THE MANAGEMENT OF CANCER OF THE BREAST

Radical mastectomy is excellent only for cases of operable breast cancer in which the tumor is limited to the breast or to the nodes in the axilla. That there is metastasis to the internal mammary lymph nodes in a high proportion of cases has been “overlooked” for many years. Also it is probable that metastasis occurs to the supraclavicular lymph nodes more often than is suspected. Hence the extended radical mastectomy operation leaves much to be desired. There has been no significant improvement in recent years in the mortality rate of mammary cancer.Simple mastectomy and thorough adequate postoperative radiation therapy have much to offer.Treatment of “operable” breast cancer should be a cooperative effort of surgeon, radiation therapist and pathologist.     

Giant intracanalicular fibroadenoma. With report of five cases

Five cases of giant intracanalicular fibroadenoma ("cystosarcoma phylloides") were observed at one hospital in a period of three years. In a search of the literature, additional reports of breast tumors of this kind, not included in previous reviews, were noted. As there is record of 229 cases, it would appear that this rapidly growing benign tumor should be kept in mind in the diagnosis of masses in the breast. If removal is incomplete, there may be recurrence. Simple mastectomy is the treatment of choice. Radical mastectomy should be avoided.     

Triple-negative breast cancer and radiation therapy

BackgroundThis study aimed to review specific indications of radiation therapy for triple-negative breast cancer (TNBC), and to introduce the hypothesis of TNBC as an independent predictor for postmastectomy radiation therapy (PMRT).Materials and methodsTwo reviewers independently searched two electronic databases (Pubmed and Embase), with the inclusion dates of January 2000 to December 2021, for the following terms: “mastectomy” or “breast conserving surgery” or “lumpectomy”, and “radiation” or “radiotherapy”, and “triple negative” and “recurrence”. All evidence was explored by two reviewers, then organized into a narrative review considering grades of recommendation.ResultsPatients with TNBC are candidates for breast conserving surgery (grade of recommendation B). Postoperative whole-breast irradiation must be offered following breast conserving surgery (grade of recommendation A). Do not omit postoperative radiation therapy in older patients with TNBC (grade of recommendation B). Do not use partial-breast irradiation in patients with TNBC (grade of recommendation B). Postmastectomy radiation therapy should be offered for women with T3–T4 or node-positive TNBC, for any number of positive nodes (grade of recommendation A). Radiation therapy following mastectomy might also benefit patients with T1–T2 node-negative TNBC (grade of recommendation B). For patients treated with neoadjuvant systemic therapy, radiation therapy indication is based on pretreatment features. Retrospective studies suggest that residual TNBC is sensitive to radiation therapy to optimize locoregional control (grade of recommendation C).ConclusionsPostoperative radiation therapy should be offered for most patients with TNBC. Upcoming studies, preferably prospective randomized trials, should evaluate the indications of radiation therapy, especially in the context of novel systemic treatments.     

Functional MRI To Evaluate “Sense of Self” following Perforator Flap Breast Reconstruction

Background

Breast reconstruction is associated with high levels of patient satisfaction. Previous patient satisfaction studies have been subjective. This study utilizes functional magnetic resonance imaging (fMRI) to objectively evaluate “sense of self” following deep inferior epigastric perforator (DIEP) flap breast reconstruction in an attempt to better understand patient perception.

Methods

Prospective fMRI analysis was performed on four patients before and after delayed unilateral DIEP flap breast reconstruction, and on four patients after immediate unilateral DIEP flap breast reconstruction. Patients were randomly cued to palpate their natural breast, mastectomy site or breast reconstruction, and external silicone models. Three regions of interest (ROIs) associated with self-recognition were examined using a general linear model, and compared using a fixed effects and random effects ANOVA, respectively.

Results

In the delayed reconstruction group, activation of the ROIs was significantly lower at the mastectomy site compared to the natural breast (p<0.01). Ten months following reconstruction, activation of the ROIs in the reconstructed breast was not significantly different from that observed with natural breast palpation. In the immediate reconstruction group, palpation of the reconstructed breast was also similar to the natural breast. This activity was greater than that observed during palpation of external artificial models (p<0.01).

