapy to combination chemotherapy alone is powered to answer important survival questions.

The promise of microarray technology in melanoma care.

BACKGROUND: Genetic aberration is responsible for the development of neoplastic potential in a number of malignancies. These DNA alterations result in significant changes in gene expression that may now be measured and catalogued. The microarray technique screens and identifies expressed genes that may be responsible for tumorigenesis. METHODS: The authors review the application of the microarray technique in malignant melanoma. RESULTS: Candidate melanoma suppressor genes have been identified in melanoma cell lines using this technique. Furthermore, molecular classification using gene expression profiling may improve the accuracy of the staging system for determining prognosis. CONCLUSIONS: The microarray technique is in its initial development for clinical application in a variety of tumor models. Melanoma is an ideal system to study the genetic changes associated with the stepwise progression of malignancy. It may be possible to efficiently screen the entire human genome to identify the particular aberrations in gene expression responsible for tumorigenesis in melanoma.

Effects of interleukin 2 therapy on lymphocyte magnesium levels.

Interleukin 2 (IL-2) can cause partial or complete tumor regression in approximately 20% of patients with renal cell carcinoma. Among the many physiologic effects of IL-2, decreased serum levels of the divalent cations magnesium (Mg) and calcium have been demonstrated, with corresponding decreases in their urinary excretion. We investigated the effect of IL-2 on lymphocyte Mg levels among patients receiving three different dosing regimens. Twenty-eight patients with metastatic renal cell carcinoma were treated with high-dose intravenous, low-dose intravenous, or subcutaneous IL-2 therapy. Serum ionized Mg, urinary Mg, and peripheral blood mononuclear cell Mg levels were measured in samples from patients during treatment and compared with pretreatment levels. Serum Mg and ionized Mg levels decreased for all patients within 12 hours of treatment (P <.005) and remained low for the duration of therapy. Urinary Mg decreased in parallel with serum levels in all patients (P <.005). The peripheral blood mononuclear cell Mg content per cell increased within 24 hours of treatment (P <.005). The magnitude of these changes was similar during the first week of treatment for patients receiving intravenous or subcutaneous administration of IL-2. During IL-2 therapy, lymphocyte Mg increases coincident with serum Mg depletion. Mg availability may have functional implications for lymphocyte proliferation and integrin function.