Israel Medical Association Journal

Background: High density breast mammography has been associated with a greater risk for breast cancer and an increased likelihood of false negative results. 

Objectives: To assess whether the degree of mammographic breast density correlates with an increased risk for the presence of radiographic findings requiring further histological investigation. 

Methods: Included in the study were 2760 consecutive screening mammograms performed in a large volume, early detection mammography unit. All mammograms were complemented by high resolution ultrasound and interpreted by a single expert radiologist. Breast density (BD) was evaluated using a semi-quantitative 5 grade scale and grouped into low breast density (LBD) and high breast density (HBD) mammograms. Demographic and all relevant obstetric, personal and family history of breast cancer data were recorded. 

Results: Of the 2760 mammograms 2096 (76%) were LBD and 664 (24%) were HBD. Mean age of the LBD and HBD groups was 59 ± 10.5 and 50.9 ± 9.3 years respectively (P = 0.001). Breast density significantly correlated with presence of mammographic findings requiring further histological assessment (8.7% and 12.3% for LBD and HBD respectively, P < 0.01). In women younger than 60 years in whom histological assessment was required due to these findings, malignant pathology was significantly more prevalent in the HBD group (2.3% and 4.1% respectively, P = 0.03). Age, parity, patient history and HBD were identified as independent risk factors for any pathological mammographic finding. 

Conclusions: Highly dense mammography, aside from being an indicator of higher risk for breast cancer, appears to be associated with a significantly higher incidence of findings that will prompt further investigation to achieve a definite diagnosis. 

 

Background: The treatment of rectal cancer has changed significantly over the last few decades. Advanced surgical techniques have led to an increase in the rate of sphincter-preserving operations, even for low rectal tumors. This was facilitated by preoperative oncologic treatment and the use of chemoradiation to downstage the tumor before resection. The introduction of total mesorectal excision further improved the oncologic outcome and became the standard of care. The use of laparoscopy for rectal resection is the most recent addition to this series of improvements, but in contrast to the use of laparoscopy in colon cancer its role is not yet well defined.

Objectives: To present our experience with laparoscopic surgery for upper and lower rectal tumors.

Methods: A database was used to prospectively collect all data on laparoscopic rectal surgery in our department since we started performing these procedures in 1997. Follow-up data were collected from outpatient clinic visits, oncology files and telephone interviews. Updated survival data were retrieved from the national census.

Results: Of 750 laparoscopic colorectal procedures performed over a 13 year period, 67 were for rectal cancer. Of these, 29 were resections for tumors in the upper rectum (11–15 cm from the anal verge) and 38 for tumors at 10 cm or below. Surgery was performed in 24 patients after neoadjuvant chemoradiation. There were 54 sphincter-preserving operations and 13 abdominoperineal resections. The mean operative time was 283 minutes. Conversion to an open procedure was required in 22% of the cases. Anastomotic leaks occurred in 17% of cases. Postoperative mortality was 4.5%. Long-term follow-up was available for 77% of the group, for a mean period of 42 months. Local recurrence was diagnosed in 4.5% of the patients and overall 5 year survival was 68%.

Conclusions: Laparoscopic rectal resection is a demanding procedure. However, laparoscopy may become the preferred approach since it is a minimally invasive procedure and has an acceptable oncologic outcome that is comparable to the open approach. This conclusion, however, needs further validation.
 

The introduction of novel targeted therapies into the clinic in recent years has had a considerable impact on the management of several neoplastic diseases – such as gastrointestinal stromal tumors, hepatocellular carcinomas and renal cell carcinomas – considered until recently refractory to systemic therapies. We describe here two such novel biological agents, sunitinib and sorafenib, as a paradigm of the successful clinical application of new concepts. Sunitinib and sorafenib are small molecule tyrosine kinase inhibitors that target vascular endothelial growth factor receptor, platelet-derived growth factor receptor, C-Kit and others. Both agents are administered orally; sunitinib is typically given in cycles for 4 consecutive weeks with 2 weeks off, while sorafenib is given continually. Side effects occur in most patients, similar for both agents; they may affect several systems and organs but are mostly mild and easily manageable, rarely requiring discontinuation of the drug. However, these toxicities require prompt attention and intervention. The most frequently observed effects are hypertension, nausea, anorexia, asthenia and cutaneous manifestations; cardiac abnormalities may include congestive failure. Sunitinib, and markedly less frequently sorafenib, may cause thyroid gland dysfunction, mainly hypothyroidism. Antitumor activity has been shown for renal cell carcinoma in pivotal trials, for sunitinib as first-line treatment and for sorafenib in previously treated patients as second-line. Sunitinib is now approved as second-line therapy for patients with GIST[1] refractory to imatinib; sorafenib has resulted in a significant prolongation in median survival in patients with hepatocellular carcinoma. Ongoing clinical trials will further define the spectrum of these agents' antitumor activity, their role in combination with other drugs, as well as their optimal dose and schedule of administration.