Conclusions

Similar activation patterns were observed during palpation of the reconstructed and natural breasts as compared to the non-reconstructed mastectomy site and artificial models. The cognitive process represented by this pattern may be a mechanism by which breast reconstruction improves self-perception, and thus patient satisfaction following mastectomy.     

Wavelet-Based 3D Reconstruction of Microcalcification Clusters from Two Mammographic Views: New Evidence That Fractal Tumors Are Malignant and Euclidean Tumors Are Benign

The 2D Wavelet-Transform Modulus Maxima (WTMM) method was used to detect microcalcifications (MC) in human breast tissue seen in mammograms and to characterize the fractal geometry of benign and malignant MC clusters. This was done in the context of a preliminary analysis of a small dataset, via a novel way to partition the wavelet-transform space-scale skeleton. For the first time, the estimated 3D fractal structure of a breast lesion was inferred by pairing the information from two separate 2D projected mammographic views of the same breast, i.e. the cranial-caudal (CC) and mediolateral-oblique (MLO) views. As a novelty, we define the “CC-MLO fractal dimension plot”, where a “fractal zone” and “Euclidean zones” (non-fractal) are defined. 118 images (59 cases, 25 malignant and 34 benign) obtained from a digital databank of mammograms with known radiologist diagnostics were analyzed to determine which cases would be plotted in the fractal zone and which cases would fall in the Euclidean zones. 92% of malignant breast lesions studied (23 out of 25 cases) were in the fractal zone while 88% of the benign lesions were in the Euclidean zones (30 out of 34 cases). Furthermore, a Bayesian statistical analysis shows that, with 95% credibility, the probability that fractal breast lesions are malignant is between 74% and 98%. Alternatively, with 95% credibility, the probability that Euclidean breast lesions are benign is between 76% and 96%. These results support the notion that the fractal structure of malignant tumors is more likely to be associated with an invasive behavior into the surrounding tissue compared to the less invasive, Euclidean structure of benign tumors. Finally, based on indirect 3D reconstructions from the 2D views, we conjecture that all breast tumors considered in this study, benign and malignant, fractal or Euclidean, restrict their growth to 2-dimensional manifolds within the breast tissue.     

MANDIBULAR HERPES ZOSTER—With Report on the Use of Cortisone in a Case with Geniculate Ganglion Symptoms

Herpes zoster, an acute specific viral infection, occurs more commonly than is generally supposed. It should be differentiated from other diseases involving the ear and skin; it must be considered as a possible etiologic agent in some palsies of the facial, glossopharyngeal or vagal nerves.The type of cephalic herpes zoster should be carefully differentiated; cases involving the “geniculate zone” may be other than “Ramsay Hunt''s syndrome.” This syndrome is now defined as a herpes zoster eruption of the external ear at the “geniculate zone” with involvement of the seventh or seventh and eighth nerves.The “topognostic” method is the best for determining the level at which the facial nerve has been affected.It is questioned whether there is a single outstanding therapeutic agent for this disease. Cortisone had no apparent therapeutic effect in a case reported herein.     

Evidence for a stromal-epithelial “lactate shuttle” in human tumors: MCT4 is a marker of oxidative stress in cancer-associated fibroblasts

