Long-term prognosis in breast cancer is associated with residual disease after neoadjuvant systemic therapy but not with initial nodal status.

BACKGROUND: This follow-up analysis of a Swedish prospective multicentre trial had the primary aim to determine invasive disease-free (IDFS), breast cancer-specific (BCSS) and overall survival (OS) rates, and their association with axillary staging results before and after neoadjuvant systemic therapy for breast cancer. METHODS: Women who underwent neoadjuvant systemic therapy for clinically node-positive (cN+) or -negative (cN0) primary breast cancer between 2010 and 2015 were included. Patients had a sentinel lymph node biopsy before and/or after neoadjuvant systemic therapy, and all underwent completion axillary lymph node dissection. Follow-up was until February 2019. The main outcome measures were IDFS, BCSS and OS. Univariable and multivariable Cox regression analyses were used to identify independent factors associated with survival. RESULTS: The study included a total of 417 women. Median follow-up was 48 (range 7-114) months. Nodal status after neoadjuvant systemic therapy, but not before, was significantly associated with crude survival: residual nodal disease (ypN+) resulted in a significantly shorter 5-year OS compared with a complete nodal response (ypN0) (83·3 versus 91·0 per cent; P = 0·017). The agreement between breast (ypT) and nodal (ypN) status after neoadjuvant systemic therapy was high, and more so in patients with cN0 tumours (64 of 66, 97 per cent) than those with cN+ disease (49 of 60, 82 per cent) (P = 0·005). In multivariable analysis, ypN0 (hazard ratio 0·41, 95 per cent c.i. 0·22 to 0·74; P = 0·003) and local radiotherapy (hazard ratio 0·23, 0·08 to 0·64; P = 0·005) were associated with improved IDFS, and triple-negative molecular subtype with worse IDFS. CONCLUSION: The present findings underline the prognostic significance of nodal status after neoadjuvant systemic therapy. This confirms the clinical value of surgical axillary staging after neoadjuvant systemic therapy.

Lymphatic Drainage in the Breast Before and Up to Five Years After a Reduction Mammaplasty.

The aim of this study was to investigate lymph circulation before and after breast reduction mammaplasty in different parts of the breast and with two different carriers of the radiopharmaceutical. Nine patients with breast hypertrophy planned for bilateral breast reduction mammaplasty were prospectively included in the study. The breast operation procedure was decided on intraoperatively. The regional lymph circulation in the breast was measured preoperatively by Technetium (99mTc) clearance in 4 different locations in each breast 1, 2 and 3 hours after injection. The procedure was repeated at one month and in six of the nine women also five years postoperatively with injection sites chosen to correspond to the preoperative location of that breast pedicle. Two different types of carriers of the radiopharmaceutical were tested, dextran in the right and nanocoll in the left breast. Dextran had a much more rapid clearance than nanocoll. There was no significant regional difference in lymph drainage up to five years after the mammaplasty, independent of dextran or nanocoll as being the carrier of the radiopharmaceutical.

Arm lymphoedema after axillary surgery in women with invasive breast cancer.

BACKGROUND: The primary aim was to compare arm lymphoedema after sentinel lymph node biopsy (SLNB) alone versus axillary lymph node dissection (ALND) in women with node-negative and node-positive breast cancer. The secondary aim was to examine the potential association between self-reported and objectively measured arm lymphoedema. METHODS: Women who had surgery during 1999-2004 for invasive breast cancer in four centres in Sweden were included. The study groups were defined by the axillary procedure performed and the presence of axillary metastases: SLNB alone, ALND without axillary metastases, and ALND with axillary metastases. Before surgery, and 1, 2 and 3 years after operation, arm volume was measured and a questionnaire regarding symptoms of arm lymphoedema was completed. A mixed model was used to determine the adjusted mean difference in arm volume between the study groups, and generalized estimating equations were employed to determine differences in self-reported arm lymphoedema. RESULTS: One hundred and forty women had SLNB alone, 125 had node-negative ALND and 155 node-positive ALND. Women who underwent SLNB had no increase in postoperative arm volume over time, whereas both ALND groups showed a significant increase. The risk of self-reported arm lymphoedema 1, 2 and 3 years after surgery was significantly lower in the SLNB group compared with that in both ALND groups. Three years after surgery there was a significant association between increased arm volume and self-reported symptoms of arm lymphoedema. CONCLUSION: SLNB is associated with a minimal risk of increased arm volume and few symptoms of arm lymphoedema, significantly less than after ALND, regardless of lymph node status.