Polyubiquitylation of cellular proteins has long been recognized as a prelude to a degradative fate in proteasomes. In recent years, however, ubiquitin conjugation has emerged as a regulatory strategy of considerable versatility. Most notably, monoubiquitylation is attributed an intimate role in trafficking of membrane proteins between various cellular compartments. Diverse classes of transmembrane proteins from across the eukaryotic spectrum (e.g., epidermal growth factor-receptor and other receptor tyrosine kinases) become modified with monoubiquitin molecules. Monoubiquitylation of substrates, in turn, regulates both their endocytosis at the plasma membrane and sorting in endosomes for delivery to lysosomes or vacuoles. A mechanistic rationale lies in the identification of a growing list of ubiquitin-binding domains carried by a variety of endocytic adaptor proteins. Thus, ubiquitin-conjugated membrane proteins may form extensive contacts with the endocytic machinery. Further, ubiquitin-binding adaptors and other endocytic components are, likewise, often monoubiquitylated. In this case, ubiquitin conjugation may serve to enhance intermolecular avidity in cargo-bound endocytic complexes, or alternatively, to mediate timely inactivation of ubiquitin-binding adaptors. Interestingly, the ubiquitin/endocytosis interface is appropriated by pathogenic organisms, for instance, during budding of viruses from host-infected cells. Moreover, compromised ubiquitin-mediated transport of certain signaling receptors is associated with disease states, including oncogenic transformation.

Due to the increase in longevity today, advanced illness in the elderly exists together with severe disability and often dementia that generally become less responsive to known treatment. This leads to repeated admissions to an internal ward in a general hospital, which results not only in a lack of treatment continuity but also in inappropriate management resulting in over- or under-treatment. Towards the end of their lives, the treatment problems of non-oncologic elderly patients with advanced diseases stem from a number of factors: multiple pathology, difficulty in predicting irreversibility, staff reluctance to discontinue active specific treatment and resort to palliative care only, and the lack of a framework to ensure continuity of treatment in the community or hospital. These advanced systemic illnesses are characterized by fluctuating exacerbations and remissions, making it very difficult to assess irreversibility. This article proposes the establishment of advance centralized care planning, based on community care, the geriatric hospital and, in particular, a geriatric support unit within the skilled nursing department, catering holistically for the ongoing needs of the patient and his/her family and supplying a backup to the community care.

Background: An organ sharing system should achieve fairness and optimal graft longevity. Balancing between social and utilitarian considerations is a sensitive ethical, public and medical issue that requires a means to examine the consequences of any allocation policy or planned changes thereof.

Objective: To evaluate the performance and applicability of a computerized simulation model by examining the impact of two opposing organ allocation policies (social or utilitarian) on predicted organ distribution regarding age, waiting time, recipient sensitization measured by panel reactive antibody level and overall donor-recipient tissue matching (measured by the number of HLA antigen mismatches).

Methods: Using a computerized simulation model, virtual donors and recipients were emulated and organs were allocated according to either social algorithms or utilitarian policies. The resulting number of HLA mismatches, PRA[1], age, and waiting time distributions were compared between allocation strategies.

Results: Simulating allocation of 7,000 organs to 17,000 candidate recipients and implementing social policies yielded donor-recipient compatibility comparable to utilitarian policies (0–1 mm: 19.4% vs. 28%) while allocating 66.7% of organs to long waiters (>48 months).

Conclusion: This computerized simulation model is a valuable tool for decision-makers establishing or modifying organ allocation policies.

Background: Primary hyperparathyroidism in elderly patients is usually associated with additional co-morbidity that increases operative risk, and thus many geriatric patients are denied the benefit of surgery for a single parathyroid adenoma.

Objectives:  To evaluate the safety and efficacy of accurate single photon emission computed tomography sestamibi scintigraphy, enabling precise localization of a single adenoma, in the geriatric population

Methods: Twenty-two patients aged 70 years and over with biochemically proven PHPT[1] and with a single parathyroid adenoma identified by localization studies (sestamibi SPECT[2] scan and ultrasonography) underwent 23 operations over 29 months (out of a total of 140 patients operated upon during the same period). Immediate preoperative sestamibi scintigraphy and marking of focal adenoma uptake followed by intraoperative hand-held gamma probe were used for the removal of the parathyroid adenoma by unilateral minimal access surgery. Associated major co-morbid conditions and pre- and postoperative calcium, phosphorus and parathormone levels were recorded. Indications for surgery were listed and operative and postoperative complications were noted. The patients were followed for a mean period of 17.7 months using the same parameters.

Results: The 22 patients with PHPT had a mean age of 76.3 ± 5.9 years (range 70–88 years)  and a female to male ratio of 13:9. Associated co-morbidity included ischemic heart disease (n=15), hypertension (n=22), non-insulin-dependent diabetes mellitus (n=9), chronic obstructive pulmonary disease (n=3), and previous neck surgery (n=3). Mean preoperative serum calcium, phosphorous and PTH[3] were 11.7 ± 1.3 mg/dl, 2.5 ± 0.5 mg/dl and 160.9 ± 75.4 pg/ml respectively. In 20 of the 22 patients, surgery was successful in curing PHPT (91%). One patient had persistent hypercalcemia due to a missed adenoma, and repeat operation (by focused minimal access surgery) was successfully performed 2 weeks later. There were no complications and no morbidity postoperatively. Mean postoperative serum calcium, phosphorous and PTH were 9.6 ± 1.2 mg/dl, 3.0 ± 0.5 mg/dl and 35.2 ± 24 pg/ml respectively. In all patients, serum calcium levels remained normal (9.7 ± 1.3 mg/ml) after long-term follow-up (mean 17.7 ± 9.6 months).

Conclusions: Minimally invasive, radio-guided focused parathyroidectomy for a single adenoma is a safe and effective method to cure hyperparathyroidism in the elderly. Success of surgery is directly related to the surgeon's experience and to the precise localization marking provided by sestamibi scintigraphic SPECT localization and concurrent sonographic findings.