Recently, we proposed a new mechanism for understanding the Warburg effect in cancer metabolism. In this new paradigm, cancer-associated fibroblasts undergo aerobic glycolysis, and extrude lactate to “feed” adjacent cancer cells, which then drives mitochondrial biogenesis and oxidative mitochondrial metabolism in cancer cells. Thus, there is vectorial transport of energy-rich substrates from the fibroblastic tumor stroma to anabolic cancer cells. A prediction of this hypothesis is that cancer-associated fibroblasts should express MCT4, a mono-carboxylate transporter that has been implicated in lactate efflux from glycolytic muscle fibers and astrocytes in the brain. To address this issue, we co-cultured MCF7 breast cancer cells with normal fibroblasts. Interestingly, our results directly show that breast cancer cells specifically induce the expression of MCT4 in cancer-associated fibroblasts; MCF7 cells alone and fibroblasts alone, both failed to express MCT4. We also show that the expression of MCT4 in cancer-associated fibroblasts is due to oxidative stress, and can be prevented by pre-treatment with the anti-oxidant N-acetyl-cysteine. In contrast to our results with MCT4, we see that MCT1, a transporter involved in lactate uptake, is specifically upregulated in MCF7 breast cancer cells when co-cultured with fibroblasts. Virtually identical results were also obtained with primary human breast cancer samples. In human breast cancers, MCT4 selectively labels the tumor stroma, e.g., the cancer-associated fibroblast compartment. Conversely, MCT1 was selectively expressed in the epithelial cancer cells within the same tumors. Functionally, we show that overexpression of MCT4 in fibroblasts protects both MCF7 cancer cells and fibroblasts against cell death, under co-culture conditions. Thus, we provide the first evidence for the existence of a stromal-epithelial lactate shuttle in human tumors, analogous to the lactate shuttles that are essential for the normal physiological function of muscle tissue and brain. These data are consistent with the “reverse Warburg effect,” which states that cancer-associated fibroblasts undergo aerobic glycolysis, thereby producing lactate, which is utilized as a metabolic substrate by adjacent cancer cells. In this model, “energy transfer” or “metabolic-coupling” between the tumor stroma and epithelial cancer cells “fuels” tumor growth and metastasis, via oxidative mitochondrial metabolism in anabolic cancer cells. Most importantly, our current findings provide a new rationale and novel strategy for anti-cancer therapies, by employing MCT inhibitors.Key words: caveolin-1, oxidative stress, pseudohypoxia, lactate shuttle, MCT1, MCT4, metabolic coupling, tumor stroma, predictive biomarker, SLC16A1, SLC16A3, monocarboxylic acid transporter     

“HIDDEN” ALCOHOLICS—Medical Implications of Undiscovered Addiction

“Hidden alcoholics”—those who drink surreptitiously to keep their addiction secret—far out-number the overt habitues of skid rows. The former rather than the latter should be considered “typical” alcoholics. Even though they have severe problems, they maintain fairly good employment stability and stability in marriage. Yet they steadily deteriorate.Often “hidden” alcoholics go to physicians because of symptoms referable to alcoholism but contrive to conceal their addiction and so make diagnosis difficult. Hence, physicians observing certain kinds of symptoms that cannot be attributed to a readily observable or demonstrable pathologic change should make searching inquiry as to the patient''s drinking habits. For not until the proper diagnosis is made in such cases can there be hope of effective treatment.     

Clinical Diagnostic Process: An Analysis

An analysis of observations made during 1,307 diagnoses by a total of 28 clinicians (503 diagnoses in real life, and 804 on simulated patients) concerned primarily the interview of patients suffering from abdominal pain. Interviews ranged from 10 to 35 questions, and from “stereotyped” procedures, in which identical (and often irrelevant) questions were asked to each patient, to “adaptive” interviews, in which specific relevant questions were put to each patient. Senior clinicians tended to ask fewer, more relevant questions than their junior counterparts; and urgent cases were dealt with in a more adaptive fashion than routine cases in outpatients. Disappointingly, there was considerable difference between real-life and simulated situations. From these results it is suggested (a) that the “diagnostic process” does not exist, (b) that any automated diagnostic system must be flexible to accommodate the wishes of a variety of clinicians, and (c) that studies based on artificial clinical situations should be treated with extreme caution.     

An “elite hacker”: Breast tumors exploit the normal microenvironment program to instruct their progression and biological diversity

The year 2011 marked the 40 year anniversary of Richard Nixon signing the National Cancer Act, thus declaring the beginning of the “War on Cancer” in the United States. Whereas we have made tremendous progress toward understanding the genetics of tumors in the past four decades, and in developing enabling technology to dissect the molecular underpinnings of cancer at unprecedented resolution, it is only recently that the important role of the stromal microenvironment has been studied in detail. Cancer is a tissue-specific disease, and it is becoming clear that much of what we know about breast cancer progression parallels the biology of the normal breast differentiation, of which there is still much to learn. In particular, the normal breast and breast tumors share molecular, cellular, systemic and microenvironmental influences necessary for their progression. It is therefore enticing to consider a tumor to be a “rogue hacker”—one who exploits the weaknesses of a normal program for personal benefit. Understanding normal mammary gland biology and its “security vulnerabilities” may thus leave us better equipped to target breast cancer. In this review, we will provide a brief overview of the heterotypic cellular and molecular interactions within the microenvironment of the developing mammary gland that are necessary for functional differentiation, provide evidence suggesting that similar biology—albeit imbalanced and exaggerated—is observed in breast cancer progression particularly during the transition from carcinoma in situ to invasive disease. Lastly we will present evidence suggesting that the multigene signatures currently used to model cancer heterogeneity and clinical outcome largely reflect signaling from a heterogeneous microenvironment—a recurring theme that could potentially be exploited therapeutically.     