Lymph drainage studied by lymphoscintigraphy in the arms after sentinel node biopsy compared with axillary lymph node dissection following conservative breast cancer surgery.

PURPOSE: To investigate lymphatic drainage as measured by lymphoscintigraphy in the arms of patients undergoing either sentinel lymph node biopsy (SNB) or axillary lymph node dissection (ALND). MATERIAL AND METHODS: From January 2001 to December 2002, 30 patients with unilateral invasive breast carcinoma underwent breast-conserving surgery with SNB and 30 patients with ALND. All patients received radiotherapy to the breast. Lymphoscintigraphy was performed, and skin circulation, skin temperature, and arm volume were measured 2-3 years after radiotherapy. RESULTS: None of the 30 patients who underwent SNB showed any clinical manifestation of lymphedema. Of the 30 patients undergoing ALND, six (20%) had clinical lymphedema, with an arm volume that was >10% larger on the operated than on the non-operated side (P<0.01). Scintigraphically, visual analysis revealed lymphatic dysfunction in three patients, manifested as forearm dermal back flow. Two of these patients also had an increased arm volume. Quantitative analysis showed no differences between the groups, apart from a smaller amount of isotope in the axilla in the ALND group. There was no difference in skin circulation or skin temperature. CONCLUSION: Our study shows that lymph drainage in the operated arm compared with the non-operated arm was less affected by SNB than by ALND, and that morbidity associated with SNB was lower than with ALND. However, the results do not confirm our hypothesis that lymphoscintigraphy can reveal differences in lymph circulation that are not evident clinically in the form of manifest lymphedema. The most sensitive clinical method of assessing lymph drainage seems to be measurement of arm volume.

Sentinel node biopsy in non-palpable breast cancer and in patients with a previous diagnostic excision.

AIM: As a means of staging the axilla with minimal surgical trauma, sentinel lymph node biopsy (SNB) has dramatically altered the management of early-stage breast cancer. The aim of this prospective multicentre study was to assess the safety of the method in cases of non-palpable tumours and in cases with an open biopsy prior to SNB. METHOD: In the period 1999-2001, 57 non-palpable breast cancers and 75 patients with diagnostic biopsy were collected prospectively to the first part of the study. In the second part, 745 patients with non-palpable breast cancers and 86 cases with prior open surgery diagnosed between 2000 and 2005 were followed up till the end of 2005. All patients in the first part of the study had an axillary clearance irrespective of sentinel node status, whereas in the second part axillary clearance was done only if the sentinel node was metastatic. RESULTS: The detection rate was 95% in the group of non-palpable breast cancers, with a false negative rate of 5.6% (1/18), and the corresponding figures for the group with prior intervention were 96% and 10% (2/20). Two axillary recurrences, after a negative SNB at primary surgery, were found in the non-palpable group after 16 and 17 months, respectively. No axillary recurrence has been observed in the group of cancers with a prior open biopsy. Four women in the non-palpable group and two women with a diagnostic operation experienced distant metastases. CONCLUSION: We conclude that SNB is a safe procedure for women with non-palpable breast cancer, as well as after previous open diagnostic excision.

Lymph circulation in the breast after radiotherapy and breast conservation.

The aim of this study was to investigate the breast lymph circulation and skin blood circulation after radiotherapy and breast conservation. In 23 patients who had undergone lumpectomy for breast cancer (mean age 58 years, range 44-75) and 12 patients with lumpectomy for benign lesions (mean age 51 years, range 33-72), lymph circulation in the breast was measured by 99mTc-nanocolloid clearance and skin circulation by Laser Doppler Fluxmetry (LDF). Measurements were made 2-5 years after radiotherapy (50 Gy) in the former group and at a corresponding time in the latter. The lymph circulation was measured 2 cm above and medial or lateral to the areolar border in the quadrant not operated on for carcinoma. Skin circulation was measured at corresponding sites. The lymph circulation expressed as the ratio of 99mTc-nanocolloid clearance in the operated irradiated to that in the non-operated (radiation 2-4 Gy) breast was 2.33 (2.66) (median, interquartile range) (p value 0.01) and the skin circulation ratio over the corresponding area was 0.92 (0.21). Corresponding ratios in the non-radiotherapy group were 2.07 (1.96) (p value 0.03) and 1.04 (0.18) respectively. Compared with the control breast (i.e., the non-operated non-irradiated breast), there was a 4-fold increase in lymph flow in the operated, irradiated breast, a 2.5-fold increase in the contralateral non-operated (2-4 Gy) breast and a 1.5-fold increase in the operated non-irradiated breast. Radiotherapy after breast conservation surgery leads to increased long-term changes in basal lymph circulation and smaller increases in lymph flow in the contralateral breast receiving 2-4 Gy and after surgery. If maximal lymph transport capacity is unchanged, edema may be more likely in this circumstance of reduced lymphatic transport reserve.