Breast cancer local recurrence under the form of inflammatory carcinoma,treated with concurrent radiation and chemotherapy,a case report

The authors present a case report of a patient with breast cancer diagnosed in 2005, treated with conservative surgery, adjuvant chemotherapy and radiotherapy, followed by hormonal therapy until 2010, who relapsed under the form of inflammatory breast cancer in 2011. After tumor progression detected during primary systemic therapy, a concurrent radiation and radiosensitizing chemotherapy were proposed. There was a significant clinical response to this treatment, enabling curative chance with total mastectomy. The histological examination of the breast and regional lymph nodes revealed a complete response, since there was no evidence of residual tumor.There are few reports concerning concurrent radiotherapy and chemotherapy in locally advanced breast cancer, but it could be a suitable “loco regional rescue therapy” to further reduce tumor progression and allow curative surgery. Study of this treatment strategy in randomized clinical trials is warranted.     

Factitious Aortic Valve Insufficiency

One hundred consecutive aortograms, performed with careful attention to recommended technical details, were reviewed to identify cases of “factitious” aortic valve insufficiency, viz. aortic regurgitation seen during aortography for which there is no clinical evidence. Five patients with this condition were identified. Two of these subsequently underwent mitral valve replacement under cardiopulmonary by-pass. Aortic insufficiency was not detected during this procedure and the aortic valve appeared to be anatomically normal at postmortem examination. That factitious aortic insufficiency may exist should be remembered when aortography is used to differentiate aortic from pulmonary valve insufficiency.     

Current Trends in and Indications for Endoscopy-Assisted Breast Surgery for Breast Cancer: Results from a Six-Year Study Conducted by the Taiwan Endoscopic Breast Surgery Cooperative Group

Background

Endoscopy-assisted breast surgery (EABS) performed through minimal axillary and/or periareolar incisions is a possible alternative to open surgery for certain patients with breast cancer. In this study, we report the early results of an EABS program in Taiwan.

Methods

The medical records of patients who underwent EABS for breast cancer during the period May 2009 to December 2014 were collected from the Taiwan Endoscopic Breast Surgery Cooperative Group database. Data on clinicopathologic characteristics, type of surgery, method of breast reconstruction, complications and recurrence were analyzed to determine the effectiveness and oncologic safety of EABS in Taiwan.

Results

A total of 315 EABS procedures were performed in 292 patients with breast cancer, including 23 (7.8%) patients with bilateral disease. The number of breast cancer patients who underwent EABS increased initially from 2009 to 2012 and then stabilized during the period 2012–2014. The most commonly performed EABS was endoscopy-assisted total mastectomy (EATM) (85.4%) followed by endoscopy-assisted partial mastectomy (EAPM) (14.6%). Approximately 74% of the EATM procedures involved breast reconstruction, with the most common types of reconstruction being implant insertion and autologous pedicled TRAM flap surgery. During the six-year study period, there was an increasing trend in the performance of EABS for the management of breast cancer when total mastectomy was indicated. The positive surgical margin rate was 1.9%. Overall, the rate of complications associated with EABS was 15.2% and all were minor and wound-related. During a median follow-up of 26.8 (3.3–68.6) months, there were 3 (1%) cases of local recurrence, 1 (0.3%) case of distant metastasis and 1 (0.3%) death.

Conclusion

The preliminary results from the EABS program in Taiwan show that EABS is a safe procedure and results in acceptable cosmetic outcome. These findings could help to promote this under-used surgical technique in the field of breast cancer.     

An Evaluation of Bilateral Breast Carcinoma: Simultaneous and Sequential Lesions

The detection of bilateral breast carcinoma, simultaneous or nonsimultaneous, appears to be increasing. Undoubtedly a major factor in this is the increased use of mammography and xeromammography. In a 21-year period at Saint John''s Hospital and Health Center, 1,189 cases of primary breast carcinoma were treated, of which 34 (2.9 percent) were bilateral. However, from 1972 to 1974 the incidence has risen from 1.9 to 10.8 percent, with a simultaneous rise in numbers of xeromammograms made. Xeromammography should be done routinely in patients in whom carcinoma of the breast is suspected. Its use should also be an integral part of the follow-up in patients in whom mastectomy has been carried out previously.     

Prophylactic mastectomy: indications, options, and reconstructive alternatives

Prophylactic mastectomy continues to be a controversial procedure as a preventive tool against breast cancer. Recent research and other scientific advances, however, have refocused attention on better risk estimation, evidence of efficacy, and improvements in reconstruction. The recently discovered genetic markers BRCA1 and BRCA2 have become increasingly important in determining risk; a BRCA1-positive patient's risk of developing breast cancer by the age of 65 is estimated at 50 percent to 80 percent. BRCA1- and BRCA2-positive breast cancers also tend to be higher grade and occur in younger women (making mammography less effective). Genetically linked breast cancers are usually estrogen receptor negative, making them less susceptible to chemoprevention. Various predictive models and recommendations by experts in the field are also available for today's clinicians to ascertain who should be genetically tested. The benefit of bilateral prophylactic mastectomy, although difficult to estimate, can be evaluated by looking at the incidence of breast cancer in studies of patients who have previously undergone prophylactic mastectomy. The estimated risk reduction from these studies is 80 percent to 95 percent. Similarly, life expectancy is believed to be increased from 2.9 to 5.3 years. The psychological benefits include a 70 percent rate of satisfaction and a decrease in emotional concern over developing breast cancer by 74 percent of women who underwent prophylactic mastectomy. Although reconstruction results may vary, most patients have been very satisfied and some may achieve cosmetic results that are better than their preoperative situation. Patient selection for specific types of reconstruction after prophylactic mastectomy and the decision to proceed should be based on surgical risk and the likelihood of a good outcome. The choice of mastectomy incision should consider the size of the breast, preexisting scars, patient risk factors, and the planned method and goal of reconstruction. The authors propose certain guidelines based on degree of ptosis and cup size when planning prophylactic mastectomies with reconstruction. In certain cases, a nipple-sparing mastectomy may provide cosmetic advantages that could outweigh the additional oncologic risk.     

Breast reconstruction using modified tissue expansion

Inadequate chest-wall skin following mastectomy for carcinoma continues to be a problem in many breast reconstructions. To avoid extensive surgery, serial tissue expansion has been advocated. Since 1977, one of the authors has used a simple method of tissue expansion that we have termed "modified tissue expansion", defined as the creation of an adequate breast mound in one or two stages using a permanent prosthesis. Ninety percent of patients undergoing breast reconstruction between 1978 and 1983 were reconstructed using this method. A retrospective analysis of these 208 patients is presented. There were no mortalities, and only a 6.3 percent complication rate. Skin necroses related directly to the prosthesis occurred once, and there were no prosthetic deflations. Eighteen percent had first-step reconstruction only. The initial prosthesis averaged 400 cc in size. Selected Halsted radical mastectomy and postradiotherapy patients were successfully reconstructed. Seventy-eight percent felt their results were excellent at 1 year. Two percent were dissatisfied. Multiple office visits and the potential problems of serial expansion were avoided. Modified tissue expansion is a simple and viable method and should be considered among the options for breast reconstruction following mastectomy.     

Mitochondrial biogenesis in epithelial cancer cells promotes breast cancer tumor growth and confers autophagy resistance