Intraoperative sentinel lymph node examination by frozen section, immunohistochemistry and imprint cytology during breast surgery--a prospective study.

The aim of this study was to compare the sensitivity of intraoperative frozen section with hematoxyllin-eosin (H&E) staining, immunohistochemistry (IHC) or imprint cytology (IC) in the analysis of sentinel node (SN) in breast cancer. Towards this end, a prospective study of 102 patients undergoing mastectomy or sector resection with SN biopsy was conducted. Frozen sections of SN with H&E, IHC staining and IC had sensitivities of 73.5%, 75.5% and 51.0%, respectively. The combination of H&E and IHC raised the overall sensitivity to 83.7%. Macrometastases (>2 mm) were detected in 100% of the cases with H&E, 92.6% with IHC and 81.5% with IC; and micrometastases (2 mm) in 35.0%, 45.0% and 5.0%, respectively. The combination of H&E and IHC staining raised the sensitivity to 55.0%. Frozen-section analysis with H&E staining showed high sensitivity in detecting macrometastases but not micrometastases. The sensitivity for detection of micrometastases was not substantially increased by the use of intraoperative IHC. Imprint cytology did not provide any additional information.

Multicentre study of detection and false-negative rates in sentinel node biopsy for breast cancer.

BACKGROUND: Sentinel node biopsy has recently evolved as a means of staging the axilla in breast cancer with minimal surgical trauma. The aim of this prospective multicentre study was to identify factors that influenced the detection and false-negative rates during the learning phase. METHODS: Data on all 498 sentinel node biopsies performed between August 1997 and December 1999 in Sweden were collected. RESULTS: A sentinel node was found in 450 patients (90 per cent). Preoperative scintigraphy visualized 83 per cent of all sentinel nodes. The detection rate was higher with same-day injection of tracer than with injection the day before (96 versus 86 per cent; P < 0.01). Dye injected less than 5 min or more than 30 min before the start of the operation lowered the detection rate (less than 60 per cent versus more than 65 per cent; P = 0.02). The detection rate varied from 61 to 100 per cent between surgeons. The false-negative rate was 11 per cent. The presence of multiple tumour foci and a high S-phase fraction increased the risk of a false-negative sentinel node, whereas the number of operations performed by each surgeon was less important. CONCLUSION: Training of the individual surgeon influenced the detection rate, as did timing of tracer and dye injection. The false-negative rate seemed to be related to biological factors.

Circulation in the breast after radiotherapy and breast conservation.

OBJECTIVE: To investigate the breast circulation after radiotherapy and breast conservation. DESIGN: Open clinical study. SETTING: University hospital, Sweden. SUBJECTS: 24 patients with breast cancer (mean age 54 years, range 41-64). INTERVENTIONS: The glandular and the subcutaneous circulation in the breast were measured by Xenon (133Xe) clearance and the skin circulation by laser Doppler fluxmetry (LDF) two to five years after radiotherapy (50 Gy) following lumpectomy. The subcutaneous circulation was measured 2 cm above and medial or lateral to the areolar border and the glandular circulation 2 cm below and medial or lateral to the areolar border in the quadrant not previously operated on for carcinoma. The skin circulation was measured at the corresponding sites. MAIN OUTCOME MEASURES: Circulation in the subcutaneous and glandular tissue measured by 133Xe clearance and in the skin by LDF. RESULTS: The subcutaneous circulation, expressed as the ratio of 133Xe clearance in the operated irradiated: non-operated non-irradiated breast, was 0.88 (0.94) (median, interquartile range) and the glandular circulation 0.93 (0.75). The skin circulation ratios over the corresponding areas were 1.00 (0.37) and 1.00 (0.38), respectively. CONCLUSION: Radiotherapy after breast conservation surgery does not lead to long-term changes in basal glandular, subcutaneous, or skin circulation in the breast.

Influence of radiation therapy on skin circulation in the breast after breast conservative surgery.