Here, we set out to test the novel hypothesis that increased mitochondrial biogenesis in epithelial cancer cells would “fuel” enhanced tumor growth. For this purpose, we generated MDA-MB-231 cells (a triple-negative human breast cancer cell line) overexpressing PGC-1α and MitoNEET, which are established molecules that drive mitochondrial biogenesis and increased mitochondrial oxidative phosphorylation (OXPHOS). Interestingly, both PGC-1α and MitoNEET increased the abundance of OXPHOS protein complexes, conferred autophagy resistance under conditions of starvation and increased tumor growth by up to ~3-fold. However, this increase in tumor growth was independent of neo-angiogenesis, as assessed by immunostaining and quantitation of vessel density using CD31 antibodies. Quantitatively similar increases in tumor growth were also observed by overexpression of PGC-1β and POLRMT in MDA-MB-231 cells, which are also responsible for mediating increased mitochondrial biogenesis. Thus, we propose that increased mitochondrial “power” in epithelial cancer cells oncogenically promotes tumor growth by conferring autophagy resistance. As such, PGC-1α, PGC-1β, mitoNEET and POLRMT should all be considered as tumor promoters or “metabolic oncogenes.” Our results are consistent with numerous previous clinical studies showing that metformin (a weak mitochondrial “poison”) prevents the onset of nearly all types of human cancers in diabetic patients. Therefore, metformin (a complex I inhibitor) and other mitochondrial inhibitors should be developed as novel anticancer therapies, targeting mitochondrial metabolism in cancer cells.     

INITIAL CARE OF ACUTE BACK INJURIES

The mechanism of injury to the back should be obtained with the utmost accuracy and set down in the history as a separate paragraph under that heading. This is usually best obtained by questioning and requestioning the patient during the course of the examination. A history of any previous back affections should also be obtained at the first visit.The detailed examination of the back is not complete without a general physical examination.X-ray studies should be done immediately in all cases in which the injury has been caused by direct violence or forceful indirect violence (as in “jackknife” injury).Terms such as “disc disease,” “ruptured intervertebral disc” and various others that convey a similar meaning should not be used as the initial diagnosis and should be withheld until such a diagnosis is definitely established.The plan of treatment may include a period in hospital or of rest at home, or it may be carried out with the patient ambulatory. Corsets and braces should be prescribed only when they are to serve a definite function and the same can be said of physiotherapy.     

Reconstructive management of contralateral breast cancer in patients who previously underwent unilateral breast reconstruction

When a patient who has had unilateral breast reconstruction presents with a new cancer on the opposite side, the reconstructive management of the second breast can be unclear. This study was performed to determine whether reconstruction of the second breast is oncologically reasonable and to evaluate the reconstructive options available to these patients.Patients who had mastectomy with unilateral breast reconstruction between 1988 and 1994 and who had a minimal follow-up of 5 years from the initial breast cancer were reviewed. Of 469 patients reviewed, 18 patients (4 percent) were identified who developed contralateral breast cancer. Mean age at the initial breast cancer presentation was 43 years (range, 26 to 57 years), and mean age at presentation with contralateral breast cancer was 48 years (range, 36 to 67). The mean interval between the initial and contralateral breast cancer presentations was 5 years (range, 1 to 10 years). Mean follow-up from the time of contralateral breast cancer was 5 years (range, 1 to 9 years). In most cases, contralateral breast cancer presented at an early stage (13 of 18 patients; 72 percent), and a shift to an earlier stage at presentation of the contralateral cancer was evident compared with the initial breast cancer. Of the 18 patients who developed contralateral breast cancer, 16 (89 percent) had no evidence of disease, one was alive with disease, and one died. Reconstructive management after the initial mastectomy included 16 transverse rectus abdominis myocutaneous flaps (seven free and nine pedicled), one latissimus dorsi myocutaneous flap with implant, and one superior gluteal free flap. Surgical management of the second breast after contralateral breast cancer included breast conservation in two patients, mastectomy without reconstruction in four, and mastectomy with reconstruction in 12. Reconstruction of the second breast included one free transverse rectus abdominis myocutaneous flap, three extended latissimus dorsi flaps, two latissimus dorsi myocutaneous flaps with implants, three implants alone, two Rubens flaps, and one superior gluteal free flap. No major complications were noted after the reconstruction of the second breast. The best symmetry was obtained when similar methods and tissues were used on both sides.The incidence of contralateral breast cancer after mastectomy and unilateral breast reconstruction is low. In most cases, contralateral breast cancer presents at an earlier stage compared with the initial breast cancer, and the prognosis is good. In patients who develop a contralateral breast cancer after mastectomy and unilateral breast reconstruction, the reconstruction of the second breast after mastectomy is oncologically reasonable and should be offered to provide optimal breast symmetry and a better quality of life. The best result is obtained when similar methods and tissues are used on both sides.