It is not known whether the skin circulation is altered in the long term by radiotherapy following breast conservative surgery. The skin circulation in the breast was therefore measured in 24 breast cancer patients (mean age 57 years; range 40-76), one year after radiotherapy (50 Gy) following lumpectomy. None of the patients showed any persistent redness of the skin. The skin circulation was measured using laser Doppler fluxmetry (LDF) and fluorescein flowmetry within three areas: 2 cm above the border of the areola (position 1), within the nipple areola complex (position 2) and 2 cm below the border of the areola (position 3). It was found that when measured with LDF, the skin circulation expressed as the ratio of operated irradiated to non-operated non-irradiated breast was 0.99 in position 1, 1.07 in position 2 and 0.91 in position 3; and when measured by fluorescein flowmetry, 1.00 in position 1, 1.08 in position 2 and 1.00 in position 3. The results indicate that radiotherapy following breast conservative surgery does not lead to long-term changes in basal skin circulation in the breast.

Non-ulcer dyspepsia in the long-term perspective.

OBJECTIVE: To study the natural history of non-ulcer dyspepsia. DESIGN: Retrospective study on consecutive cases of non-ulcer dyspepsia diagnosed in 1980 and 1981. The long-term course was ascertained from medical records and from answers to a questionnaire completed by the patients at 10-year follow-up. SETTING: Out-patients at the endoscopy unit of a county hospital. PATIENTS: The diagnosis was based on typical symptoms of dyspepsia, a normal index endoscopy and a lack of evidence of organic disease related to the symptoms during the subsequent 12-month period. Two hundred and seventy-one patients were entered into the study. Of the 195 who received a questionnaire at 10-year follow-up, 165 (85%) responded. RESULTS: The median age at inclusion was 51 years (25-75 percentiles 38-65 years), and 130 men and 141 women were included in the study. The cumulative death rate after 10 years was 18%, a value no greater than that in the general population: 8% had died of cardiovascular disease, 1.5% of gastrointestinal cancer and 3% of other malignancies. One patient had died of a perforated gastric ulcer. At 10-year follow-up, a further three patients had developed peptic ulcers (expected number 4.2), 64% had experienced dyspeptic symptoms during the preceding 12 months and 41% had been taking analgesics during the previous week. Of the symptoms listed by the patients, 30% were typical of irritable bowel syndrome. CONCLUSION: Non-organic dyspepsia seems to be a chronic disease in most patients. The course is benign and unrelated to peptic ulcer disease.

On the natural history of peptic ulcer.

BACKGROUND: Three out of 1000 individuals have peptic ulcer every year, and 20% of the ulcer episodes are associated with bleeding. Whether major innovations such as endoscopy and strong acid-suppressing drugs have had any impact on the natural course of peptic ulcer disease is largely unknown. METHODS: Three hundred and fifty-one patients (median age, 63 years) with endoscopically proven peptic ulcer during 1979-1984 were included in the study and retrospectively followed up via medical records. The total population is based on two different groups of patients, the first comprising 229 consecutively diagnosed ulcer patients during 1979-81 and, to increase the number of bleeders, a second group including 122 bleeding ulcer patients consecutively diagnosed during 1981-84. At the end of the follow-up period all non-ulcer-operated patients were asked to answer a questionnaire on symptoms, investigations, and medication. RESULTS: The male to female ratio was 2.4:1 in duodenal ulcer patients, but a 1:1 ratio was shown both in gastric and prepyloric/pyloric ulcer patients (p < 0.001). Patients with bleeding ulcers were significantly older than non-bleeders (68 years versus 58 years; p < 0001), as were patients with gastric ulcers compared with prepyloric/pyloric or duodenal ulcer patients (68 years versus 63 and 61 years, respectively; p < 0.01). The 10-year cumulative mortality in the unselected group (median age, 62 years) was 43%, and the annual risk of dying of peptic ulcer disease was 0.6%. No difference in 10-year recurrence rate was seen between patients with bleeding ulcer at inclusion and non-bleeders (46.2% versus 44.3%; p = NS), but the annual risk of bleeding was 5.3% and 0.8%, respectively (p < 0.0001). In the group of patients answering the questionnaire 51% reported upper abdominal pain during the last year of follow-up. CONCLUSIONS: In spite of today's treatment regimens almost half of the patients with peptic ulcer disease experienced recurrence during a 10-year period, and more than half had ulcer symptoms after 10 years. Most probably, maintenance treatment with H2-receptor antagonists should have been offered more liberally during the 1980s.